The evolutionary history of ACE2 usage within the coronavirus subgenus Sarbecovirus

SARS-CoV-1 and SARS-CoV-2 are not phylogenetically closely related;however, both use the ACE2 receptor in humans for cell entry. This is not a universal sarbecovirus trait;for example, many known sarbecoviruses related to SARS-CoV-1 have two deletions in the receptor binding domain of the spike protein that render them incapable of using human ACE2. Here, we report three novel sarbecoviruses from Rwanda and Uganda which are phylogenetically intermediate to SARS-CoV-1 and SARS-CoV-2 and demonstrate via in vitro studies that they are also unable to utilize human ACE2. Furthermore, we show that the observed pattern of ACE2 usage among sarbecoviruses is most likely due to recombination. We show that the lineage that includes SARS-CoV-2 is most likely the ancestral ACE2-using lineage, and that recombination with at least one virus from this group conferred ACE2 usage to the progenitor of SARS-CoV-1 at some time in the past. We argue that alternative scenarios such as convergent evolution are much less parsimonious;we show that biogeography and patterns of host tropism support the plausibility of a recombination scenario;and we propose a competitive release hypothesis to explain how this recombination event could have occurred and why it is evolutionarily advantageous. The findings provide important insights into the natural history of ACE2 usage for both SARS-CoV-1 and SARS-CoV-2, and a greater understanding of the evolutionary mechanisms that shape zoonotic potential of coronaviruses. This study also underscores the need for increased surveillance for sarbecoviruses in southwestern China, where most ACE2-using viruses have been found to date, as well as other regions including Africa, where these viruses have only recently been discovered.

The evolutionary history of ACE2 usage within the coronavirus subgenus Sarbecovirus.

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 are not phylogenetically closely related; however, both use the angiotensin-converting enzyme 2 (ACE2) receptor in humans for cell entry. This is not a universal sarbecovirus trait; for example, many known sarbecoviruses related to SARS-CoV-1 have two deletions in the receptor binding domain of the spike protein that render them incapable of using human ACE2. Here, we report three sequences of a novel sarbecovirus from Rwanda and Uganda that are phylogenetically intermediate to SARS-CoV-1 and SARS-CoV-2 and demonstrate via in vitro studies that they are also unable to utilize human ACE2. Furthermore, we show that the observed pattern of ACE2 usage among sarbecoviruses is best explained by recombination not of SARS-CoV-2, but of SARS-CoV-1 and its relatives. We show that the lineage that includes SARS-CoV-2 is most likely the ancestral ACE2-using lineage, and that recombination with at least one virus from this group conferred ACE2 usage to the lineage including SARS-CoV-1 at some time in the past. We argue that alternative scenarios such as convergent evolution are much less parsimonious; we show that biogeography and patterns of host tropism support the plausibility of a recombination scenario, and we propose a competitive release hypothesis to explain how this recombination event could have occurred and why it is evolutionarily advantageous. The findings provide important insights into the natural history of ACE2 usage for both SARS-CoV-1 and SARS-CoV-2 and a greater understanding of the evolutionary mechanisms that shape zoonotic potential of coronaviruses. This study also underscores the need for increased surveillance for sarbecoviruses in southwestern China, where most ACE2-using viruses have been found to date, as well as other regions such as Africa, where these viruses have only recently been discovered.

Using a One Health approach to chart a path out of the Pandemic Era

Threats posed by pandemics and epidemics are now clear to every household around the world. A single lethal microbe can emerge suddenly and spread rapidly to every community without regard to national borders or to social and economic standing. The SARS, Ebola and Zika outbreaks did little to prepare us for the COVID-19 pandemic sweeping the world, which serves as a clarion call that we are vulnerable to emerging viral threats. Since the mid-20th Century, new and deadly diseases have emerged at an alarming rate in animals and people, and the threats from this vast pool of unknown viruses are accelerating exponentially, driven by our expanding population and an increasingly interconnected world. After a decade of employing a One Health approach to viral detection, discovery and characterization, we can reasonably estimate that there are >500,000 zoonotic viruses, about which we know nothing or very little, that have the potential to spill over from evolutionary host species to vulnerable ones and cause disease. We know how to identify nearly all of the viral diversity in every species and can begin to rank the risks of these viruses for interspecies transmission. Understanding the disease threats and developing mitigation strategies to prevent infection and spread of viruses are key to preventing future devastating pandemics. The Global Virome Project is a strategic response to the growing need to better predict, prevent and respond to future viral pandemic threats, and toprotect us all from their worst consequences. By bringing health professionals and scientists from many disciplines together to share protocols and data under one umbrella, a global consortium can be established to implement a joint coordinated effort, whereby countries will gain the benefits of shared global and regional virus identification and disease mitigation strategies, while maintaining autonomy to respond to local needs.