Identifying zoonotic origin of SARS-CoV-2 by modeling the binding affinity between Spike receptor-binding domain and host ACE2

Abstract

Despite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that the recognition of the binding ACE2 proteins is the first step for the coronaviruses to invade host cells, we proposed a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated on the modeled Spike-RBD/ACE2 complex structures correlate closely with the effectiveness of animal infections as determined by multiple experimental datasets. Built on the optimized binding affinity cutoff, we suggested a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggested a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation; but more importantly, it proposed a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.

Predicting the zoonotic capacity of mammals to transmit SARS-CoV-2

“…For instance, in pigs ( Sus scrofa ) this study along with multiple other computational and experimental studies predicted susceptibility to SARS-CoV-2 (Figure 1), but this prediction has not been supported by results from whole animal inoculations, which so far have showed unproductive infection 38,53 . As an example of how methods influence predictions, our model incorporating both molecular structure and species traits generally estimated weaker binding strengths for cetaceans, and high probabilities for catarrhine primates compared to other studies that employed different structural modeling methods 27,28,30 .…”

“…Our model combined species traits and viral binding strength to predict zoonotic capacity (susceptibility and onward transmission), which was defined as a threshold value based on experimental studies confirming intraspecific transmission among animals, and is therefore more conservative than thresholds adopted by other studies (e.g., based on binding strength, 30 ). In addition, our modeling approach (machine learning) and prediction targets (zoonotic capacity) differed compared to existing computational approaches, which applied sequence-based or structure-based analyses constrained by the small number of published ACE2 sequences.…”

Is the Origin and Emergence of SARS-CoV-2 Ingenuous?

“…As a consequence, the ecological barrier between man and the reservoirs of several known or unknown diseases are getting narrower, thereby changing the transmission dynamics of these diseases. 1,2 The emergence of the novel coronavirus (SARS-CoV-2) might not be an exception to this as postulated by several groups of scientists. 2,3 Further, in today's highly globalised and wellconnected world, the transfer and transport of pathogens and reservoir hosts is not unusual.…”

“…1,2 The emergence of the novel coronavirus (SARS-CoV-2) might not be an exception to this as postulated by several groups of scientists. 2,3 Further, in today's highly globalised and wellconnected world, the transfer and transport of pathogens and reservoir hosts is not unusual. Consequently, emerging infectious diseases, such as COVID-19, are spreading like wildfire.…”

Variations in cell-surface ACE2 levels alter direct binding of SARS-CoV-2 Spike protein and viral infectivity: Implications for measuring Spike protein interactions with animal ACE2 orthologs

“…Even though ACE2 is a well conserved protein across the vertebrate clade, human polymorphisms have been documented [10], and ACE2 orthologs from different animals have unique amino acid sequences, which potentially alter the ability of a particular S-protein to bind to specific cells [11,12]. The difference in ACE2 orthologs is thought to be a potential mechanism by which certain species appear to be protected from infection, or how other species can act as an intermediate when SARS-like coronavirus's transition between host species [13,14].…”