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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Dromedary MERS-CoV replicates in human respiratory tissues</title>
<author><name sortKey="Reperant, Leslie A" sort="Reperant, Leslie A" uniqKey="Reperant L" first="Leslie A" last="Reperant">Leslie A. Reperant</name>
<affiliation><nlm:aff id="aff1">Artemis One Health Research Foundation, Yalelaan 1, 3584 CL Utrecht, Netherlands</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D M E" last="Osterhaus">Albert D M E. Osterhaus</name>
<affiliation><nlm:aff id="aff1">Artemis One Health Research Foundation, Yalelaan 1, 3584 CL Utrecht, Netherlands</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands</nlm:aff>
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<idno type="doi">10.1016/S2213-2600(14)70184-5</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Dromedary MERS-CoV replicates in human respiratory tissues</title>
<author><name sortKey="Reperant, Leslie A" sort="Reperant, Leslie A" uniqKey="Reperant L" first="Leslie A" last="Reperant">Leslie A. Reperant</name>
<affiliation><nlm:aff id="aff1">Artemis One Health Research Foundation, Yalelaan 1, 3584 CL Utrecht, Netherlands</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D M E" last="Osterhaus">Albert D M E. Osterhaus</name>
<affiliation><nlm:aff id="aff1">Artemis One Health Research Foundation, Yalelaan 1, 3584 CL Utrecht, Netherlands</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">The Lancet. Respiratory Medicine</title>
<idno type="ISSN">2213-2600</idno>
<idno type="eISSN">2213-2619</idno>
<imprint><date when="2014">2014</date>
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</author>
<author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name>
</author>
<author><name sortKey="Muller, Ma" uniqKey="Muller M">MA Muller</name>
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<biblStruct><analytic><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name>
</author>
<author><name sortKey="Al Dhahiry, Sh" uniqKey="Al Dhahiry S">SH Al Dhahiry</name>
</author>
<author><name sortKey="Reusken, Cb" uniqKey="Reusken C">CB Reusken</name>
</author>
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<biblStruct><analytic><author><name sortKey="Alagaili, An" uniqKey="Alagaili A">AN Alagaili</name>
</author>
<author><name sortKey="Briese, T" uniqKey="Briese T">T Briese</name>
</author>
<author><name sortKey="Mishra, N" uniqKey="Mishra N">N Mishra</name>
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<biblStruct><analytic><author><name sortKey="Chan, Rwy" uniqKey="Chan R">RWY Chan</name>
</author>
<author><name sortKey="Hemida, Mg" uniqKey="Hemida M">MG Hemida</name>
</author>
<author><name sortKey="Kayali, G" uniqKey="Kayali G">G Kayali</name>
</author>
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<biblStruct><analytic><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name>
</author>
<author><name sortKey="Mou, H" uniqKey="Mou H">H Mou</name>
</author>
<author><name sortKey="Smits, Sl" uniqKey="Smits S">SL Smits</name>
</author>
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</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, W" uniqKey="Li W">W Li</name>
</author>
<author><name sortKey="Moore, Mj" uniqKey="Moore M">MJ Moore</name>
</author>
<author><name sortKey="Vasilieva, N" uniqKey="Vasilieva N">N Vasilieva</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name>
</author>
<author><name sortKey="Zheng, Bj" uniqKey="Zheng B">BJ Zheng</name>
</author>
<author><name sortKey="He, Yq" uniqKey="He Y">YQ He</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, W" uniqKey="Li W">W Li</name>
</author>
<author><name sortKey="Zhang, C" uniqKey="Zhang C">C Zhang</name>
</author>
<author><name sortKey="Sui, J" uniqKey="Sui J">J Sui</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Reperant, La" uniqKey="Reperant L">LA Reperant</name>
</author>
<author><name sortKey="Kuiken, T" uniqKey="Kuiken T">T Kuiken</name>
</author>
<author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name>
</author>
</analytic>
</biblStruct>
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<pmc article-type="discussion"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Lancet Respir Med</journal-id>
<journal-id journal-id-type="iso-abbrev">Lancet Respir Med</journal-id>
<journal-title-group><journal-title>The Lancet. Respiratory Medicine</journal-title>
</journal-title-group>
<issn pub-type="ppub">2213-2600</issn>
<issn pub-type="epub">2213-2619</issn>
<publisher><publisher-name>Elsevier Ltd.</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25174550</article-id>
<article-id pub-id-type="pmc">7128619</article-id>
<article-id pub-id-type="publisher-id">S2213-2600(14)70184-5</article-id>
<article-id pub-id-type="doi">10.1016/S2213-2600(14)70184-5</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Dromedary MERS-CoV replicates in human respiratory tissues</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="au10"><name><surname>Reperant</surname>
<given-names>Leslie A</given-names>
</name>
<email>l.reperant@erasmusmc.nl</email>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="aff2" ref-type="aff">b</xref>
</contrib>
<contrib contrib-type="author" id="au20"><name><surname>Osterhaus</surname>
<given-names>Albert D M E</given-names>
</name>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="aff2" ref-type="aff">b</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>a</label>
Artemis One Health Research Foundation, Yalelaan 1, 3584 CL Utrecht, Netherlands</aff>
<aff id="aff2"><label>b</label>
Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands</aff>
<pub-date pub-type="pmc-release"><day>28</day>
<month>8</month>
<year>2014</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>10</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>28</day>
<month>8</month>
<year>2014</year>
</pub-date>
<volume>2</volume>
<issue>10</issue>
<fpage>779</fpage>
<lpage>781</lpage>
<permissions><copyright-statement>Copyright © 2014 Elsevier Ltd. All rights reserved.</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Elsevier Ltd</copyright-holder>
<license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights 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 free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p>
</license>
</permissions>
<related-article related-article-type="article-reference" id="d32e255" ext-link-type="doi" xlink:href="10.1016/S2213-2600(14)70158-4"></related-article>
</article-meta>
</front>
<body><p id="para10">Since its discovery in the autumn of 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has caused more than 800 laboratory-confirmed cases of human infection, with a case-fatality rate of about a third.<xref rid="bib1" ref-type="bibr"><sup>1</sup>
</xref>
Patients admitted to hospital with MERS are characterised by symptoms of severe pneumonia, often accompanied by renal failure. However, mild and asymptomatic infections have been reported, especially in secondary cases. Dromedary camels have been identified as the putative source of human MERS-CoV infections, although nosocomial transmission is increasingly reported. So far, all cases of human MERS-CoV infection were identified in Middle Eastern countries, or in individuals who had recently travelled from that area.</p>
<p id="para20">At present, endeavours to control this emerging pathogen target two main efforts. First, identification of the source of zoonotic MERS-CoV infections might guide control strategies at the human–animal interface. Second, source and contact tracing in combination with hygiene and isolation measures will restrict human-to-human transmission of MERS-CoV. Although MERS-CoV is phylogenetically related to bat β-coronaviruses, epidemiological investigations have provided evidence that contact with livestock, especially dromedary camels, represents a risk factor for infection; serological and virological data have shown the circulation of MERS-CoV in dromedary camels in the Middle East and beyond.<xref rid="bib2" ref-type="bibr">2</xref>
, <xref rid="bib3" ref-type="bibr">3</xref>
, <xref rid="bib4" ref-type="bibr">4</xref>
</p>
<p id="para30">In <italic>The Lancet Respiratory Medicine,</italic>
Renee Chan and colleagues<xref rid="bib5" ref-type="bibr"><sup>5</sup>
</xref>
provide additional support for the putative role of dromedary camels as the direct source of MERS-CoV infections in human beings, by showing that Saudi and Egyptian isolates of MERS-CoV from dromedary camels replicate in tissues of the human respiratory tract. MERS-CoV isolates from Saudi Arabia were phylogenetically closely related to human isolates, whereas those from Egypt were genetically divergent from previously characterised MERS-CoV isolates. Nonetheless, MERS-CoV isolates of either origin replicated in primate cell cultures and in human bronchus and lung explants at similar levels as did a human MERS-CoV isolate. The tropism of both dromedary camel and human MERS-CoV isolates included bronchial non-ciliated epithelial cells, alveolar type II pneumocytes, and lung endothelial cells, in accordance with the distribution of the MERS-CoV cellular receptor, dipeptidyl-peptidase-4.<xref rid="bib6" ref-type="bibr"><sup>6</sup>
</xref>
The MERS-CoV viruses studied were all weak inducers of innate immune responses in a human cell line, further suggesting phenotypic similarities between camel and human MERS-CoV viruses.</p>
<p id="para40">Severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in China about a decade ago, was also related to bat β-coronaviruses. Angiotensin-converting enzyme 2 (ACE2) was identified as its functional receptor.<xref rid="bib7" ref-type="bibr"><sup>7</sup>
</xref>
Wild carnivores sold at live-animal markets for human consumption were implicated as intermediary hosts for SARS-CoV between bats and human beings. These animals included masked palm civets (<italic>Paguma larvata</italic>
), raccoon dogs (<italic>Nyctereutes procyonoides</italic>
), and Chinese ferret badgers (<italic>Melogale moschata</italic>
).<xref rid="bib8" ref-type="bibr"><sup>8</sup>
</xref>
The spike proteins of SARS-CoVs isolated from these animals and from early zoonotic cases mediated more efficiently infection of cells expressing palm-civet ACE2 than infection of cells expressing human ACE2.<xref rid="bib9" ref-type="bibr"><sup>9</sup>
</xref>
Subsequent evolution of the receptor-binding domain of SARS-CoV spike protein enhanced SARS-CoV infection efficiency of human cells, probably contributing to its increased human-to-human transmissibility, resulting in the emergence of a pandemic threat.</p>
<p id="para50">The tropism of both dromedary camel and human MERS-CoV for the human lower respiratory tract could well account for the alveolar damage and pneumonia in severe human cases. However, naturally infected camels apparently show little disease.<xref rid="bib3" ref-type="bibr"><sup>3</sup>
</xref>
Studies of the pathogenesis of MERS-CoV infection in camels are awaited to identify possible differences in within-host virus distribution patterns between the animal and human hosts, as was reported for SARS-CoV.<xref rid="bib9" ref-type="bibr"><sup>9</sup>
</xref>
Ex-vivo cultures of, for example, lung slices are useful and could be further standardised for quantitative assessment of virus tropism. Because MERS-CoV seems to be endemic in dromedary camels, such differences could provide clues about their ability to be transmitted within and between species. One remarkable difference between SARS-CoV and MERS-CoV is in their tropism within the human respiratory tract, targeting ciliated and non-ciliated epithelial cells, respectively. Interestingly, a similar difference in tropism between human and zoonotic influenza A viruses correlates with their transmissibility among human beings.<xref rid="bib10" ref-type="bibr"><sup>10</sup>
</xref>
</p>
<p id="para60">After the outbreak of SARS, global collaboration under WHO guidance (initiated in March, 2003) resulted in the identification of SARS-CoV as the causative agent within a month. This knowledge allowed the implementation of effective intervention strategies that terminated chains of human-to-human transmission and the associated pandemic threat within 3 months. The functional receptor of the SARS-CoV was identified soon thereafter,<xref rid="bib7" ref-type="bibr"><sup>7</sup>
</xref>
leading to improved understanding of the pathogenesis of SARS-CoV infection and its evolution towards efficient human-to-human transmissibility. A decade later, MERS-CoV was identified as the aetiological agent of MERS within 2 weeks of the discovery of the new illness. Its receptor was also reported soon thereafter.<xref rid="bib6" ref-type="bibr"><sup>6</sup>
</xref>
Reported human-to-human transmission of MERS-CoV in household and health-care settings is worryingly reminiscent of the situation at the start of the SARS epidemic. Building on lessons learned from the successful combat against the emerging SARS pandemic, studies such as that reported by Chan and colleagues—addressing questions about MERS-CoV pathogenesis and epidemiology at the human–animal interface—could well contribute to an equally successful interruption of the emerging MERS epidemic, one step ahead of its development into a pandemic threat.</p>
<p id="para70"><fig id="f10"><graphic xlink:href="fx1"></graphic>
<permissions><copyright-statement>© 2014 Bjorn Svensson/Science Photo Library</copyright-statement>
<copyright-year>2014</copyright-year>
<license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights 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 free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p>
</license>
</permissions>
</fig>
</p>
</body>
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<ack><p>ADMEO reports a patent, owned by Erasmus Medical Centre regarding MERS-CoV pending as a co-inventor. LAR declares no competing interests.</p>
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</back>
</pmc>
</record>
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