ABOVE: Civet cats are thought to have passed SARS-CoV, the virus that caused the 2003 SARS outbreak, from bats to humans.

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When a new zoonotic outbreak occurs, scientists rush to trace the species the infection originated from. Often the infection jumps from its initial animal carrier to an intermediate host species, which then transmits the virus to humans. Identifying intermediate host species enable risk-mitigating public health policies to be implemented and gives researchers a better understanding of the disease evolution and pathogenesis.

SARS-CoV-2, the virus that causes COVID-19, belongs to the same family of viruses as SARS-CoV and MERS-CoV, which first circulated in bats before transmitting via intermediate hosts to humans. While SARS-CoV-2 is likely to have come to humans through a similar route, “we currently don’t have any evidence that there’s an intermediate host,” says William Karesh, the executive vice president for health and policy at EcoHealth Alliance, who notes that coronaviruses can directly transmit from bats to humans without an intermediate.

The 2003 SARS outbreak began with virus transmission between bats and civet cats, which then passed it on to humans. Similarly, the intermediate host during the 2012 MERS outbreak is believed to have been dromedary camels.

See “Where Coronaviruses Come From”

While the COVID-19 pandemic continues, scientists are using models to look for potential intermediate hosts. As of today (March 16), there have been more than 164,000 cases reported and 6,507 deaths. The first full COVID-19 genome sequences were released in January 2020, enabling researchers to compare the human version of the coronavirus to coronavirus strains already isolated in animals.

A recent paper from the labs of Ralph Baric and Fang Li, published in the Journal of Virology, used the 2003 SARS-CoV as a template to simulate the structure of key COVID-19 proteins and predict in which other species the virus strain could bind in a manner similar to how it does in humans.

The models support the well-accepted idea that the interaction between the receptor-binding domain (RBD) of the coronavirus spike protein and the host receptor angiotensin-converting enzyme 2 (ACE2) controls disease transmission in SARS and COVID-19. In other words, the spike protein grabs hold of ACE2 on host cells to gain entry into cells, where it replicates, bursts open the cell, and spreads to other cells. The researchers then modeled ACE2 receptor proteins belonging to different species to see which ones are vulnerable to SARS-CoV-2 infection. It turns out that pigs, ferrets, cats, orangutans, monkeys, at least some species of bats, and humans have similar levels of affinity for SARS-CoV-2 based on the structural similarity of their ACE2 receptors.

While the team did not rule out civets as intermediate hosts for the current outbreak, they noted several differences in the civet ACE2 receptor that made it less able to bind SARS-CoV-2. The going hypothesis is that the current outbreak started in bats, then moved to another species. While many of the earliest cases in Wuhan were linked to the Huanan Seafood market—which sold seafood and wildlife, including snakes and birds—not every case has a link to it. The wide variety of animal produce available at the market, and structural similarities of ACE2 receptors in many “suspect species” means scientists are still not confident about the transmission chain of SARS-CoV-2.

Although these models create a shortlist of potential reservoir species, “this study doesn’t identify intermediate hosts,” cautions Baric. He says he wants the findings to help researchers develop new coronavirus animal models to test vaccines and drugs and to study disease progression.

“There’s a lot of ongoing experimental work, which I think will be important for actually confirming some of the hypotheses advanced in this paper,” says Andrew Ward, a computational biologist at the Scripps Research Institute who was not involved in the study.

A similar modeling study by a different set of researchers was recently published in the Journal of Medical Virology. The authors propose—based on structural similarities between the viral RBD and host ACE2—that pangolins, snakes, and turtles could be possible intermediate hosts of SARS-CoV-2. The authors note that further research is needed to confirm these findings, while other experts have discredited the idea put forth by a different group of researchers in January that snakes are SARS-CoV-2 hosts.

Confirming the identity of any intermediate host through wet lab experimentation is a difficult process, and researchers may never nab the definitive culprit. “You can test thousands of bats, but to get the coronavirus you have to catch them on the day they’re shedding it,” says Karesh. He explains that it’s now several months since the initial animal-to-human SARS-CoV-2 transmission occurred, and the coronavirus circulation in animals may have dropped off, which would make the original strain even harder to find.

Y. Wan et al., “Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS,” J Virology, doi:10.1128/JVI.00127-20, 2020.