Hedgehog coronaviruses entered cells through the cat version of aminopeptidase N

Identifying the receptor is what makes host range testable, because once you know the molecule a spike binds, you can put that molecule from any species in front of it and watch for entry. Until this paper, aminopeptidase N had not been shown to be an entry receptor for any betacoronavirus, the group that includes MERS-CoV and SARS-CoV-2 ^[10]. ErinCoVs sit close to the MERS virus on the family tree ^[2]. The closeness did not predict the answer.

Nobody has managed to grow ErinCoVs under laboratory conditions, so the group worked without live virus ^[9]. They rebuilt the harmless parts that matter for entry, including the spike protein, from genetic data, and tested how those interacted with cells ^[9]. Then they put APN from about 30 species in front of the spike ^[11]. Human APN did not work. Cat, rat and elephant shrew APN did ^[11]. Ten institutions contributed ^[17].

"When we see viruses that can get into multiple species, that's something we pay attention to," said Michael Letko, a virologist in WSU's Paul G. Allen School for Global Health and senior author of the study ^[12][6]. "Each jump into a new host gives the pathogen more opportunities to pick up mutations that could change what it can infect," he said ^[13].

On the human side, the block sits at the receptor itself. Victoria Jefferson, a co-first author and a postdoctoral fellow in Letko's Laboratory of Functional Viromics, said, "In humans, there are multiple barriers at that receptor level" ^[14]. She added, "Those differences make it much harder for the virus to enter cells" ^[15]. A screen of this design tests one step of infection, so it cannot say how many mutations would be needed to clear that step, or how reachable they are ^[20].

The hedgehog prevalence figures have a denominator problem. Since the viruses were first detected more than a decade ago, surveys have reported infection in about 10 percent of sampled hedgehogs in the United Kingdom and around 60 percent in Germany and Italy ^[7], roughly a sixfold spread between the low and high numbers ^[18]. The report does not give sample sizes. Infected hedgehogs do not appear to get seriously ill ^[8].

Cats are the strongest species signal in the screen. That signal comes entirely from cells. The authors conclude the viruses are unlikely to infect humans without first undergoing multiple genetic mutations, while posing more immediate risk to other animals, cats among them ^[3]. No infection in a cat has been confirmed, and the authors say the frequent contact between hedgehogs and cats in places where hedgehogs are common makes it biologically plausible ^[16]. The paper is in Nature Microbiology ^[4].