Comparative susceptibility of SARS-CoV-2, SARS-CoV, and MERS-CoV across mammals.

Exploring wild reservoirs of pathogenic viruses is critical for their long-term control and for predicting future pandemic scenarios. Here, a comparative in vitro infection analysis was first performed on 83 cell cultures derived from 55 mammalian species using pseudotyped viruses bearing S proteins from SARS-CoV-2, SARS-CoV, and MERS-CoV. Cell cultures from Thomas's horseshoe bats, king horseshoe bats, green monkeys, and ferrets were found to be highly susceptible to SARS-CoV-2, SARS-CoV, and MERS-CoV pseudotyped viruses. Moreover, five variants (del69-70, D80Y, S98F, T572I, and Q675H), that beside spike receptor-binding domain can significantly alter the host tropism of SARS-CoV-2. An examination of phylogenetic signals of transduction rates revealed that closely related taxa generally have similar susceptibility to MERS-CoV but not to SARS-CoV and SARS-CoV-2 pseudotyped viruses. Additionally, we discovered that the expression of 95 genes, e.g., PZDK1 and APOBEC3, were commonly associated with the transduction rates of SARS-CoV, MERS-CoV, and SARS-CoV-2 pseudotyped viruses. This study provides basic documentation of the susceptibility, variants, and molecules that underlie the cross-species transmission of these coronaviruses.

Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy.

Bats are responsible for the zoonotic transmission of several major viral diseases, including those leading to the 2003 SARS outbreak and likely the ongoing COVID-19 pandemic. While comparative genomics studies have revealed characteristic adaptations of the bat innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the viral tolerance in bats. Here we report the establishment of genome-wide RNA interference (RNAi) and CRISPR libraries for the screening of the model megabat, Pteropus alecto. We used the complementary RNAi and CRISPR libraries to interrogate P. alecto cells for infection with two different viruses: mumps virus and influenza A virus, respectively. Independent screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells and human cells. The MTHFD1 inhibitor, carolacton, potently blocked replication of several RNA viruses, including SARS-CoV-2. We also discovered that bats have lower expression levels of MTHFD1 than humans. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad-spectrum antiviral therapy.

Comprehensive Knowledge of Reservoir Hosts is Key to Mitigating Future Pandemics.

Coronavirus disease 2019 (COVID-19) and other epidemics (such as severe acute respiratory syndrome [SARS], Ebola, and H1N1) are stark reminders that knowledge of animal behavior and ecosystem health are key to controlling the spread of zoonotic diseases early in their onset. However, we have very limited information about the set of behavioral and ecological factors that promote viral spillover and the effects that has on ecosystem health and disease transmission. Thus, expanding our current knowledge of reservoir hosts and pandemics represents an urgent and critical tool in ecological epidemiology. We also propose to create an integrative database that ranks animal species in terms of their likelihood as hosts for specific infectious diseases. We call for a global and cooperative effort of field and laboratory scientists to create, maintain, and update this information in order to reduce the severity of future pandemics.

Thoughts on Convergence Science of high-risk animals responsible for zoonotic epidemics

Since the beginning of the 21st Century, large viral outbreaks have threatened human health, economies, and biosecurity. On April 20, 2020, World Health Organization (WHO) reported more than 2.2 million confirmed cases and 150000 deaths from a novel coronavirus (Coronavirus disease 2019, COVID-19;strain SARS-CoV-2). According to a macroeconomic forecast from Standard & Poor's Global Ratings, the global GDP will fall 2.4% this year, and the economic impact of COVID-19 is sure to be far-reaching. It is suspected that COVID-19 has a wildlife origin. Indeed, most emerging human infectious diseases, such as SARS, Ebola, and H1N1, originate in animals. However, animals that host infectious diseases not only play critical roles in disease transmission, control, and prevention, but also serve the basis for the maintenance and stability of natural ecosystems. Although the COVID-19 and other epidemic diseases remind us that information on animals and their pathogenic microbes is necessary to control the spread of zoonotic diseases before they turn into epidemics or pandemics, we have little knowledge on the behavior, ecology, life history, and the pathology of infected animals. Therefore, comprehensive and solid research should be performed on animals that carry pathogens (e.g., viruses, bacteria, parasites, fungi, and prions). We searched published articles on infectious, endemic, and epidemic diseases in the Web of Science database and found that only 11.75% of articles (2930727 in total) were in the field of zoology. In contrast, more than half of the articles were in infectious diseases (biomedicine). Chinese researchers have published 221105 papers, 26.72% of the output of the United States. Even in the field of zoology, the US has published 86233 articles (2.83 times more than Chinese researchers). As solutions to the challenges of zoonotic epidemics require a public and comprehensive approach, we propose to develop a Convergence Science approach (transdisciplinary science) to study high-risk animals responsible for zoonotic epidemics. It aims to answer and resolve basic but essential questions. For example, what is the biological background of these animals, and how many ways can zoonotic diseases spillover? This effort is not limited to species classification, biological characters, evolutionary footprints, hosted microbes, behavior, and spillover approaches, nor field investigation, genetics, molecular biology, physiological, microbiology, mathematics, management, and veterinary medicine/science. While we appreciate the efforts of the medical research community to develop vaccines and medications to mitigate the spread of emerging diseases and to reduce human mortality rates, we argue that generating a dynamic list of pathogenic microbes and their wildlife hosts also represents an urgent and critical tool in ecological epidemiology. We call for a global and cooperative effort to create, maintain, and update this information in order to reduce the severity of future pandemics. A Convergence Science approach to the study of animals that host potential infectious diseases may allow the prediction and prevention of zoonotic epidemics, reduce or ablate the risk of zoonotic infection, and ensure biosecurity and public health.