Correlating Cell Line Studies With Tissue Distribution of DPP4/TMPRSS2 and Human Biological Samples May Better Define the Viral Tropism of MERS-CoV
Identifieur interne : 000871 ( Pmc/Corpus ); précédent : 000870; suivant : 000872Correlating Cell Line Studies With Tissue Distribution of DPP4/TMPRSS2 and Human Biological Samples May Better Define the Viral Tropism of MERS-CoV
Auteurs : Melvin Khee-Shing LeowSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2013.
Url:
DOI: 10.1093/infdis/jit330
PubMed: 23878322
PubMed Central: 7107381
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Infect Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Infect. Dis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-title-group><journal-title>The Journal of Infectious Diseases</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher><publisher-name>Oxford University Press</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23878322</article-id>
<article-id pub-id-type="pmc">7107381</article-id>
<article-id pub-id-type="doi">10.1093/infdis/jit330</article-id>
<article-id pub-id-type="publisher-id">jit330</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Correspondence</subject>
</subj-group>
</article-categories>
<title-group><article-title>Correlating Cell Line Studies With Tissue Distribution of DPP4/TMPRSS2 and Human Biological Samples May Better Define the Viral Tropism of MERS-CoV</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Leow</surname>
<given-names>Melvin Khee-Shing</given-names>
</name>
<xref ref-type="aff" rid="d792295e38"></xref>
<pmc-comment>melvin_leow@ttsh.com.sg </pmc-comment>
<xref ref-type="corresp" rid="d792309e50"></xref>
</contrib>
</contrib-group>
<aff id="d792295e38"><addr-line>Department of Endocrinology</addr-line>
,<institution>Tan Tock Seng Hospital</institution>
,<country>Singapore</country>
</aff>
<author-notes><corresp id="d792309e50">Correspondence: Melvin K.S. Leow, MBBS, MMed(Int Med), MSc, PhD, FAMS, FACE, FACP, FRCP(Edin), Department of Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433 (<email>melvin_leow@ttsh.com.sg</email>
).</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>10</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub" iso-8601-date="2013-07-21"><day>21</day>
<month>7</month>
<year>2013</year>
</pub-date>
<volume>208</volume>
<issue>8</issue>
<fpage>1350</fpage>
<lpage>1351</lpage>
<history><date date-type="received"><day>6</day>
<month>5</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>13</day>
<month>6</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: <email>journals.permissions@oup.com</email>
.</copyright-statement>
<copyright-year>2013</copyright-year>
<license><license-p>This article is made available via the PMC Open Access Subset for unrestricted 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 COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.</license-p>
</license>
</permissions>
<self-uri xlink:href="jit330.pdf"></self-uri>
<related-article related-article-type="letter" id="RA1" vol="208" page="1351" xlink:href="23878323" ext-link-type="pubmed"></related-article>
</article-meta>
</front>
<body><p>T<sc>o</sc>
T<sc>he</sc>
E<sc>ditor</sc>
—A decade after the severe acute respiratory syndrome (SARS) epidemic caused by the notorious SARS-coronavirus (CoV), it is disconcerting that a novel human coronavirus, Middle East respiratory syndrome (MERS)-CoV, has eerily emerged in the Middle East with a threat to exact yet another grim toll on humankind. It is indeed timely to find a paper published in the recent issue of the <italic>Journal of Infectious Diseases</italic>
by Chan et al describing the wide tissue tropism of MERS-CoV across a range of human and nonhuman cell lines and its rapidity of induction of cytopathic effects in an attempt to explain the apparently high fatality rate encountered [<xref rid="JIT330C1" ref-type="bibr">1</xref>
].</p>
<p>At least 3 issues should be considered in the implications of their findings. First, endocrine tissues such as adrenal or pituitary cell lines were conspicuously unrepresented in their list. Previously, we showed that a sizeable proportion of SARS patients had evidence of disordered cortisol secretion that had conceivably contributed to mortality [<xref rid="JIT330C2" ref-type="bibr">2</xref>
]. Thus, it is of paramount importance to suspect that MERS-CoV could share a similar predilection for the hypothalamus–pituitary–adrenal axis.</p>
<p>Second, the authors did not address the mechanisms of cell entry by MERS-CoV into tissue cultures. As the specificity of the coronavirus-host tissue receptors governs cell invasion and determines the sites of organ pathogenicity, research in this area in the wake of their findings should be a priority. Notably, a group has recently established a hitherto uncharacterized surface receptor targeted by the viral spike-protein of the Human Coronavirus-Erasmus Medical Center (HCoV-EMC) for protease-activated cellular entry mediated by type II transmembrane serine proteases (TMPRSS2) potentially exploitable for antiviral intervention [<xref rid="JIT330C3" ref-type="bibr">3</xref>
]. Close on the heel of this discovery came the findings of Raj et al [<xref rid="JIT330C4" ref-type="bibr">4</xref>
] who independently unraveled yet another critical lead on the same puzzle. Apparently, MERS-CoV also capitalizes on dipeptidyl-peptidase 4 (DPP4) as a key portal of entry into cells. Interestingly, DPP4 has an uncanny dual nature, being an immunologic signaling glycoprotein component cluster of differentiation-26 on T cells [<xref rid="JIT330C5" ref-type="bibr">5</xref>
] as well as an enzyme best known for its catalytic affinity on incretins from which DPP4-inhibitor therapy was developed as an additional sword in the arsenal against the diabetes “pandemic” [<xref rid="JIT330C6" ref-type="bibr">6</xref>
].</p>
<p>Although the data are compelling, it is premature to assume that this new villain capitalizes on no other receptors, given that much remains unknown in the face of this looming outbreak. It would bode us well to remember the cautionary tale that even though the most poignant assault of SARS-CoV was on the lungs, other organs including the endocrine system bore the hallmarks of collateral damage [<xref rid="JIT330C7" ref-type="bibr">7</xref>
]. SARS-CoV employs a variant of the angiotensin-converting enzyme known as ACE2 for cell entry [<xref rid="JIT330C7" ref-type="bibr">7</xref>
]. However, ACE2 was not the sole receptor, as the organ distribution of SARS-CoV provided clues to a second receptor called CD209L that was also shown to facilitate its cellular invasion [<xref rid="JIT330C8" ref-type="bibr">8</xref>
]. While both TMPRSS2 and DPP4 are functionally serine proteases, they are unequivocally different molecules encoded by distinct genes on separate chromosomal loci (21q22.3 and 2q24.3, respectively). TMPRSS2 exhibits tissue distributions (aerodigestive tract) [<xref rid="JIT330C9" ref-type="bibr">9</xref>
] that are different from those of DPP4 (endothelial membranes of most organs including the liver, pancreas, and kidneys) [<xref rid="JIT330C10" ref-type="bibr">10</xref>
]. Because viral tropism is ultimately constrained by engagement of the virus with specific cellular receptors/coreceptors, it is prudent to investigate for the existence of other receptors co-utilized by MERS-CoV, which is hinted at by the broad array of cell types shown by Chan et al to be affected before our new enemy gains further ground.</p>
<p>Finally, the extrapolation of data from such human cell lines to tissues of the intact human host is often fraught with difficulties. Hence, tissue culture tropism may depart significantly from the actual sites of organ involvement and correlate imperfectly with clinical manifestation in afflicted patients. Whenever possible, tissue samples from bodily fluids, organ biopsies of patients, and even necropsies obtained from a thorough autopsy study of those who succumbed to MERS-CoV infection will be insightful to better define the repertoire and tissue distribution of relevant target receptors involved. After all, there is no wisdom in hindsight from the SARS epidemic if it does not extend our foresight further in the face of this present novel MERS-CoV outbreak.</p>
</body>
<back><ack><title>Note</title>
<p><bold><italic>Potential conflicts of interest.</italic>
</bold>
Author certifies no conflicts of interest.</p>
<p>The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. I do not have a commercial or other association that might pose a conflict of interest.</p>
</ack>
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