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

 

Ilya R. Fischhoff†

, 

Adrian A. Castellanos†

, 

João P. G. L. M. Rodrigues

, 

Arvind Varsani

 and 

Barbara A. Han

DOI: https://doi.org/10.1098/rspb.2021.1651

PDF: https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2021.1651

Abstract

Back and forth transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between humans and animals will establish wild reservoirs of virus that endanger long-term efforts to control COVID-19 in people and to protect vulnerable animal populations. Better targeting surveillance and laboratory experiments to validate zoonotic potential requires predicting high-risk host species. A major bottleneck to this effort is the few species with available sequences for angiotensin-converting enzyme 2 receptor, a key receptor required for viral cell entry. We overcome this bottleneck by combining species' ecological and biological traits with three-dimensional modelling of host-virus protein–protein interactions using machine learning. This approach enables predictions about the zoonotic capacity of SARS-CoV-2 for greater than 5000 mammals—an order of magnitude more species than previously possible. Our predictions are strongly corroborated by in vivo studies. The predicted zoonotic capacity and proximity to humans suggest enhanced transmission risk from several common mammals, and priority areas of geographic overlap between these species and global COVID-19 hotspots. With molecular data available for only a small fraction of potential animal hosts, linking data across biological scales offers a conceptual advance that may expand our predictive modelling capacity for zoonotic viruses with similarly unknown host ranges.

(a) Captive, farmed or domesticated species

Given that contact with humans fundamentally underlies transmission risk, it is notable that our model predicted high zoonotic capacity for multiple captive species that have also been confirmed as susceptible to SARS-CoV-2. These include numerous carnivores, such as large cats from multiple zoos and pet dogs and cats. Our model also predicted high SARS-CoV-2 zoonotic capacity for many farmed and domesticated species. The water buffalo (Bubalus bubalis), widely kept for dairy and plowing, had the highest probability of zoonotic capacity among livestock (0.91). Model predictions in the 90th percentile also included American mink (Neovison vison), red fox (Vulpes vulpes), sika deer (Cervus nippon), white-lipped peccary (Tayassu pecari), nilgai (Boselaphus tragocamelus) and raccoon dogs (Nyctereutes procyonoides), all of which are farmed. The escape of farmed individuals into wild populations has implications for the enzootic establishment of SARS-CoV-2 [33]. These findings also have implications for vaccination strategies, for instance, prioritizing people in contact with potential bridge species (e.g. slaughterhouse workers, farmers, veterinarians).

(b) Live traded or hunted wildlife species

The Macaca genus comprised the majority of live-traded primates. Our model predicted high zoonotic capacity for all Macaca species (20/21 species, with all species within the top 10% of predictions except M. assamensis). Several live-traded carnivores and pangolins were also assigned high zoonotic capacity, including the Asiatic black bear (Ursus thibetanus), grey wolf (Canis lupus) and jaguar (Panthera onca), and the Philippine pangolin (Manis culionensis) and Sunda pangolin (M. javanica). One of the betacoronaviruses with the highest sequence similarity to SARS-CoV-2 was isolated from Sunda pangolins [70]. Interestingly, pangolin burrows are known to be occupied by other animal species, including numerous bats [71].

Commonly hunted species in the top 10% of predictions include duiker (Cephalophus zebra, West Africa), warty pig (Sus celebes, Southeast Asia) and two deer (Odocoileus hemionus and O. virginianus, Americas). The white-tailed deer (O. virginianus) was recently confirmed to transmit SARS-CoV-2 to conspecifics via aerosolized virus particles [72].

(c) Bats

Our model identified 35 bat species within the 90th percentile of zoonotic capacity. Within the genus Rhinolophus, our model identified the large rufous horseshoe bat (Rhinolophus rufus) as having the highest probability of zoonotic capacity (0.89). Rhinolophus rufus is a known natural host for bat betacoronaviruses [73] and a congener to three other horseshoe bats harbouring betacoronaviruses with high nucleotide sequence similarity to SARS-CoV-2 (approx. 92–96%) [6,74,75]. For these other three species, our model assigned a range of probabilities for SARS-CoV-2 zoonotic capacity (Rhinolophus affinis (0.58), R. malayanus (0.70) and R. shameli (0.71)) and also predicted relatively high probabilities for two congeners, Rhinolophus acuminatus (0.84) and R. macrotis (0.70). These predictions agree with recent experiments demonstrating efficient viral binding of SARS-CoV-2 RBD for R. macrotis [76] and confirmation of SARS-CoV-2-neutralizing antibodies in field-caught R. acuminatus harbouring a closely related betacoronavirus [77].

Our model also identified 17 species in the genus Pteropus (flying foxes) with high probabilities of zoonotic capacity for SARS-CoV-2. Some of these species are confirmed reservoirs of other zoonotic viruses (e.g. henipaviruses in P. lylei, P. vampyrus, P. conspicillatus and P. alecto), with Southeast Asia also having the most mammal species with a high predicted zoonotic capacity (figure 4). Annual outbreaks attributed to spillover transmission from bats illustrate a persistent epizootic risk to humans [78–80] and confirm that gaps in systematic surveillance of zoonotic viruses, including betacoronaviruses, remain an urgent priority (e.g. [81]).

(d) Rodents

Our model identified 76 rodent species with high zoonotic capacity. Among these are the deer mouse (Peromyscus maniculatus) and white-footed mouse (P. leucopus), which are reservoirs for multiple zoonotic pathogens and parasites in North America [82–84]. Experimental infection, viral shedding and sustained intraspecific transmission of SARS-CoV-2 were recently confirmed for P. maniculatus [65,66]. Also in the top 10% were two rodents considered to be human commensals whose geographic ranges are expanding due to human activities: Rattus argentiventer (0.84) and R. tiomanicus (0.79) (electronic supplementary material, file S1) [85–87]. It is notable that many of these rodent species are preyed upon by carnivores, such as the red fox (Vulpes vulpes) or domestic cats (Felis catus) who themselves were predicted to have high zoonotic capacity by our model.

https://royalsocietypublishing.org/doi/10.1098/rspb.2021.1651