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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Integration of Global Analyses of Host Molecular Responses
with Clinical Data To Evaluate Pathogenesis and Advance Therapies
for Emerging and Re-emerging Viral Infections</title>
<author><name sortKey="Falcinelli, Shane D" sort="Falcinelli, Shane D" uniqKey="Falcinelli S" first="Shane D." last="Falcinelli">Shane D. Falcinelli</name>
<affiliation><nlm:aff id="aff1">Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chertow, Daniel S" sort="Chertow, Daniel S" uniqKey="Chertow D" first="Daniel S." last="Chertow">Daniel S. Chertow</name>
<affiliation><nlm:aff id="aff1">Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kindrachuk, Jason" sort="Kindrachuk, Jason" uniqKey="Kindrachuk J" first="Jason" last="Kindrachuk">Jason Kindrachuk</name>
<affiliation><nlm:aff id="aff1">Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">27933782</idno>
<idno type="pmc">6131701</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131701</idno>
<idno type="RBID">PMC:6131701</idno>
<idno type="doi">10.1021/acsinfecdis.6b00104</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000151</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000151</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Integration of Global Analyses of Host Molecular Responses
with Clinical Data To Evaluate Pathogenesis and Advance Therapies
for Emerging and Re-emerging Viral Infections</title>
<author><name sortKey="Falcinelli, Shane D" sort="Falcinelli, Shane D" uniqKey="Falcinelli S" first="Shane D." last="Falcinelli">Shane D. Falcinelli</name>
<affiliation><nlm:aff id="aff1">Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chertow, Daniel S" sort="Chertow, Daniel S" uniqKey="Chertow D" first="Daniel S." last="Chertow">Daniel S. Chertow</name>
<affiliation><nlm:aff id="aff1">Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kindrachuk, Jason" sort="Kindrachuk, Jason" uniqKey="Kindrachuk J" first="Jason" last="Kindrachuk">Jason Kindrachuk</name>
<affiliation><nlm:aff id="aff1">Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">ACS Infectious Diseases</title>
<idno type="eISSN">2373-8227</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="id6b00104_0005" id="ab-tgr1"></graphic>
</p>
<p>Outbreaks
associated with emerging and re-emerging viral pathogens continue
to increase in frequency and are associated with an increasing burden
to global health. In light of this, there is a need to integrate basic
and clinical research for investigating the connections between molecular
and clinical pathogenesis and for therapeutic development strategies.
Here, we will discuss this approach with a focus on the emerging viral
pathogens Middle East respiratory syndrome coronavirus (MERS-CoV),
Ebola virus (EBOV), and monkeypox virus (MPXV) from the context of
clinical presentation, immunological and molecular features of the
diseases, and OMICS-based analyses of pathogenesis. Furthermore, we
will highlight the role of global investigations of host kinases,
the kinome, for investigating emerging and re-emerging viral pathogens
from the context of characterizing cellular responses and identifying
novel therapeutic targets. Lastly, we will address how increased integration
of clinical and basic research will assist treatment and prevention
efforts for emerging pathogens.</p>
</div>
</front>
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<pmc article-type="review-article" xml:lang="EN"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">ACS Infect Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">ACS Infect Dis</journal-id>
<journal-id journal-id-type="publisher-id">id</journal-id>
<journal-id journal-id-type="coden">aidcbc</journal-id>
<journal-title-group><journal-title>ACS Infectious Diseases</journal-title>
</journal-title-group>
<issn pub-type="epub">2373-8227</issn>
<publisher><publisher-name>American Chemical
Society</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27933782</article-id>
<article-id pub-id-type="pmc">6131701</article-id>
<article-id pub-id-type="doi">10.1021/acsinfecdis.6b00104</article-id>
<article-categories><subj-group><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>Integration of Global Analyses of Host Molecular Responses
with Clinical Data To Evaluate Pathogenesis and Advance Therapies
for Emerging and Re-emerging Viral Infections</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="ath1"><name><surname>Falcinelli</surname>
<given-names>Shane D.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" id="ath2"><name><surname>Chertow</surname>
<given-names>Daniel S.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author" corresp="yes" id="ath3"><name><surname>Kindrachuk</surname>
<given-names>Jason</given-names>
</name>
<xref rid="cor1" ref-type="other">*</xref>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<aff id="aff1"><label>†</label>
Critical Care Medicine Department, Clinical Center,<institution>National Institutes of Health</institution>
, Bethesda, Maryland 20814,<country>United States</country>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
(J.K.) Postal address: Critical Care Medicine Department, Clinical
Center, National Institutes of Health, 10 Center Drive, Bethesda,
MD 20814, USA. Phone: <phone>(301) 443-5961</phone>
. E-mail: <email>kindrachuk.kenneth@nih.gov</email>
.</corresp>
</author-notes>
<pub-date pub-type="epub"><day>29</day>
<month>07</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><day>11</day>
<month>11</month>
<year>2016</year>
</pub-date>
<volume>2</volume>
<issue>11</issue>
<issue-title>Host-Pathogen Interactions</issue-title>
<fpage>787</fpage>
<lpage>799</lpage>
<history><date date-type="received"><day>10</day>
<month>06</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 U.S. Government</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>U.S. Government</copyright-holder>
<license license-type="open-access"><license-p>This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p>
</license>
</permissions>
<abstract><p content-type="toc-graphic"><graphic xlink:href="id6b00104_0005" id="ab-tgr1"></graphic>
</p>
<p>Outbreaks
associated with emerging and re-emerging viral pathogens continue
to increase in frequency and are associated with an increasing burden
to global health. In light of this, there is a need to integrate basic
and clinical research for investigating the connections between molecular
and clinical pathogenesis and for therapeutic development strategies.
Here, we will discuss this approach with a focus on the emerging viral
pathogens Middle East respiratory syndrome coronavirus (MERS-CoV),
Ebola virus (EBOV), and monkeypox virus (MPXV) from the context of
clinical presentation, immunological and molecular features of the
diseases, and OMICS-based analyses of pathogenesis. Furthermore, we
will highlight the role of global investigations of host kinases,
the kinome, for investigating emerging and re-emerging viral pathogens
from the context of characterizing cellular responses and identifying
novel therapeutic targets. Lastly, we will address how increased integration
of clinical and basic research will assist treatment and prevention
efforts for emerging pathogens.</p>
</abstract>
<kwd-group><kwd>emerging pathogens</kwd>
<kwd>kinomics</kwd>
<kwd>cell signaling</kwd>
<kwd>virology</kwd>
<kwd>kinases</kwd>
<kwd>high-consequence pathogens</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name>
<meta-value>id6b00104</meta-value>
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</article-meta>
<notes id="notes-d1e21-autogenerated"><fn-group><fn fn-type="" id="d30e129"><p>This article is made available for a limited time sponsored by ACS under the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/page/policy/freetoread/index.html">ACS Free to Read License</ext-link>
, which permits copying and redistribution of the article for non-commercial scholarly purposes.</p>
</fn>
</fn-group>
</notes>
</front>
<body><p id="sec1">Emerging and re-emerging viruses
pose a significant threat to public health and global economies. Moreover,
outbreaks caused by emerging and re-emerging viruses continue to increase
in frequency as a result of changing socio-economic, environmental,
and ecological factors.<sup><xref ref-type="bibr" rid="ref1">1</xref>
</sup>
Notably, the zoonotic
viral pathogens, severe acute respiratory syndrome coronavirus (SARS-CoV),
Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus,
chikungunya virus, and Zika virus, have emerged on a global scale
in recent years; although less widely publicized, other emerging viral
pathogens such as monkeypox virus and Andes virus have led to smaller
recurrent outbreaks. A critical challenge for combating these outbreaks
is often the discordant relationship between the economic status of
outbreak “hotspots” and resource distribution or control
capacity within these regions. In addition, the development and delivery
of therapeutics for combating such outbreaks have been complicated
by both the associated costs in design and development for novel anti-infective
therapeutics and the requirements for regulatory approval and licensure.<sup><xref ref-type="bibr" rid="ref2">2</xref>
</sup>
Importantly, emerging infectious diseases present
the additional inherent challenge that they are only “emerging”,
and thus limited resources are made available for research until they
present a significant risk. For many emerging viral pathogens, the
requirement for high-containment facilities has further impeded widespread
research. From the perspective of drug development, the limited knowledge
and understanding of molecular pathogenesis for these agents is a
daunting challenge to overcome when outbreaks emerge.</p>
<p>In the
face of an increasing burden of emerging and re-emerging pathogens,
it is necessary to overcome the barriers imposed by a paucity of information
regarding molecular pathogenesis for these agents. OMICS-based approaches
present a mechanism to rapidly generate large amounts of data in regard
to host responses and assist in target identification for drug development
efforts. In addition, OMICS-based analyses allow for the characterization
of molecular events that mitigate cellular responses to viral pathogens
from a global perspective across multiple levels of cellular complexity
(individual cell types < tissues < organs). High-throughput
global analyses of host gene expression, including microarrays and
RNA-Seq, provide important information regarding transcriptional responses
during infection. Although these validated approaches are among the
most widespread of the OMICS-based technologies for infectious disease
investigations, they do not provide a direct measure of the activation
status of the cell signaling pathways that regulate underlying cellular
responses. In contrast, global investigations of cellular kinase activities
(the kinome) are able to provide insight into the activation status
of cell signaling networks (including those that mediate pathogen
recognition and innate immune activation, cell cycle activities, metabolic
status, wound healing and repair, and cell death) at the level of
individual kinase-mediated phosphorylation events. In addition, kinome
investigations allow for potential identification of kinase drug targets.
Kinases are currently one of the top targets for drug design and development,
and there is potential for repurposing of kinase inhibitors with existing
regulatory approval.</p>
<p>As emerging viral infections often result
in severe illness including respiratory failure [severe acute respiratory
syndrome (SARS), Middle East respiratory syndrome (MERS), and influenza]
and multiorgan failure [Ebola virus disease (EVD)], understanding
complex pathogenesis of these infections is required for effective
vaccine and therapeutic design and for improved patient care. Healthcare
providers caring for patients with severe emerging viral infections
are generally focused on clinical care and biosafety as compared to
the complex molecular events that underlie pathogenesis. In contrast,
basic researchers typically focus on discrete aspects of pathogenesis
through a variety of in vitro and in vivo analyses rather than the
complex interplay between these events and the clinical, physiologic,
and pathologic abnormalities observed by the clinician. Integrating
basic and clinical research is needed to accelerate the translation
of knowledge for emerging infections toward vaccine development and
therapeutic discovery. Specifically, detailed natural history studies
merging multiple data streams including OMICS approaches (high-throughput
gene expression and kinomics) and focused translational investigations
utilizing relevant models that can be validated to human disease are
needed to clarify disease pathogenesis, advance therapeutic discovery,
and facilitate regulatory approval.</p>
<p>Although
an integrated approach between basic and clinical research is ideal
for investigating the connections between molecular and clinical pathogenesis,
there has been a paucity of investigations for which this has been
undertaken. Here, we will discuss emerging pathogens for which there
is available information regarding the clinical course of disease,
host immune responses during natural infection, and molecular information
regarding the global cellular responses to infection, with particular
attention on host kinome investigations. In this regard we will focus
on the emerging viral pathogens MERS-CoV, Ebola virus (EBOV), and
monkeypox virus (MPXV) (<xref rid="fig1" ref-type="fig">Figure <xref rid="fig1" ref-type="fig">1</xref>
</xref>
). We will review the clinical presentation and immunological
and molecular features of the diseases and summarize available OMICS
data informing pathogenesis of these pathogens. Lastly, we will discuss
the benefit of improved integration of available clinical knowledge
or data regarding the pathologic manifestations of disease with basic
research investigations to advance treatment and prevention of severe
emerging viral infections.</p>
<fig id="fig1" position="float"><label>Figure 1</label>
<caption><p>Global outbreaks of Ebola virus, MERS-CoV, and
monkeypox: (a) Europe; (b) Africa; (c) Asia; (d) United States. Data
include all transmission-related infections that have been documented.
Laboratory accident-related infections and medical evacuations are
not included.</p>
</caption>
<graphic xlink:href="id6b00104_0002" id="gr1" position="float"></graphic>
</fig>
<sec id="sec2"><title>Investigating Molecular
Pathogenesis through Kinome Analysis</title>
<p>Global gene expression
investigations have provided information regarding host response to
emerging and re-emerging pathogens at the level of individual genes
or gene clusters. However, there is a paucity of information regarding
the relationship of cell signaling networks, and in particular their
activation status, with the biological/pathological events that occur
throughout infection.</p>
<p>It has been well established that many
biological processes can be regulated independent of transcriptional
or translational changes through post-translational modification (PTM)
events. Indeed, kinase-mediated phosphorylation of proteins, in which
kinases catalyze the transfer of the γ phosphate group from
ATP to the hydroxyl group of a specific Ser, Thr, Tyr residue, is
among the most thoroughly characterized PTM. Virtually all cell signal
transduction events are regulated by kinases independent of biological
complexity of the host (i.e., prokaryotes and eukaryotes).<sup><xref ref-type="bibr" rid="ref3">3</xref>
</sup>
Lending further credence to the biological importance
of kinases, >500 kinases have been identified in the human genome,
and ∼30% of the human proteome is modulated by kinase-mediated
phosphorylation events.<sup><xref ref-type="bibr" rid="ref4">4</xref>
,<xref ref-type="bibr" rid="ref5">5</xref>
</sup>
Thus, considering the central
role of kinases in a broad range of cellular processes (including
growth and development, metabolism, and immune responses), it has
been postulated that the activities of individual kinases may represent
more reliable predictors of cellular phenotypes than transcriptional
or translational changes.<sup><xref ref-type="bibr" rid="ref6">6</xref>
</sup>
Indeed, transcriptional
or translational-based OMICS approaches are often unable to account
for regulatory events including gene silencing, mRNA stability, translational
efficiencies, protein turnover, enzyme/substrate subcellular sequestration,
or protein activation/repression PTMs.<sup><xref ref-type="bibr" rid="ref7">7</xref>
</sup>
Given the central role of kinases in the regulation of biological
processes, kinases are a logical drug target. As a testament to this,
33 kinase inhibitors have been granted licensure by the U.S. Food
and Drug Administration (FDA) for a broad range of malignancies, and
there are a continually increasing number of kinase inhibitors that
are in various stages of preclinical trials. Furthermore, kinases
are the second most frequently targeted gene class in cancer therapy
after the G protein coupled receptors.<sup><xref ref-type="bibr" rid="ref8">8</xref>
,<xref ref-type="bibr" rid="ref9">9</xref>
</sup>
The recent
prioritization for the repurposing of approved therapeutics for alternative
malignancies by the National Institutes of Health Center for Advancing
Translational Sciences (NCATS)<sup><xref ref-type="bibr" rid="ref10">10</xref>
,<xref ref-type="bibr" rid="ref11">11</xref>
</sup>
also provides considerable
impetus for the investigation of licensed kinase inhibitors as infectious
disease therapeutics. Concerns exist regarding the therapeutic application
of kinase inhibitors as novel therapeutics for infectious disease,
in particular to the potential immunosuppressive effects following
prolonged treatment. However, it should be appreciated that the application
of kinase inhibitors in such cases would need to be targeted in terms
of timing and dose, with appropriate molecular biomarkers guiding
initiation and cessation. It should also be appreciated that the clinical
symptoms associated with many emerging and re-emerging pathogens have
been associated with dysregulated host immune responses (in particular
pro-inflammatory responses).</p>
<p>Thus, the global analysis of the
activation state of host kinases (the kinome) can provide critical
insight into the specific activation state of individual kinases,
cell signaling pathways, or larger biological networks. In addition,
kinome investigations may offer important, and predictive, insight
into the cellular mechanisms that regulate phenotypic changes within
cells.<sup><xref ref-type="bibr" rid="ref7">7</xref>
</sup>
As many kinases recognize a particular
phosphorylation motif composed of the central phosphoacceptor site
and the amino acids +4 and −4 residues from the central phosphorylation
site,<sup><xref ref-type="bibr" rid="ref12">12</xref>
</sup>
peptides representing this kinase
target motif can be synthesized with relatively high efficiency and
low expense. Indeed, kinase target motif peptides have been shown
to be appropriate substrates for their respective kinases with <italic>V</italic>
<sub>max</sub>
and <italic>K</italic>
<sub>m</sub>
values
approaching those of the full-length protein.<sup><xref ref-type="bibr" rid="ref13">13</xref>
</sup>
Thus, peptide kinome arrays can be constructed in an analogous manner
to traditional DNA microarrays where kinase target motif peptides
are spotted onto a glass slide representing hundreds to thousands
of unique peptide targets for kinases (<xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref>
</xref>
). Following this, samples in the form of
cellular lysates from whole organs, tissues, or individual cell types
can be applied to the kinome peptide arrays, allowing for the phosphorylation
of specific peptide targets by kinases within the lysate (<xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref>
</xref>
). The development
of kinome-specific bioinformatics analysis software, including the
Platform for Intelligent, Integrated Kinome Analysis (PIIKA), has
provided a mechanism to identify the complex patterns of kinase-mediated
phosphorylation events and quantitate the differences between compared
conditions.<sup><xref ref-type="bibr" rid="ref14">14</xref>
,<xref ref-type="bibr" rid="ref15">15</xref>
</sup>
</p>
<fig id="fig2" position="float"><label>Figure 2</label>
<caption><p>Generation of kinome peptide array targets
and kinome peptide arrays: (1) species-specific proteomic or genomic
information from a diverse range of species can be used to identify
kinase recognition motifs that are composed of a central phosphorylation
target and the surrounding amino acids (normally +4 and −4
amino acids from the central phosphorylated residue); (2) peptides
that comprise the kinase recognition motifs identified in (1) are
synthesized and covalently linked to a glass surface. Peptide targets
are spotted in replicates of three to nine spots on each array to
account for intra-array variability. Individual amino acids of the
peptides are represented by orange, red, purple, and green spheres.</p>
</caption>
<graphic xlink:href="id6b00104_0003" id="gr2" position="float"></graphic>
</fig>
<fig id="fig3" position="float"><label>Figure 3</label>
<caption><p>Kinome analysis of biological samples. Biological
samples for kinome analysis can encompass (1) complex biological tissues
(lung), (2) focused tissue sections (bronchioles), or (3) individual
cell types associated with a particular tissue (alveolar epithelial
cells or alveolar macrophages). (4) Biological samples are processed
to generate cell lysates that are activated with ATP and applied to
the kinome peptide array. (5) Following the application of the cell
lysate, activated kinases in the cell lysate will recognize their
respective kinase recognition motifs and phosphorylate the central
phosphorylated residue of the peptide. (6) Kinome peptide arrays are
subsequently stained with a phospho-specific fluorescent stain and
imaged followed by comparative bioinformatics analyses. Tissue and
cell images were derived and/or modified from Servier Medical Arts
under a Creative Commons Attribution 3.0 Unported License.</p>
</caption>
<graphic xlink:href="id6b00104_0004" id="gr3" position="float"></graphic>
</fig>
</sec>
<sec id="sec3"><title>Integrating Kinomics with Clinical and Molecular
Pathogenesis Investigations for Emerging and Re-emerging Pathogens</title>
<sec id="sec3.1"><title>Middle
East Respiratory Syndrome Coronavirus (MERS-CoV)</title>
<p>Human coronaviruses
are the causative agents of an estimated 30% of upper and lower respiratory
tract infections in humans resulting in rhinitis, pharyngitis, sinusitis,
bronchiolitis, and pneumonia.<sup><xref ref-type="bibr" rid="ref16">16</xref>
,<xref ref-type="bibr" rid="ref17">17</xref>
</sup>
Coronaviruses are members
of the Coronavirinae subfamily of viruses and together with the Torovirinae
subfamily comprise the Coronoviridae virus family (order Nidovirales).
Multiple coronavirus family members, including OC43 and 229E, can
be found across the globe and largely result in mild illness with
more-severe illness limited to children and the elderly.<sup><xref ref-type="bibr" rid="ref18">18</xref>
−<xref ref-type="bibr" rid="ref20">20</xref>
</sup>
Since the emergence of SARS in 2003 and MERS in 2012, there is increased
interest in coronaviruses as global public health threats.</p>
<p>SARS-CoV
was first identified in China before spreading to 37 countries resulting
in more than 8000 confirmed cases and 775 deaths. No additional cases
have been reported since 2004.<sup><xref ref-type="bibr" rid="ref21">21</xref>
</sup>
In 2012,
MERS emerged in Saudi Arabia as a severe respiratory disease with
gastrointestinal and renal complications.<sup><xref ref-type="bibr" rid="ref22">22</xref>
</sup>
MERS-CoV has subsequently spread to 26 countries (WHO), resulting
in 1733 confirmed cases and 628 deaths as of June 2016 (<uri xlink:href="http://www.who.int/emergencies/mers-cov/en/">http://www.who.int/emergencies/mers-cov/en/</uri>
). MERS may have emerged from a bat reservoir, likely spilling into
humans via dromedary intermediate hosts. Human-to-human spread occurs
primarily within healthcare settings, often leading to severe disease.
No licensed vaccines or targeted therapies are available.</p>
<sec id="sec3.1.1"><title>Clinical
Findings during MERS-CoV Infection</title>
<p>Syndromic case-definition
for MERS infection requires a compatible clinical syndrome and an
epidemiologic risk factor including travel to an affected region or
contact with a known or suspected case. Initial symptoms of MERS-CoV
infection include fever, chills, cough, shortness of breath, myalgia,
and malaise following a mean incubation period of 5 days, which can
range from 2 to 14 days.<sup><xref ref-type="bibr" rid="ref23">23</xref>
</sup>
Mildly symptomatic
or possibly asymptomatic infections have been reported, and progression
to severe disease is associated with pre-existing medical conditions
including cardiopulmonary disease, obesity, and diabetes. Most (98%)
of reported MERS cases are among adults, with a median age of 50 years.
In severe cases respiratory failure requiring mechanical ventilation
typically occurs within 7 days of symptom onset.<sup><xref ref-type="bibr" rid="ref22">22</xref>
</sup>
Laboratory abnormalities include lymphopenia, leukopenia,
thrombocytopenia, elevated serum creatinine levels consistent with
acute kidney injury, and elevated liver enzymes.<sup><xref ref-type="bibr" rid="ref23">23</xref>
−<xref ref-type="bibr" rid="ref27">27</xref>
</sup>
High lactate levels and consumptive coagulopathy
have also been reported.<sup><xref ref-type="bibr" rid="ref24">24</xref>
,<xref ref-type="bibr" rid="ref28">28</xref>
</sup>
Chest radiographic
abnormalities are observed in most cases consistent with viral pneumonitis,
secondary bacterial pneumonia, or acute respiratory distress syndrome.<sup><xref ref-type="bibr" rid="ref22">22</xref>
−<xref ref-type="bibr" rid="ref24">24</xref>
,<xref ref-type="bibr" rid="ref27">27</xref>
,<xref ref-type="bibr" rid="ref29">29</xref>
</sup>
</p>
</sec>
<sec id="sec3.1.2"><title>Soluble Immune Mediators Associated with MERS-CoV Infections</title>
<p>Data characterizing immune responses during MERS-CoV infection
are limited. Faure et al. evaluated cytokine levels in serum and bronchoalveolar
lavage (BAL) from two MERS patients, one with fatal disease and one
who survived.<sup><xref ref-type="bibr" rid="ref30">30</xref>
</sup>
Higher levels of retinoic
acid-inducible gene 1 (RIG-1), melanoma differentiation-associated
protein 5 (MDA5), interferon regulatory factor (IRF)-3 and -7, interleukin
(IL) 17A, and IL-23 and lower levels of IL-12 and IFNγ were
observed in the fatal case compared with the survivor. More recently,
Min et al. performed a temporal analysis of cytokine, chemokine, and
growth factor blood levels from 14 patients during the recent outbreak
of MERS in South Korea.<sup><xref ref-type="bibr" rid="ref31">31</xref>
</sup>
The patients
were subcategorized into four groups on the basis of disease severity:
Group I patients developed fever and recovered. Group II patients
developed mild pneumonia without hypoxemia. Group III patients had
prolonged and severe pneumonia. Group IV patients had severe pneumonia
and acute respiratory distress syndrome. Group IV patients included
five fatal cases of MERS; all patients in groups I–III fully
recovered from illness. IFNα was elevated in all groups and
largely peaked during the second week of illness. Granulocyte-colony
stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF were
similarly elevated across all patient groups; however, patients with
fatal disease had reduced GM-CSF responses following antiviral treatment
as compared to patients that recovered. Patients with pneumonia had
relative elevations of IL-1, tumor necrosis factor (TNF)-α,
IL-6, and IL-10 during the second and third weeks of illness. Elevated
IL-6 and IL-10 appeared to trend positively with the severity of illness.
A robust induction of multiple chemokines was found in most patients.
Notably, eotaxin and regulated on activation, normal T expressed and
secreted (RANTES) was elevated in all patients. In contrast, IL-8,
monocyte chemotactic protein (MCP)-3 and macrophage inflammatory protein
(MIP)-1β were more prominent in groups II and III as compared
to groups I and IV. Furthermore, elevated interferon gamma induced
protein (IP)-10 correlated with the development of pneumonia (groups
I–III). Multiple growth factors, including epidermal growth
factor (EGF), fibroblast growth factor (FGF)-2, vascular endothelial
growth factor (VEGF), and TGF-α, were significantly elevated
across all patients; however, EGF was significantly higher in patients
that recovered from disease as compared to the fatal cases. Further
evaluations are needed to characterize the natural history of immune
response during acute MERS-CoV infection and recovery.</p>
</sec>
<sec id="sec3.1.3"><title>Transcriptome Analyses of MERS-CoV</title>
<p>In an effort to better
characterize MERS-CoV pathogenesis in the absence of available samples
from human patients and, in particular, address pathologic changes
associated with infection, multiple animal species have been employed
in MERS-CoV investigations. While multiple small animals are not susceptible
to MERS-CoV infection,<sup><xref ref-type="bibr" rid="ref32">32</xref>
</sup>
rhesus macaques
and marmosets develop mild to severe lung pathology following experimental
infection. Transcriptome analysis in MERS-CoV-infected rhesus macaques
revealed that genes related to antiviral immunity, chemotaxis, and
inflammation were overexpressed in lesional versus grossly normal
lung tissue at 3 days postinfection.<sup><xref ref-type="bibr" rid="ref33">33</xref>
</sup>
A
significantly smaller number of differentially expressed genes was
found on day 6 postinfection with no obvious trends following pathway
enrichment analysis. Significant changes in the transcriptome profiles
of peripheral blood mononuclear cells (PBMCs) were observed at only
day 1 postinfection. This global analysis suggests a key role for
an initial rapid innate immune and inflammatory response (through
pattern recognition receptors) followed by rapid resolution.<sup><xref ref-type="bibr" rid="ref33">33</xref>
</sup>
A study of MERS-CoV-infected marmosets evaluated
lung lesions by RNaseq at days 3–6 postinfection.<sup><xref ref-type="bibr" rid="ref34">34</xref>
</sup>
Pathway analyses demonstrated that chemotaxis
and cell migration, cell cycle progression, and cell proliferation
and fibrogenesis were highly over-represented relative to uninfected
controls. To a lesser degree, pathways associated with inflammation,
vascularization, endothelial activation, proliferation of smooth muscle,
and tissue repair were also over-represented in infected animals.
Differences were most significant on days 4 and 6 postinfection during
illness progression relative to day 3.</p>
<p>Recently, Menachery and
colleagues examined the interaction between MERS-CoV EMC/2012 and
the host IFN-stimulated gene (ISG) response by transcriptomics.<sup><xref ref-type="bibr" rid="ref35">35</xref>
</sup>
ISG responses in MERS-CoV infected Calu3 cells,
a lung adenocarcinoma cell line, had no discernible induction initially
upon infection but were up-regulated by 12 h postinfection.<sup><xref ref-type="bibr" rid="ref35">35</xref>
</sup>
Down-regulation of a subset of ISGs resulted
in altered histone modifications, a potential epigenetic contributor
to early impairment of antiviral cellular defenses. In a separate
analysis genetically distinct MERS-CoV strains, MERS-CoV SA1 and MERS-CoV
Eng1, produced distinct gene expression profiles in Calu-3 cells.<sup><xref ref-type="bibr" rid="ref36">36</xref>
</sup>
These analyses may better inform early host-cell
antiviral responses and the impact of viral evolution on these and
other complex biological responses. Proteomics analysis corroborated
these transcriptional data with induction of ISGs observed 18 h postinfection.
Significantly reduced levels of STAT1 and PKR compared with uninfected
controls were also noted. Differential host transcriptome responses
to MERS-CoV SA1 and MERS-CoV Eng1 highlight both the propensity of
emerging viral pathogens to evolve rapidly and the importance of additional
host response analyses for augmenting and clarifying such complex
biological responses.</p>
</sec>
<sec id="sec3.1.4"><title>Kinome Analyses of MERS-CoV Infection</title>
<p>Host responses to MERS-CoV infection through kinome analysis were
recently assessed using Huh-7 cells, an immortalized human hepatocyte
cell line, that are highly permissive to MERS-CoV infection.<sup><xref ref-type="bibr" rid="ref37">37</xref>
</sup>
Temporal analysis of kinome responses by peptide
arrays revealed selective modulation of extracellular signal-regulated
kinases (ERK)/mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3-kinases
(PI3K)/AKT (also known as protein kinase B)/mechanistic target of
rapamycin (mTOR) signaling responses. Over-representation analysis
(ORA) revealed ERK/MAPK and PI3K/AKT/mTOR signaling responses were
consistently up-regulated during infection. Multiple ERK/MAPK family
members formed central components of functional networks and signaling
pathways throughout infection. Similar results were observed for intermediates
of the PI3K/AKT/mTOR signaling pathway at 1 and 24 h postinfection,
suggesting that modulation of ERK/MAPK and PI3K/AKT/mTOR signaling
may be important for productive MERS-CoV infection.</p>
<p>Downstream
analysis of the phosphorylation patterns of pathway intermediates
from the ERK/MAPK and PI3K/AKT/mTOR signaling supported observations
from the kinome analysis. Both investigations demonstrated that nuclear
factor kappa-light-chain-enhancer of activated B cells (NFκB)-regulated
family members were important mediators of MERS-CoV infection.<sup><xref ref-type="bibr" rid="ref38">38</xref>
</sup>
IL8- and IFN-mediated signalings were also modulated
during MERS-CoV infection, consistent with prior analyses.<sup><xref ref-type="bibr" rid="ref39">39</xref>
,<xref ref-type="bibr" rid="ref40">40</xref>
</sup>
These results were also in agreement with in vitro transcriptional
analysis of MERS-CoV infection.<sup><xref ref-type="bibr" rid="ref38">38</xref>
</sup>
Prophylactic
or therapeutic addition of FDA-licensed kinase inhibitors targeting
activated kinases in MERS-CoV infection impaired viral replication.
These hypothesis-generating data may inform directed investigations
into MERS-CoV pathogenesis and, importantly, demonstrate the potential
to identify novel host-centric therapeutic targets.</p>
</sec>
</sec>
<sec id="sec3.2"><title>Ebolaviruses</title>
<p>The Filoviridae family of viruses consists of three genera: Ebolavirus,
Marburgvirus, and the newly identified Cuevavirus. Structurally, filoviruses
have a pleomorphic enveloped, filamentous virion particle that encapsulates
a negative-sense single-stranded RNA genome. Ebolaviruses were first
described in 1976 following disease outbreaks in the Democratic Republic
of Congo and Sudan and are composed of five viral species, including
Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), Taï
Forest virus (TAFV), and Reston virus (RESTV). Sporadic outbreaks
of EBOV, SUDV, BDBV, and TAFV have occurred throughout central Africa
for more than three decades, resulting in thousands of infections.
Case fatality rates during these outbreaks have routinely exceeded
50%.<sup><xref ref-type="bibr" rid="ref41">41</xref>
</sup>
Isolated outbreaks of RESTV have
occurred outside Africa in nonhuman primate facilities in the United
States, Italy, and the Phillipines, and infection results in high
morbidity and mortality in nonhuman primates; however, RESTV has only
been associated with asymptomatic infections in humans.<sup><xref ref-type="bibr" rid="ref42">42</xref>
</sup>
Although ebolaviruses have been historically
associated with isolated outbreaks involving small cohorts of infected
patients (<500), an outbreak of EVD in West Africa beginning in
2014 has resulted in 28,616 cases and 11,310 deaths (40% CFR) as of
June 2016 (<uri xlink:href="http://www.who.int/csr/disease/ebola/en/">http://www.who.int/csr/disease/ebola/en/</uri>
). Although
virus transmission has greatly decreased in West Africa, surveillance
for sporadic infections continues.</p>
<sec id="sec3.2.1"><title>Clinical Findings in EVD</title>
<p>EBOV transmission occurs through exposure of infected body fluids
or tissues to mucous membranes or nonintact skin.<sup><xref ref-type="bibr" rid="ref43">43</xref>
</sup>
The mean incubation period is 6–10 days, ranging
from 2 to 21 days.<sup><xref ref-type="bibr" rid="ref43">43</xref>
</sup>
Initial signs and
symptoms are nonspecific including fever, myalgia, and malaise and
cannot be reliably distinguished from other endemic illnesses in Africa
including malaria and enteric infections.<sup><xref ref-type="bibr" rid="ref43">43</xref>
</sup>
Whereas mild illness has been described, most patients develop severe
disease within days of symptom onset. Massive gastrointestinal fluid
losses of up to 5–10 L per day due to vomiting and watery diarrhea
may result in progressive dehydration and hypovolemic shock. Even
in the setting of adequate fluid and electrolyte replacement, sequential
multiorgan failure may occur. EBOV infects multiple organs and cell
types throughout the body with the notable exception of lymphocytes
that are indirectly depleted early during infection. Organ injury
due to direct viral or indirect host-mediated responses results in
severe complications including meningo-encephalitis, uveitis, respiratory
failure, secretory diarrhea, disordered coagulation, renal failure,
hepatic necrosis, and myositis. The clinical presentation, laboratory
values, viral kinetics, and clinical management of EVD patients in
West Africa, Europe, and the United States during the 2014–2015
outbreak have been recently well-characterized.<sup><xref ref-type="bibr" rid="ref44">44</xref>
</sup>
</p>
</sec>
<sec id="sec3.2.2"><title>Soluble Immune Mediators Associated with
EBOV Infections</title>
<p>There is a paucity of information regarding
EBOV pathogenesis in humans primarily due to the limited frequency
of EVD outbreaks prior to 2014 and limitations presented by sample
acquisition from infected patients in the field as well as the overall
size of patient cohorts. Largely contradictory findings regarding
the immune responses in those who survive or succumb to EVD have further
confounded the understanding of EBOV pathogenesis in human patients.
For example, Villinger et al. reported that serum cytokine concentrations
(including IFNα, IFNγ, TNF-α, IL-2, and IL-4) were
elevated in patients with fatal infections in comparison to survivors.<sup><xref ref-type="bibr" rid="ref45">45</xref>
</sup>
In contrast, additional studies have suggested
that fatal infections were instead related to general immunosuppression
including IFNγ, IL-2, and IL-4.<sup><xref ref-type="bibr" rid="ref46">46</xref>
−<xref ref-type="bibr" rid="ref49">49</xref>
</sup>
An investigation of SUDV infection
in humans by Sanchez et al. demonstrated limited changes in the expression
levels of cytokines, Fas antigen, and Fas ligand in PBMCs from infected
patients relative to those found for uninfected patients.<sup><xref ref-type="bibr" rid="ref50">50</xref>
</sup>
Furthermore, an investigation of 42 fatally
infected EVD patients by Wauquier et al. has further confounded the
role of host immune responses in fatal EVD as hypersecretion of multiple
cytokines and growth factors and decreased secretion of T lymphocyte-derived
cytokines were associated with fatal disease.<sup><xref ref-type="bibr" rid="ref51">51</xref>
</sup>
</p>
</sec>
<sec id="sec3.2.3"><title>Transcriptome Analyses of Ebola Virus Infection</title>
<p>To
date, no investigations of host gene expression in EBOV-infected patients
have been reported, although limited data are available from animal
models of infection or from in vitro investigations.</p>
<p>In a study
of PBMCs from EBOV-infected crab-eating macaques, Rubins et al. found
few notable changes in the early stages of infection (1–2 days);
however, broad changes were observed over days 4–6 post-infection.
Pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α)
and chemokines (MIP-1α and MCP1–4) were up-regulated
at days 4–6 postinfection relative to healthy controls.<sup><xref ref-type="bibr" rid="ref52">52</xref>
</sup>
Multiple genes related to apoptosis including
Bcl-2 family members, multiple caspases, Fas-associated death domain
protein, and TNF superfamily member 10 were also up-regulated at late
time points. IFN-regulated genes were up-regulated by day 2 postinfection
and remained so through study day 6.</p>
<p>Yan et al. investigated
PBMC gene expression in EBOV-infected rhesus macaques with or without
anticoagulant administration. Untreated animals displayed up-regulation
of immune response genes, B cell receptor signaling intermediates,
NK cell mediated cytotoxicity, leukocyte activation, and lymphocyte
activation compared with anticoagulant-treated animals during the
early stages of infection. The expression levels of these gene clusters
fell to pre-infection levels at the late-stage of infection. In contrast,
genes related to defense responses, apoptosis, wounding, inflammation,
coagulation, and leukocyte activation remained elevated during early-
and late-stage infection.</p>
<p>Following the isolation of RESTV from
pigs,<sup><xref ref-type="bibr" rid="ref53">53</xref>
</sup>
subsequent investigations have
demonstrated that pigs were susceptible to both RESTV and EBOV infection
with preferential targeting of macrophages in the lungs. Recently,
Nfon et al. demonstrated that EBOV infection in pigs resulted in up-regulation
of chemokine expression beginning on day 3 postinfection as compared
to mock-infected pigs.<sup><xref ref-type="bibr" rid="ref54">54</xref>
</sup>
The most pronounced
changes in gene expression were found on days 5 and 7 postinfection
and included the up-regulation of a broad set of cytokines (IL-5,
IL-6, IL-8, IL-10, IL-22, IL-26, IL-27, resistin), chemokines (CCL2,
CCL10, CCL19, CCL20, AMCF-II, CCL3L1, CCL4), cell adhesion protein
(selectin), antimicrobial protein, palate, lung, and nasal epithelium
clone proteins, and pro-apoptotic molecules (multiple caspases, caspase
recruitment domain-containing protein 6 (CARD), apoptosis-associated
tyrosine kinase (AATK), Fas, Fas-associated protein with death domain
(FADD), TNF receptor-associated factor 3 (TRAF3), TNFα-induced
protein 3-interacting protein 1 (TNIP1)). In addition, expression
of multiple genes related to microbial sensing (pattern recognition
receptors) or antiviral responses (ISGs) was up-regulated in the lungs
of infected animals. Although the localization of the cytokine response
of pigs and humans or NHPs differs during the course of EBOV infection
(localized responses in the lungs of pigs versus a predominantly systemic
response in humans and NHPs), the cytokine profiles of pigs, humans,
and NHPs were quite similar. For example, comparison of NHP<sup><xref ref-type="bibr" rid="ref52">52</xref>
</sup>
and porcine responses<sup><xref ref-type="bibr" rid="ref54">54</xref>
</sup>
during EBOV infection demonstrated multiple gene expression similarities
between the two species (i.e., IL-6, IL-8, caspase family members).
It is also likely that direct comparison of both data sets would likely
yield many common gene signatures that are conserved in their identity
as well as their directionality (up-regulation vs down-regulation).</p>
<p>Macrophages are an early target of EBOV infection and support high-level
viral replication. EBOV attachment and entry into human macrophages
in vitro induces pro-inflammatory mediators including IL-6, IL-8,
and TNF-α as early as 1 h postinfection.<sup><xref ref-type="bibr" rid="ref55">55</xref>
</sup>
Noncardiogenic pulmonary edema is a recognized complication
of EVD, and human autopsy data support that alveolar macrophages are
a target of EBOV infection. EBOV infection of alveolar macrophages
in vitro resulted in an early, transient increase in cytokine and
chemokine expression,<sup><xref ref-type="bibr" rid="ref56">56</xref>
</sup>
supporting that
paracrine-soluble mediators of inflammation may contribute to vascular
leakage in the lungs. Gene expression responses of EBOV- and MARV-infected
Huh7 cells resulted in the global suppression of antiviral responses,
including Toll-like receptor (TLR), IRF3, and protein kinase R (PKR)-mediated
pathways.<sup><xref ref-type="bibr" rid="ref57">57</xref>
</sup>
However, signal transducers
and activators of transcription (STAT) phosphorylation in EBOV- and
MARV-infected cells were differentially modulated. EBOV-mediated IFN
inhibition has been well characterized and is thought to be attributable
to EBOV proteins VP24 and VP35.<sup><xref ref-type="bibr" rid="ref58">58</xref>
</sup>
Interestingly,
RESTV infection, which does not induce clinical illness in humans,
resulted in the activation of >20% of the IFN-stimulated genes
(ISGs).</p>
</sec>
<sec id="sec3.2.4"><title>Kinome Analysis of Ebola Virus</title>
<p>Hepatocytes are an early
target of EBOV infection, directly contributing to diffuse hepatic
necrosis observed in fatal cases. EBOV infection of Huh7 cells has
been evaluated by kinome analyses, shedding light on liver pathogenesis
in EVD.<sup><xref ref-type="bibr" rid="ref59">59</xref>
</sup>
EBOV infection of Huh-7 cells
resulted in temporal modulation of the TGF-β signaling pathway
as compared to mock-infected cells. Pathway ORA demonstrated that
multiple TGF-β-mediated signaling pathways were up-regulated
at 1 and 24 h post EBOV infection. Furthermore, these responses were
associated with changes in the expression patterns of multiple cellular
proteins associated with a mesenchyme-like transition. These included
the up-regulation of matrix metalloproteinase 9, N-cadherin, and fibronectin
and down-regulation of E-cadhering and claudin 1. In this process
cells lose polarity and cell-to-cell adhesion transforming into mesenchymal
stem cells that contribute to wound healing or organ fibrosis; however,
the role of these events in EBOV infection remains to be elucidated.
Additional analysis demonstrated that inhibition of PI3K/AKT, ERK/MAPK,
or PKC pathways with kinase inhibitors reduced EBOV replication when
administered prophylactically or therapeutically. Supporting this
observation, a subset of kinase inhibitors administered to EBOV-infected
mice reduced lethality. Defining mechanisms by which kinase inhibitors
show benefit in these models will better clarify their role as potential
therapeutics.</p>
</sec>
</sec>
<sec id="sec3.3"><title>Monkeypox Virus</title>
<p>MPXV, a member of
the genus <italic>Orthopoxvirus</italic>
, causes zoonotic
infections with a case fatality rate of ∼11%.<sup><xref ref-type="bibr" rid="ref60">60</xref>
</sup>
MPXV, vaccinia virus (VACV), cowpox virus (CPXV), ectromelia
virus, and variola virus (VARV), the etiologic agent of human smallpox,
comprise the Orthopoxviridae family of viruses. MPXV was first isolated
in 1958 from cynomolgus macaques in Denmark; however, human MPXV infections
were not recognized until 1970 following the isolation of the virus
from a suspected case of smallpox infection in the Democratic Republic
of Congo.<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
MPXV is composed of two distinct
clades that are genetically, clinically, and geographically distinct.
The Congo Basin MPXV (Central African MPXV) clade is considered to
have both higher lethality and morbidity than the West African MPXV
clade as demonstrated from comparative infection models in various
animal species (including nonhuman primates, mice, prairie dogs, and
ground squirrels) and as well natural infection in humans.<sup><xref ref-type="bibr" rid="ref61">61</xref>
−<xref ref-type="bibr" rid="ref63">63</xref>
</sup>
Fifty-four cases of human MPXV disease were recorded in West and
Central Africa from 1970 to 1979. Although no fatalities were reported
in West African cases (including Liberia, Nigeria, Ivory Coast, and
Sierra Leone), 21% of cases from the Democratic Republic of Congo
resulted in fatal disease.<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
Furthermore,
West African MPXV was responsible for the 2003 MPXV outbreak in the
United States that resulted in 69 diagnosed cases of MPXV and no associated
fatalities.<sup><xref ref-type="bibr" rid="ref64">64</xref>
</sup>
Although human MPXV infections
have been recorded in West Africa, the majority of human MPXV infections
have occurred in the Congo Basin region of Central Africa, largely
in the Democratic Republic of Congo.<sup><xref ref-type="bibr" rid="ref60">60</xref>
</sup>
</p>
<sec id="sec3.3.1"><title>Clinical
Findings in MPXV Infections</title>
<p>Clinical and epidemiological
information regarding human MPXV disease has been derived from enhanced
surveillance campaigns in the Congo Basin.<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
From this work, it has been demonstrated that human MPXV infection
and illness largely mirror those of discrete, ordinary smallpox.<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
The incubation period for both viruses (VARV
and MPXV) is 7–17 days with an initial febrile prodromal period
of 1–4 days. This prodromal period is normally accompanied
by fever, headache, backache, malaise, and prostration.<sup><xref ref-type="bibr" rid="ref61">61</xref>
</sup>
The rash period for both smallpox and MPXV (including
lesion appearance and desquamation) normally occurs 14–28 days
postinfection with highly similar appearance, distribution, and progression
of lesions.<sup><xref ref-type="bibr" rid="ref60">60</xref>
,<xref ref-type="bibr" rid="ref61">61</xref>
</sup>
As with smallpox, MPXV-associated
rash progresses through macular, papular, vesicular, and pustular
phases. A second febrile period occurs when the lesions become pustular
and is often associated with deteriorating conditions in the patient.
Lymphadenopathy (maxillay, cervical, or inguinal) is often associated
with MPXV infections prior to, or concomitant with, rash development
but is absent in VARV infections. It has been postulated that this
reflects the effective generation of host immune responses during
MPXV infection as compared to VARV; however, this has yet to be validated.<sup><xref ref-type="bibr" rid="ref60">60</xref>
,<xref ref-type="bibr" rid="ref61">61</xref>
</sup>
Severe complications have been noted late in the course of MPXV
infection, including pulmonary distress or bronchopneumonia, corneal
scarring and permanent vision loss, and encephalitis.<sup><xref ref-type="bibr" rid="ref60">60</xref>
</sup>
Severe dehydration due to excessive vomiting or diarrhea
may also occur. Long-term sequelae in survivors are most commonly
associated with pitted scarring.</p>
</sec>
<sec id="sec3.3.2"><title>Soluble Immune Mediators
Associated with MPXV Infections</title>
<p>Although MPXV infections
in humans have been recorded for over four decades, there has been
little information regarding host immune responses during the course
of natural infection. As disease presentation is highly similar during
MPXV and VARV infections, it has been postulated that immune responses
would likely be highly conserved. Recently, Johnston et al. provided
the first empirical evidence for a relationship between cytokine responses
and disease severity during MPXV infection.<sup><xref ref-type="bibr" rid="ref65">65</xref>
</sup>
Serum cytokines were analyzed from 19 patients with confirmed MPXV
infections ranging from mild to severe as assessed by the WHO smallpox
lesion scoring system.<sup><xref ref-type="bibr" rid="ref66">66</xref>
,<xref ref-type="bibr" rid="ref67">67</xref>
</sup>
Serum concentrations of IL-1β,
IL-1RA, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-13, IL-15, IL-17, MCP-1,
and RANTES were elevated in all disease groups (mild to severe) as
compared to normal serum concentrations. IL-10 concentrations were
also elevated in all disease groups and were proportional to disease
severity. However, patients with serious MPXV disease had significantly
higher concentrations of IL-10 compared to all other disease groups.
MPXV infection resulted in elevated MIP-1α and MIP-1β;
mild cases had significantly elevated levels above the moderate or
severe disease groups. Serum concentrations of IL-2R were elevated
across all disease groups; however, patients with serious disease
had significantly higher IL-2R serum levels than those with mild to
severe MPXV disease. GM-CSF levels were significantly elevated only
in those with serious MPXV disease as compared to normal serum ranges.
On the basis of these observations, MPXV infection resulted in prominent
T helper 2 (Th2) and dampened Th1 responses.</p>
</sec>
<sec id="sec3.3.3"><title>Transciptome Analyses in
MPXV Infection</title>
<p>Transcriptome analyses have largely been employed
for the in vitro investigation of the molecular pathogenesis of MPXV
infection. Alkhalil et al. investigated the host transcriptome responses
to MPXV infection during the first cycle of viral replication (3 and
7 h postinfection) in rhesus macaque kidney epithelial cells.<sup><xref ref-type="bibr" rid="ref68">68</xref>
</sup>
Interestingly, MPXV infection resulted in a
strong down-regulation of host transcriptional responses. Of the transcripts
that met the authors’ criteria for significance, 89% of the
transcripts were found to be down-regulated at both postinfection
time points. Comparative functional analysis from both time points
suggested that the primary biological functions associated with these
down-regulated transcriptional responses were largely related to cell
morphology, cell development, metabolic responses, and post-translational
modifications. Canonical pathway analysis demonstrated a general conservation
in the identities of over-represented pathways at both time points
including multiple growth factor signaling pathways, p53 signaling,
and cell cycle-related pathways. More recently, Bourquain et al. investigated
host transcriptome responses in MPXV-infected HeLa cells, a cervical
epithelial cell line.<sup><xref ref-type="bibr" rid="ref84">84</xref>
</sup>
At 6 h post-MPXV
infection, only 1.1% of the transcripts analyzed were found to have
>2-fold changes in gene expression. In contrast to Alkhalil et
al., the majority of these transcripts (∼68%) were found to
be up-regulated as compared to mock-infected controls. Functional
analysis of all transcripts with >2-fold changes in gene expression
demonstrated a strong over-representation of genes involved in the
negative regulation of MAPK signaling and the intracellular protein
cascade. Positive regulation of pathways related to Toll-like receptor
signaling, chemotaxis, and regulation of leukocyte migration was also
predicted from the data. An investigation by Rubins et al. compared
the temporal host transcriptome response to MPXV in multiple human
cells targeted by MPXV including primary macrophages, primary fibroblasts,
and HeLa cells.<sup><xref ref-type="bibr" rid="ref69">69</xref>
</sup>
The trasncriptome of
MPXV-infected fibroblasts was found to have the most significant changes
where MPXV infection resulted in the depletion of ∼2000 genes
by a factor of ≥3. Interestingly, MPXV infection resulted in
the broad repression of many transcripts related to innate immune
responses in all cell types tested. In contrast, inactivated MPXV
resulted in strong up-regulation of innate immune responses in all
of the cell types. It was also noted that MPXV infection resulted
in strong cytopathic effects across all of the cell types in contrast
to an almost universal repression of innate immune responses.</p>
</sec>
<sec id="sec3.3.4"><title>Kinome Analyses in MPXV Infection</title>
<p>Human MPXV infections
and infection models of MPXV in various animal species have demonstrated
that the Congo Basin MPXV clade is more virulent than the West African
MPXV clade. However, there has been a paucity of information regarding
the underlying molecular mechanisms mitigating these virulence differences.
Furthermore, previous investigations focusing on gene expression or
proteomic changes during MPXV infection have focused solely on Congo
Basin MPXV. To address this, host kinome analysis was performed on
Congo Basin and West African MPXV-infected human monocytes, a host
cell targeted by orthopoxviruses.<sup><xref ref-type="bibr" rid="ref70">70</xref>
</sup>
As
the genomes of both MPXV clades demonstrate considerable diversity
in the regions coding host response modifier proteins, and in particular
in genes associated with anti-apoptotic activities, it was postulated
that the virulence differences of the two MPXV clades may be related
to differential modulation of host cellular responses. Hierarchical
clustering of the kinome data sets suggested limited similarities
at the level of host kinase modulation between the two MPXV clades.
The Congo Basin MPXV kinome data set clustered most strongly with
the kinome data set from CPXV-infected monocytes and moderately with
the VACV-infected monocyte data set. Both CPXV and VACV can cause
serious disease in humans. The pathway ORA of the kinome data demonstrated
that Congo Basin MPXV infection resulted in strong down-regulation
of a large proportion of host cell responses, most notably apoptosis,
in comparison to West African MPXV. Biological validation through
fluorescence-activated cell sorting (FACS) and caspase 3 activity
analyses confirmed this phenomenon. From the perspective of individual
phosphorylation events, the kinome data also suggested that AKT phosphorylation
at Ser473 was increased in Congo Basin MPXV-infected cells as compared
to West African MPXV-infected cells. Pharmacologic inhibition of AKT
phosphorylation at Ser473 resulted in a >250-fold inhibition of
Congo Basin MPXV virus yields, whereas those for West African MPXV
were unaffected. Prior investigations with CPXV and VACV demonstrated
that pharmacological inhibition of AKT resulted in decreased viral
yields for both viruses.<sup><xref ref-type="bibr" rid="ref71">71</xref>
</sup>
Overall, this
investigation provided significant insight into the host cellular
response differences between the two MPXV clades.</p>
</sec>
</sec>
</sec>
<sec id="sec4"><title>Conclusions</title>
<p>Emerging and re-emerging pathogens are a continual threat to global
health. In recent years, disease outbreaks associated with SARS and
the 2009 influenza pandemic have also demonstrated that these pathogens
can have considerable effects on local, national, and international
economies. As a consequence, regional outbreaks of emerging and re-emerging
pathogens can have deleterious effects on global stability. Thus,
it is prudent that a concerted effort is employed to assimilate data
that bridge both clinical and molecular information in investigations
of these pathogens. These efforts will not only provide considerable
context in regard to the molecular events that potentiate clinical
manifestations of pathogenesis but also better inform the design and
implementation of novel therapeutics. To this end, global analyses
of host molecular responses can provide considerable insight into
the complex molecular events that underlie cellular responses. Indeed,
transcriptome analyses have provided important information regarding
host transcriptional responses during emerging and re-emerging pathogen
infection. These investigations often provide critical insight into
the kinetics of host immune responses during the course of infection
as well as mechanistic information regarding the cellular intermediates
involved in these processes. However, the role of PTMs in the regulation
of these events cannot be captured by traditional transcriptome technologies.
In particular, the role of kinase-mediated regulation of cell signaling
pathways has remained poorly understood. Given the central role of
kinases in the regulation of cellular processes (e.g., homeostasis,
metabolism, proliferation, and stress responses), it is of inherent
importance that future investigations also address the role of the
kinome in the cellular response to pathogen insult. Furthermore, kinomics
also provides a mechanism for the identification of novel therapeutic
targets based on the direct assessment of the activation state of
cell signaling pathways. For example, pro-inflammatory responses during
early stages of infection, and in particular the dysregulation of
specific cytokines or cell signaling events that contribute to these,
may represent potential therapeutic targets in the early stages of
high-consequence viral pathogen infection. However, the selection
of immunomodulatory therapeutics that target these dysregulated host
responses is complicated by the regulatory events (i.e., kinase-mediated
cell signaling events) that occur upstream of changes in gene expression.
In addition, mRNA is subject to a variety of regulatory processes
(including gene silencing, mRNA stability, translational efficiencies,
protein turnover, enzyme/substrate subcellular sequestration, and/or
protein activation/repression PTMs). Thus, from the standpoint of
therapeutic discovery, the sole reliance on technologies for the global
investigations of host responses that do not account for these regulatory
processes or the role of PTMs in the modulation of cellular responses
could impede the identification of efficacious therapeutics.</p>
<p>To this end, kinome analysis may also facilitate the identification
of immunomodulatory therapeutics that have gained licensure through
analysis of a quantifiable biological event (kinase-mediated phosphorylation)
or for identifying novel host therapeutic targets for which therapeutics
could be designed/developed. Furthermore, kinase inhibitors may serve
as primary or adjunctive therapies for emerging infectious diseases.
In addition, preclinical data and the increasing number of kinase
inhibitors that have gained regulatory approval for cancer and other
maladies suggest this approach is feasible and efficacious. From the
perspective of this review, kinome investigations have identified
several therapeutic targets and licensed kinase inhibitors that have
impaired viral replication in vitro and reduced the severity of disease
in vivo (<xref rid="tbl1" ref-type="other">Table <xref rid="tbl1" ref-type="other">1</xref>
</xref>
).
For example, it has been demonstrated that the ERK/MAPK and PI3K/AKT/mTOR
signaling pathways have a role in viral propagation during MERS-CoV
infection.<sup><xref ref-type="bibr" rid="ref37">37</xref>
</sup>
Indeed, licensed kinase inhibitors
that targeted these pathways (i.e., everolimus, selumetinib, and trametinib)
resulted in decreased viral replication in vitro when added prior
to, or following, infection. Furthermore, the pharmacologic inhibition
of PI3K and PKC following EBOV infection provided partial protection
in a lethal model of EVD in mice.<sup><xref ref-type="bibr" rid="ref59">59</xref>
</sup>
It
should be noted that although the modulation of an individual kinase
may have suppressive effects on infection (i.e., viral replication),
this might not provide the level of inhibition required to completely
negate viral escape. In addition, given the ability of many cell signaling
pathways to signal through both canonical and noncanonical mechanisms,
inhibition at a single intermediary point within a pathway may not
provide the overall level of inhibition required to negate a deleterious
response (i.e., viral replication, changes in cellular phenotypes,
etc.). Thus, although previous investigations have demonstrated that
individual kinases or cell signaling pathways may represent novel
targets for anti-infective therapies, it is prudent that future investigations
also examine combinations of inhibitors for efficacy and anti-infective
activities. Furthermore, the targeting of cell signaling pathways
at or near the origin point for the cell signaling cascade should
also be examined as these likely represent stronger inhibitory targets
given the generally reduced branching of cell signaling networks at
or near the cell receptor.</p>
<table-wrap id="tbl1" position="float"><label>Table 1</label>
<caption><title>Kinase Inhibitors
Tested against EBOV, MERS-CoV, or MPXV</title>
</caption>
<table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead><tr><th style="border:none;" align="center">kinase inhibitor</th>
<th style="border:none;" align="center">host target</th>
<th style="border:none;" align="center">impact
of inhibitor on viral replication (reduction in viral replication
considered to be >40% inhibition)</th>
<th style="border:none;" align="center">impact of inhibitor on animal survival</th>
<th style="border:none;" align="center">reference</th>
</tr>
</thead>
<tbody><tr><td colspan="5" style="border:none;" align="center"><bold>MERS-CoV</bold>
</td>
</tr>
<tr><td style="border:none;" align="left">Rapamycin</td>
<td style="border:none;" align="left">mTOR</td>
<td style="border:none;" align="left">in vitro
reduction in viral replication with prophylatic and therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">GF109203X</td>
<td style="border:none;" align="left">PKC</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic
and therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Ro-31-8220</td>
<td style="border:none;" align="left">PKC</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic and
therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">U0126</td>
<td style="border:none;" align="left">MEK1, MEK2</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic
treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Wortmannin</td>
<td style="border:none;" align="left">PI3K</td>
<td style="border:none;" align="left">in vitro reduction in
viral replication with prophylatic treatment</td>
<td style="border:none;" align="left">no data
available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">GW5074</td>
<td style="border:none;" align="left">c-Raf1</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Imatinib</td>
<td style="border:none;" align="left">c-Abl1 family</td>
<td style="border:none;" align="left">in vitro reduction in viral replication
with prophylatic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref78">78</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">SB203580</td>
<td style="border:none;" align="left">p38 MAPK</td>
<td style="border:none;" align="left">in vitro
reduction in viral replication with prophylatic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
, <xref ref-type="bibr" rid="ref38">38</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Dasatinib (BMS-354825)</td>
<td style="border:none;" align="left">Src,
Abl family kinases</td>
<td style="border:none;" align="left">in vitro reduction in viral replication
with prophylatic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref78">78</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">PP2</td>
<td style="border:none;" align="left">Src family kinases</td>
<td style="border:none;" align="left">no
significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data
available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Bay 11-7082</td>
<td style="border:none;" align="left">IKBα</td>
<td style="border:none;" align="left">no significant inhibition
of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">PKC-412</td>
<td style="border:none;" align="left">PKC</td>
<td style="border:none;" align="left">no significant inhibition
of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">AG490</td>
<td style="border:none;" align="left">EGFR; ERBB2</td>
<td style="border:none;" align="left">no significant
inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">L-NAME</td>
<td style="border:none;" align="left">nitric oxide synthase</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data
available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref37">37</xref>
)</td>
</tr>
<tr><td colspan="5" style="border:none;" align="center"><bold>EBOV</bold>
</td>
</tr>
<tr><td style="border:none;" align="left">AG879</td>
<td style="border:none;" align="left">ErbB2 and FLK-1 (VEGF receptor)</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic and therapeutic
treatment</td>
<td style="border:none;" align="left">improvement in mouse survival</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">LY294002</td>
<td style="border:none;" align="left">PI3K</td>
<td style="border:none;" align="left">in vitro reduction
in viral replication with prophylatic and therapeutic treatment</td>
<td style="border:none;" align="left">improvement in mouse survival</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
, <xref ref-type="bibr" rid="ref79">79</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">SB431542</td>
<td style="border:none;" align="left">activin receptor-like kinase receptors, ALK5, ALK4 and ALK7</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic and
therapeutic treatment</td>
<td style="border:none;" align="left">improvement in mouse survival</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">SU1498</td>
<td style="border:none;" align="left">VEGF receptor 2</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">improvement in mouse survival</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Rottlerin</td>
<td style="border:none;" align="left">PKC</td>
<td style="border:none;" align="left">in vitro reduction in viral
replication with prophylatic and therapeutic treatment</td>
<td style="border:none;" align="left">improvement in mouse survival</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Wortmannin</td>
<td style="border:none;" align="left">PI3K</td>
<td style="border:none;" align="left">in vitro reduction in
viral replication with prophylatic and therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Indirubin-3-monoxamine</td>
<td style="border:none;" align="left">glycogen synthase kinase 3β</td>
<td style="border:none;" align="left">in vitro reduction
in viral replication with prophylatic and therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">SP600125</td>
<td style="border:none;" align="left">JNK</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic
and therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">GF109203X</td>
<td style="border:none;" align="left">PKC</td>
<td style="border:none;" align="left">in vitro reduction
in viral replication with prophylatic and therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Genistein</td>
<td style="border:none;" align="left">EGFR</td>
<td style="border:none;" align="left">in vitro inhibition of vsv-ebov pseudotype transduction
with prophylatic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref80">80</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Tyrphostin</td>
<td style="border:none;" align="left">tyrosine kinases</td>
<td style="border:none;" align="left">in vitro inhibition of vsv-ebov pseudotype transduction with prophylatic
treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref80">80</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">KN-93</td>
<td style="border:none;" align="left">CAMK2</td>
<td style="border:none;" align="left">in vitro reduction in infectivity</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref79">79</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">U0126</td>
<td style="border:none;" align="left">MEK1, MEK2</td>
<td style="border:none;" align="left">in vitro reduction in viral replication
with prophylatic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Nilotinib</td>
<td style="border:none;" align="left">c-Abl1 family</td>
<td style="border:none;" align="left">in
vitro reduction in viral replication with therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref81">81</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Imatinib</td>
<td style="border:none;" align="left">c-Abl1 family</td>
<td style="border:none;" align="left">in vitro reduction in viral replication
with therapeutic treatment</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref81">81</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">p38inK II</td>
<td style="border:none;" align="left">p38 MAPK</td>
<td style="border:none;" align="left">in vitro
reduction of viral entry</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref82">82</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">SB202190</td>
<td style="border:none;" align="left">p38 MAPK</td>
<td style="border:none;" align="left">In vitro reduction
of viral entry</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref82">82</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">AG1024</td>
<td style="border:none;" align="left">insulin-like growth factor 1 receptor</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Tricirbine</td>
<td style="border:none;" align="left">Akt</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">GW5074</td>
<td style="border:none;" align="left">c-Raf1</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">ZM336372</td>
<td style="border:none;" align="left">c-Raf1</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">HBDDE</td>
<td style="border:none;" align="left">PKC</td>
<td style="border:none;" align="left">no significant inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref59">59</xref>
)</td>
</tr>
<tr><td colspan="5" style="border:none;" align="center"><bold>MPXV</bold>
</td>
</tr>
<tr><td style="border:none;" align="left">Dasatinib (BMS-354825)</td>
<td style="border:none;" align="left">Src, Abl family
kinases</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with
prophylatic and therapeutic treatment (Congo Basin and West African
clades)</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref83">83</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Staurosporine</td>
<td style="border:none;" align="left">nonspecific kinase inhibitor</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic treatment
(Congo Basin and West African clades)</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref70">70</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">SB202190</td>
<td style="border:none;" align="left">p38 MAPK</td>
<td style="border:none;" align="left">in vitro
reduction in viral replication with prophylatic treatment (Congo Basin
and West African clades)</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref70">70</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">BML-257</td>
<td style="border:none;" align="left">Akt</td>
<td style="border:none;" align="left">in vitro reduction
in viral replication with prophylatic treatment (Congo Basin and West
African clades)</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref70">70</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">LY294002</td>
<td style="border:none;" align="left">PI3K</td>
<td style="border:none;" align="left">in vitro reduction in viral
replication with prophylatic treatment (Congo Basin clade only)</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref70">70</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Akt-X</td>
<td style="border:none;" align="left">Akt</td>
<td style="border:none;" align="left">in vitro reduction in viral replication with prophylatic
treatment (Congo Basin clade only)</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref70">70</xref>
)</td>
</tr>
<tr><td style="border:none;" align="left">Nutlin 3</td>
<td style="border:none;" align="left">MDM-2</td>
<td style="border:none;" align="left">no significant
inhibition of viral replication</td>
<td style="border:none;" align="left">no data available</td>
<td style="border:none;" align="left">(<xref ref-type="bibr" rid="ref70">70</xref>
)</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>In addition to host-directed
therapeutic targeting, kinomics also confers the ability to identify
novel inhibitors of pathogens through detailed characterization of
the viral life cycle. Host-mediated PTMs, and in particular kinase-mediated
phosphorylation, have been implicated in the viral life cycle and
pathogenesis for several members of the order Mononegavirales, including
EBOV.<sup><xref ref-type="bibr" rid="ref72">72</xref>
−<xref ref-type="bibr" rid="ref74">74</xref>
</sup>
Thus, therapeutic targeting of kinases may represent
a novel therapeutic strategy that can be employed to modulate host-centric
or pathogen-centric molecular events during infection. For example,
in silico prediction of viral protein phosphorylation sites provides
a mechanism for the construction and, ultimately, the annotation of
viral protein PTMs that are critical to the viral life cycle. Furthermore,
the use of kinome peptide arrays has extended beyond the human kinome
and now extends to a variety of animal species.<sup><xref ref-type="bibr" rid="ref75">75</xref>
−<xref ref-type="bibr" rid="ref77">77</xref>
</sup>
It has been
suggested that the interspecies phenotypic variability may reflect
differences in phosphorylation sites found within the proteome.<sup><xref ref-type="bibr" rid="ref77">77</xref>
</sup>
Thus, the development of species-specific kinome
peptide arrays provides additional utility for kinome analysis as
peptide arrays representing traditional laboratory animal species
(mouse, guinea pig, nonhuman primate) can be employed to detail the
species-specific host response. The results from such analyses, and
the overlap between these and those described previously from the
analysis of human infections, may inform the selection of appropriate
animal models that meet regulatory approval through the FDA Animal
Efficacy Rule.<sup><xref ref-type="bibr" rid="ref29">29</xref>
</sup>
</p>
<p>Taken together,
it is of inherent importance that future investigations of emerging
and re-emerging pathogens address the complex nature of biological
responses. Thus, molecular investigations of pathogenesis should be
guided by available knowledge regarding the clinical and pathologic
manifestations of disease. Indeed, technologies that provide further
granularity into the precise molecular events that potentiate cellular
responses during the course of infection will assist investigations
of emerging and re-emerging pathogens and the identification of novel
therapeutic targets. To this end, kinomics-based analyses of host
responses provide a mechanism to directly address the cellular events
at the level of specific cell signaling phenomena that underlie the
biological responses and, ultimately, the clinical presentation of
disease for emerging infectious pathogens.</p>
</sec>
</body>
<back><notes notes-type="COI-statement" id="NOTES-d131e1063-autogenerated"><p>The authors declare no competing
financial interest.</p>
</notes>
<ack><title>Acknowledgments</title>
<p>The Intramural Research Programs of National Institute of Health
(Clinical Center, Critical Care Medicine Department) supported this
work. The content of this publication does not necessarily reflect
the views or policies of the U.S. Department of Health and Human Services,
nor does mention of trade names, commercial products, or organizations
imply endorsement by the U.S. government.</p>
</ack>
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