Human endemic coronavirus emergence in the context of past and recent zoonotic outbreaks

Abstract Understanding the evolutionary dynamics of the four human endemic coronaviruses might provide insight into the future trajectories of SARS-CoV-2 evolution. We re-assessed the timing of endemic coronavirus emergence and we show that all viruses entered human populations in a time-frame ranging from ~500 to 55 years ago. Because the three highly pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) spilled-over in tight temporal succession, the pattern of coronavirus emergence, in analogy to that of influenza pandemics, is highly irregular. To contextualize this observation in a wider perspective of viral diseases emergence since 1945, we mined epidemiology database information. After controlling for reporting bias, we find that, contrary to widespread beliefs, the occurrence of viral diseases (either zoonotic or not) has not increased over the last decades. Analysis of the recent and ongoing evolution of HCoV-229E and HCoV-OC43 indicated that positive selection most likely contributed to fine-tune the interaction with the human interferon/inflammatory response. Conversely, integration of evolutionary inference and molecular dating provided evidence that these viruses are not undergoing antigenic drift and the temporal emergence of spike protein variants is best explained by optimization of receptor binding affinity. These data provide a fresh look on viral disease emergence and on coronavirus evolution.