SARS-CoV-2-Related Bat Virus in Human Relevant Models Sheds Light on the Proximal Origin of COVID-19

Abstract

Bat sarbecovirus BANAL-236 is highly related to SARS-CoV-2 and infects human cells, albeit lacking the furin cleavage site in its spike protein. To inform on the origin of SARS-CoV-2, we evaluated the clinical, epidemiological and evolutionary consequences of a potential BANAL-236 spillover into humans using animal models. The virus replicates efficiently and pauci-symptomatically in humanized mice and in macaques, where its tropism is enteric, strongly differing from that of SARS-CoV-2. BANAL-236 infection leads to protection against superinfection by a more virulent strain like Wuhan SARS-CoV-2. Yet we found no evidence of antibodies recognizing bat sarbecoviruses in populations highly exposed to bats, indicating that such infections, if they occur, are rare. Six passages in mice or in human intestinal cells, mimicking putative early spillover events, selected adaptive mutations without appearance of a furin cleavage site and not change in virulence. We thus conclude that the hypothesis of the SARS-CoV-2 pandemic being preceded by silent circulation in humans of BANAL-236-like strains leading to the acquisition of a furin cleavage site is unlikely. Our studies suggest that a specific search for a furin cleavage site in sarbecoviruses in the wild should be pursued to understand the origin of the SARS-CoV-2 pandemics.

Variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Vaccine Effectiveness

“…However, individuals infected with either of the other three coronaviruses—severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERSCoV), and SARS-CoV-2—develop severe respiratory distress and viral pneumonia and may ultimately succumb to the disease [ 28 , 29 , 30 ]. Jiang, Xiaowei, and Ruoqi Wang stated that although bats are the most probable reservoir animal for SARS-CoV-2 [ 31 ], zoonotic spillovers likely involving an intermediate animal and multiple transmissions from wildlife at a market in Wuhan probably led to SARS-CoV-2 emergence [ 32 ].…”