The SARS-CoV-2 origin dilemma: Zoonotic transfer or laboratory leak?

The COVID-19 pandemic is responsible for millions of deaths worldwide yet its origin remains unclear. Two potential scenarios of how infection of humans initially occurred include zoonotic transfer from wild animals and a leak of the pathogen from a research laboratory. The Wuhan wet markets where wild animals are sold represent a strong scenario for zoonotic transfer. However, isolation of SARS-CoV-2 or its immediate predecessor from wild animals in their natural environment has yet to be documented. Due to incomplete evidence for a zoonotic origin, a laboratory origin is plausible. The Wuhan Institute of Virology is at the epicenter of the pandemic and their work has included manipulation of wild-type coronavirus to enable infection of human cells. Although stronger evidence supports the zoonotic transfer, inconclusive reports maintain the laboratory leak hypothesis alive. It is imperative to reach a factual conclusion to prevent future pandemics.

Evolutionary Perspective and Theories on the Possible Origin of SARS-CoV-2.

OBJECTIVE: From the currently available next-generation sequencing data, we have tried to analyze different theories on the origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and thereby to identify the origin of its intermediate host. Genome sequence-based phylogenetic analysis and multiple sequence alignment were performed. METHODS: We used the Virus Pathogen Resource (ViPR) platform for phylogenetic analysis and the MUltiple Sequence Comparison by Log- Expectation (MUSCLE) algorithm for whole genome sequence alignment of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), BJ01, Middle East respiratory syndrome coronavirus (MERS-CoV), bat coronavirus RaTG13, and pangolin coronavirus. RESULTS: From these two analyses, we have found that RaTG13 is the closest relative to SARS-CoV-2 and not the pangolin coronavirus in spite of having sequence homology-based similarity in the genes. Comparing the RNA-dependent RNA polymerase (RdRp) and interacting spike (S) protein that interacts directly with the host human angiotensin-converting enzyme 2 (hACE2), the bat coronavirus RaTG13 was found to be the closest relative to SARS-CoV-2. Through multiple sequence alignment of the amino acid sequences, we found the furin-like cleavage site RRARS only in SARS-CoV-2 at the junction of the two subunits S1/S2 of the spike protein. CONCLUSIONS: The possible zoonotic transfer that has happened in SARS-CoV-2 seems to not be from the pangolin, but RaTG13 remains closest relative to SARS-CoV-2. Further studies, such as systematic reviews of the literature and meta-analyses, are needed to reach a conclusion regarding the evolutionary trajectory of the SARS-CoV-2 outbreak.

Comparative Computational Modeling of the Bat and Human Immune Response to Viral Infection with the Comparative Biology Immune Agent Based Model.

Given the impact of pandemics due to viruses of bat origin, there is increasing interest in comparative investigation into the differences between bat and human immune responses. The practice of comparative biology can be enhanced by computational methods used for dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. We present an agent based model that encompasses and bridges differences between bat and human responses to viral infection: the comparative biology immune agent based model, or CBIABM. The CBIABM examines differences in innate immune mechanisms between bats and humans, specifically regarding inflammasome activity and type 1 interferon dynamics, in terms of tolerance to viral infection. Simulation experiments with the CBIABM demonstrate the efficacy of bat-related features in conferring viral tolerance and also suggest a crucial role for endothelial inflammasome activity as a mechanism for bat systemic viral tolerance and affecting the severity of disease in human viral infections. We hope that this initial study will inspire additional comparative modeling projects to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and aid in preparation for future viral pandemics of zoonotic origin.

Viewpoint: Origin of SARS-CoV-2.

The origin of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virus causing the COVID-19 pandemic has not yet been fully determined. Despite the consensus about the SARS-CoV-2 origin from bat CoV RaTG13, discrepancy to host tropism to other human Coronaviruses exist. SARS-CoV-2 also possesses some differences in its S protein receptor-binding domain, glycan-binding N-terminal domain and the surface of the sialic acid-binding domain. Despite similarities based on cryo-EM and biochemical studies, the SARS-CoV-2 shows higher stability and binding affinity to the ACE2 receptor. The SARS-CoV-2 does not appear to present a mutational "hot spot" as only the D614G mutation has been identified from clinical isolates. As laboratory manipulation is highly unlikely for the origin of SARS-CoV-2, the current possibilities comprise either natural selection in animal host before zoonotic transfer or natural selection in humans following zoonotic transfer. In the former case, despite SARS-CoV-2 and bat RaTG13 showing 96% identity some pangolin Coronaviruses exhibit very high similarity to particularly the receptor-binding domain of SARS-CoV-2. In the latter case, it can be hypothesized that the SARS-CoV-2 genome has adapted during human-to-human transmission and based on available data, the isolated SARS-CoV-2 genomes derive from a common origin. Before the origin of SARS-CoV-2 can be confirmed additional research is required.