Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model
Identifieur interne : 003914 ( Ncbi/Merge ); précédent : 003913; suivant : 003915Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model
Auteurs : Luther A. Bartelt [États-Unis] ; David T. Bolick [États-Unis] ; Glynis L. Kolling [États-Unis] ; James K. Roche [États-Unis] ; Edna I. Zaenker [États-Unis] ; Ana M. Lara [États-Unis] ; Francisco Jose Noronha [États-Unis] ; Carrie A. Cowardin [États-Unis] ; John H. Moore [États-Unis] ; Jerrold R. Turner [États-Unis] ; Cirle A. Warren [États-Unis] ; Gregory A. Buck [États-Unis] ; Richard L. Guerrant [États-Unis]Source :
- PLoS Neglected Tropical Diseases [ 1935-2727 ] ; 2016.
Abstract
Url:
DOI: 10.1371/journal.pntd.0004820
PubMed: 27467505
PubMed Central: 4965189
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Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model</title>
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<author><name sortKey="Kolling, Glynis L" sort="Kolling, Glynis L" uniqKey="Kolling G" first="Glynis L." last="Kolling">Glynis L. Kolling</name>
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</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>Cryptosporidium</italic>
Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model</title>
<author><name sortKey="Bartelt, Luther A" sort="Bartelt, Luther A" uniqKey="Bartelt L" first="Luther A." last="Bartelt">Luther A. Bartelt</name>
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<author><name sortKey="Bolick, David T" sort="Bolick, David T" uniqKey="Bolick D" first="David T." last="Bolick">David T. Bolick</name>
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<author><name sortKey="Kolling, Glynis L" sort="Kolling, Glynis L" uniqKey="Kolling G" first="Glynis L." last="Kolling">Glynis L. Kolling</name>
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</nlm:aff>
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<author><name sortKey="Roche, James K" sort="Roche, James K" uniqKey="Roche J" first="James K." last="Roche">James K. Roche</name>
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</nlm:aff>
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<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zaenker, Edna I" sort="Zaenker, Edna I" uniqKey="Zaenker E" first="Edna I." last="Zaenker">Edna I. Zaenker</name>
<affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lara, Ana M" sort="Lara, Ana M" uniqKey="Lara A" first="Ana M." last="Lara">Ana M. Lara</name>
<affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Noronha, Francisco Jose" sort="Noronha, Francisco Jose" uniqKey="Noronha F" first="Francisco Jose" last="Noronha">Francisco Jose Noronha</name>
<affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cowardin, Carrie A" sort="Cowardin, Carrie A" uniqKey="Cowardin C" first="Carrie A." last="Cowardin">Carrie A. Cowardin</name>
<affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Moore, John H" sort="Moore, John H" uniqKey="Moore J" first="John H." last="Moore">John H. Moore</name>
<affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Turner, Jerrold R" sort="Turner, Jerrold R" uniqKey="Turner J" first="Jerrold R." last="Turner">Jerrold R. Turner</name>
<affiliation wicri:level="2"><nlm:aff id="aff004"><addr-line>Department of Pathology, The University of Chicago, Chicago, Illinois, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, The University of Chicago, Chicago, Illinois</wicri:regionArea>
<placeName><region type="state">Illinois</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff005"><addr-line>Departments of Pathology and Medicine—Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Pathology and Medicine—Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Warren, Cirle A" sort="Warren, Cirle A" uniqKey="Warren C" first="Cirle A." last="Warren">Cirle A. Warren</name>
<affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Buck, Gregory A" sort="Buck, Gregory A" uniqKey="Buck G" first="Gregory A." last="Buck">Gregory A. Buck</name>
<affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Guerrant, Richard L" sort="Guerrant, Richard L" uniqKey="Guerrant R" first="Richard L." last="Guerrant">Richard L. Guerrant</name>
<affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Neglected Tropical Diseases</title>
<idno type="ISSN">1935-2727</idno>
<idno type="eISSN">1935-2735</idno>
<imprint><date when="2016">2016</date>
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<front><div type="abstract" xml:lang="en"><p><italic>Cryptosporidium</italic>
is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of <italic>C</italic>
. <italic>parvum</italic>
oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to <italic>C</italic>
. <italic>parvum</italic>
challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to <italic>Cryptosporidium</italic>
, priming with <italic>C</italic>
. <italic>parvum</italic>
(10<sup>6</sup>
oocysts) provides robust protective immunity against re-challenge despite ongoing PM. <italic>C</italic>
. <italic>parvum</italic>
priming restores mucosal Th1-type effectors (CD3<sup>+</sup>
CD8<sup>+</sup>
CD103<sup>+</sup>
T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with <italic>Cryptosporidium</italic>
antigens expressed in the <italic>S</italic>
. Typhi vector 908<italic>htr</italic>
, however, do not enhance Th1-type responses to <italic>C</italic>
. <italic>parvum</italic>
challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated <italic>S</italic>
. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate <italic>C</italic>
. <italic>parvum</italic>
severity during PM, but neither as effectively as viable <italic>C</italic>
. <italic>parvum</italic>
priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to <italic>C</italic>
. <italic>parvum</italic>
, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically <italic>C</italic>
. <italic>parvum</italic>
priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of <italic>Cryptosporidium</italic>
immunity and future vaccine strategies in malnourished children.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Black, Re" uniqKey="Black R">RE Black</name>
</author>
<author><name sortKey="Victora, Cg" uniqKey="Victora C">CG Victora</name>
</author>
<author><name sortKey="Walker, Sp" uniqKey="Walker S">SP Walker</name>
</author>
<author><name sortKey="Bhutta, Za" uniqKey="Bhutta Z">ZA Bhutta</name>
</author>
<author><name sortKey="Christian, P" uniqKey="Christian P">P Christian</name>
</author>
<author><name sortKey="De Onis, M" uniqKey="De Onis M">M de Onis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rytter, Mjh" uniqKey="Rytter M">MJH Rytter</name>
</author>
<author><name sortKey="Kolte, L" uniqKey="Kolte L">L Kolte</name>
</author>
<author><name sortKey="Briend, A" uniqKey="Briend A">A Briend</name>
</author>
<author><name sortKey="Friis, H" uniqKey="Friis H">H Friis</name>
</author>
<author><name sortKey="Christensen, Vb" uniqKey="Christensen V">VB Christensen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Haque, R" uniqKey="Haque R">R Haque</name>
</author>
<author><name sortKey="Snider, C" uniqKey="Snider C">C Snider</name>
</author>
<author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name>
</author>
<author><name sortKey="Ma, Jz" uniqKey="Ma J">JZ Ma</name>
</author>
<author><name sortKey="Liu, L" uniqKey="Liu L">L Liu</name>
</author>
<author><name sortKey="Nayak, U" uniqKey="Nayak U">U Nayak</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="M Lbak, K" uniqKey="M Lbak K">K Mølbak</name>
</author>
<author><name sortKey="H Jlyng, N" uniqKey="H Jlyng N">N Højlyng</name>
</author>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Negl Trop Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Negl Trop Dis</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosntds</journal-id>
<journal-title-group><journal-title>PLoS Neglected Tropical Diseases</journal-title>
</journal-title-group>
<issn pub-type="ppub">1935-2727</issn>
<issn pub-type="epub">1935-2735</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27467505</article-id>
<article-id pub-id-type="pmc">4965189</article-id>
<article-id pub-id-type="doi">10.1371/journal.pntd.0004820</article-id>
<article-id pub-id-type="publisher-id">PNTD-D-16-00151</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Protozoans</subject>
<subj-group><subject>Parasitic Protozoans</subject>
<subj-group><subject>Cryptosporidium</subject>
<subj-group><subject>Cryptosporidium Parvum</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Protozoans</subject>
<subj-group><subject>Cryptosporidium</subject>
<subj-group><subject>Cryptosporidium Parvum</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Protozoans</subject>
<subj-group><subject>Parasitic Protozoans</subject>
<subj-group><subject>Cryptosporidium</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Protozoans</subject>
<subj-group><subject>Cryptosporidium</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Infectious Diseases</subject>
<subj-group><subject>Bacterial Diseases</subject>
<subj-group><subject>Salmonella</subject>
<subj-group><subject>Salmonella Typhi</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical Microbiology</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Bacterial Pathogens</subject>
<subj-group><subject>Salmonella</subject>
<subj-group><subject>Salmonella Typhi</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Pathology and Laboratory Medicine</subject>
<subj-group><subject>Pathogens</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Bacterial Pathogens</subject>
<subj-group><subject>Salmonella</subject>
<subj-group><subject>Salmonella Typhi</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Bacteria</subject>
<subj-group><subject>Enterobacteriaceae</subject>
<subj-group><subject>Salmonella</subject>
<subj-group><subject>Salmonella Typhi</subject>
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<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune Response</subject>
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<subj-group><subject>Nutrition</subject>
<subj-group><subject>Malnutrition</subject>
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<subj-group><subject>Nutrition</subject>
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<subj-group><subject>Cytokines</subject>
</subj-group>
</subj-group>
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<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Physiology</subject>
<subj-group><subject>Immune Physiology</subject>
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</subj-group>
</subj-group>
</subj-group>
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<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune System</subject>
<subj-group><subject>Innate Immune System</subject>
<subj-group><subject>Cytokines</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune System</subject>
<subj-group><subject>Innate Immune System</subject>
<subj-group><subject>Cytokines</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Developmental Biology</subject>
<subj-group><subject>Molecular Development</subject>
<subj-group><subject>Cytokines</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Cell Biology</subject>
<subj-group><subject>Cellular Types</subject>
<subj-group><subject>Animal Cells</subject>
<subj-group><subject>Blood Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>T Cells</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Cell Biology</subject>
<subj-group><subject>Cellular Types</subject>
<subj-group><subject>Animal Cells</subject>
<subj-group><subject>Immune Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>T Cells</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>T Cells</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune Cells</subject>
<subj-group><subject>White Blood Cells</subject>
<subj-group><subject>T Cells</subject>
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</subj-group>
</subj-group>
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<title-group><article-title><italic>Cryptosporidium</italic>
Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model</article-title>
<alt-title alt-title-type="running-head"><italic>C</italic>
. <italic>parvum</italic>
Priming Protects against Cryptosporidiosis Despite Protein Malnutrition</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Bartelt</surname>
<given-names>Luther A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bolick</surname>
<given-names>David T.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kolling</surname>
<given-names>Glynis L.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" deceased="yes"><name><surname>Roche</surname>
<given-names>James K.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zaenker</surname>
<given-names>Edna I.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lara</surname>
<given-names>Ana M.</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Noronha</surname>
<given-names>Francisco Jose</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cowardin</surname>
<given-names>Carrie A.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Moore</surname>
<given-names>John H.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Turner</surname>
<given-names>Jerrold R.</given-names>
</name>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Warren</surname>
<given-names>Cirle A.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Buck</surname>
<given-names>Gregory A.</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guerrant</surname>
<given-names>Richard L.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>Department of Pathology, The University of Chicago, Chicago, Illinois, United States of America</addr-line>
</aff>
<aff id="aff005"><label>5</label>
<addr-line>Departments of Pathology and Medicine—Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Vinetz</surname>
<given-names>Joseph M.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of California San Diego School of Medicine, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="conflict" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: LAB DTB GLK JKR CAW GAB RLG. Performed the experiments: LAB DTB GLK JKR EIZ AML FJN CAC JHM. Analyzed the data: LAB DTB GLK JKR EIZ AML JRT CAW RLG. Contributed reagents/materials/analysis tools: LAB AML JRT CAW GAB RLG. Wrote the paper: LAB DTB GLK JKR JRT CAW RLG. Contributed to final manuscript revisions: LAB DTB GLK EIZ AML FJN CAC JHM JRT CAW GAB RLG.</p>
</fn>
<corresp id="cor001">* E-mail: <email>luther_bartelt@med.unc.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>28</day>
<month>7</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><month>7</month>
<year>2016</year>
</pub-date>
<volume>10</volume>
<issue>7</issue>
<elocation-id>e0004820</elocation-id>
<history><date date-type="received"><day>28</day>
<month>1</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>11</day>
<month>6</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© 2016 Bartelt et al</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Bartelt et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="pntd.0004820.pdf"></self-uri>
<abstract><p><italic>Cryptosporidium</italic>
is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of <italic>C</italic>
. <italic>parvum</italic>
oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to <italic>C</italic>
. <italic>parvum</italic>
challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to <italic>Cryptosporidium</italic>
, priming with <italic>C</italic>
. <italic>parvum</italic>
(10<sup>6</sup>
oocysts) provides robust protective immunity against re-challenge despite ongoing PM. <italic>C</italic>
. <italic>parvum</italic>
priming restores mucosal Th1-type effectors (CD3<sup>+</sup>
CD8<sup>+</sup>
CD103<sup>+</sup>
T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with <italic>Cryptosporidium</italic>
antigens expressed in the <italic>S</italic>
. Typhi vector 908<italic>htr</italic>
, however, do not enhance Th1-type responses to <italic>C</italic>
. <italic>parvum</italic>
challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated <italic>S</italic>
. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate <italic>C</italic>
. <italic>parvum</italic>
severity during PM, but neither as effectively as viable <italic>C</italic>
. <italic>parvum</italic>
priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to <italic>C</italic>
. <italic>parvum</italic>
, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically <italic>C</italic>
. <italic>parvum</italic>
priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of <italic>Cryptosporidium</italic>
immunity and future vaccine strategies in malnourished children.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p><italic>Cryptosporidium</italic>
attributable morbidities in malnourished children are increasingly recognized. Exactly how malnutrition interferes with host mucosal immunity to diarrheal pathogens and mucosal vaccine responses remains unclear. Dissecting these interactions in an experimental model of cryptosporidiosis can uncover new insights into novel therapeutic approaches against a pathogen for which effective therapies and vaccines are currently unavailable. We demonstrate that although malnutrition diminishes baseline (primary) Th1-type mucosal immunity these deficits can be partially overcome via non-specific mucosal strategies (<italic>S</italic>
. Typhi and CpG) and completely restored after a sub-clinical (low-dose) exposure to viable <italic>C</italic>
. <italic>parvum</italic>
. These results add insight into preventive strategies to help alleviate <italic>Cryptosporidium</italic>
-specific diarrhea in children in low-resource settings and abrogate prolonged post-infection sequelae.</p>
</abstract>
<funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000060</institution-id>
<institution>National Institute of Allergy and Infectious Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>U54 AI57168</award-id>
<principal-award-recipient><name><surname>Guerrant</surname>
<given-names>Richard L.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000060</institution-id>
<institution>National Institute of Allergy and Infectious Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>K08 AI108730-01</award-id>
<principal-award-recipient><name><surname>Bartelt</surname>
<given-names>Luther A.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award003"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000060</institution-id>
<institution>National Institute of Allergy and Infectious Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>U19 AI109776</award-id>
<principal-award-recipient><name><surname>Guerrant</surname>
<given-names>Richard L.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award004"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000062</institution-id>
<institution>National Institute of Diabetes and Digestive and Kidney Diseases (US)</institution>
</institution-wrap>
</funding-source>
<award-id>R01-DK68271</award-id>
<principal-award-recipient><name><surname>Turner</surname>
<given-names>Jerrold R.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award005"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000865</institution-id>
<institution>Bill and Melinda Gates Foundation (US)</institution>
</institution-wrap>
</funding-source>
<award-id>OPP1066140</award-id>
<principal-award-recipient><name><surname>Guerrant</surname>
<given-names>Richard L.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award006"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000865</institution-id>
<institution>Bill and Melinda Gates Foundation</institution>
</institution-wrap>
</funding-source>
<award-id>OPP1137923</award-id>
<principal-award-recipient><name><surname>Guerrant</surname>
<given-names>Richard L.</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>This work was supported in part by the following NIH grants: NIAID Mid-Atlantic Regional Center of Excellence U54 AI57168 (RLG and GB), NIAID Centers for Excellence for Translational Research U19 AI109776 (RLG; Myron Levine University of Maryland, Principal Investigator), and NIAID K08-AI108730-01 (LAB), NIDDK grant R01-DK68271 (JRT), and the Bill and Melinda Gates Foundation OPP1066140 (RLG and JRT) and OPP1137923 (RLG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="9"></fig-count>
<table-count count="0"></table-count>
<page-count count="29"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Caroline du Nord</li>
<li>Illinois</li>
<li>Massachusetts</li>
<li>Virginie</li>
</region>
<settlement><li>Chapel Hill (Caroline du Nord)</li>
</settlement>
<orgName><li>Université de Caroline du Nord à Chapel Hill</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Bartelt, Luther A" sort="Bartelt, Luther A" uniqKey="Bartelt L" first="Luther A." last="Bartelt">Luther A. Bartelt</name>
</region>
<name sortKey="Bolick, David T" sort="Bolick, David T" uniqKey="Bolick D" first="David T." last="Bolick">David T. Bolick</name>
<name sortKey="Buck, Gregory A" sort="Buck, Gregory A" uniqKey="Buck G" first="Gregory A." last="Buck">Gregory A. Buck</name>
<name sortKey="Cowardin, Carrie A" sort="Cowardin, Carrie A" uniqKey="Cowardin C" first="Carrie A." last="Cowardin">Carrie A. Cowardin</name>
<name sortKey="Guerrant, Richard L" sort="Guerrant, Richard L" uniqKey="Guerrant R" first="Richard L." last="Guerrant">Richard L. Guerrant</name>
<name sortKey="Kolling, Glynis L" sort="Kolling, Glynis L" uniqKey="Kolling G" first="Glynis L." last="Kolling">Glynis L. Kolling</name>
<name sortKey="Lara, Ana M" sort="Lara, Ana M" uniqKey="Lara A" first="Ana M." last="Lara">Ana M. Lara</name>
<name sortKey="Moore, John H" sort="Moore, John H" uniqKey="Moore J" first="John H." last="Moore">John H. Moore</name>
<name sortKey="Noronha, Francisco Jose" sort="Noronha, Francisco Jose" uniqKey="Noronha F" first="Francisco Jose" last="Noronha">Francisco Jose Noronha</name>
<name sortKey="Roche, James K" sort="Roche, James K" uniqKey="Roche J" first="James K." last="Roche">James K. Roche</name>
<name sortKey="Turner, Jerrold R" sort="Turner, Jerrold R" uniqKey="Turner J" first="Jerrold R." last="Turner">Jerrold R. Turner</name>
<name sortKey="Turner, Jerrold R" sort="Turner, Jerrold R" uniqKey="Turner J" first="Jerrold R." last="Turner">Jerrold R. Turner</name>
<name sortKey="Warren, Cirle A" sort="Warren, Cirle A" uniqKey="Warren C" first="Cirle A." last="Warren">Cirle A. Warren</name>
<name sortKey="Zaenker, Edna I" sort="Zaenker, Edna I" uniqKey="Zaenker E" first="Edna I." last="Zaenker">Edna I. Zaenker</name>
</country>
</tree>
</affiliations>
</record>
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