Forty years with coronaviruses

Weiss, Susan R.

In addition to viral glycoprotein cleavages impacting tropism, defining the cellular receptor used by each coronavirus has also informed our understanding of infection. In 1991, Kathryn Holmes identified the MHV receptor as CEACAM1a (MHVR), a carcinoembryonic antigen family member (Williams et al., 1991) , one of the earliest identified viral receptors. Subsequently, ACE2 for SARS-CoV and DPP4 for MERS were identified as receptors, and within only a short period of time, it was found that ACE2 is also used by SARS-CoV-2 (Zhou et al., 2020) . However, while understanding the expression pattern of the receptor can define which cells can be infected, it does not mean all cells that express the receptor or even the cells with the highest expression are the major targets. This is exemplified by MHV studies in which the receptor, MHVR, is expressed highly in the liver but at barely detectable levels in neurons. In contrast, during infection, the MHV strain JHM.SD is highly neurovirulent and cannot replicate in the liver (Bender et al., 2010) . We devoted considerable time and energy to mapping viral tropism in vivo and virulence factors that contributed to pathogenesis. Perhaps surprisingly, our studies showed it was not only the spike protein that impacted tissue tropism; other "background genes," including nucleocapsid and replicase, as well as accessory genes, were also important determinants of tropism (reviewed in Weiss and Leibowitz, 2011) . Therefore, one cannot infer pathogenesis from knowledge of the spike protein and receptor alone. Future studies on SARS-CoV-2 will define tissue tropism and whether it parallels SARS-CoV or not.