Correlating Cell Line Studies With Tissue Distribution of DPP4/TMPRSS2 and Human Biological Samples May Better Define the Viral Tropism of MERS-CoV

TO THE EDITOR—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 Journal of Infectious Diseases 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 [1]. 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 [2]. Thus, it is of paramount importance to suspect that MERS-CoV could share a similar predilection for the hypothalamus–pituitary–adrenal axis. 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 CoronavirusErasmus Medical Center (HCoV-EMC) for protease-activated cellular entry mediated by type II transmembrane serine proteases (TMPRSS2) potentially exploitable for antiviral intervention [3]. Close on the heel of this discovery came the findings of Raj et al [4] 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 [5] 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” [6].