Recombination alters the receptor binding and furin cleavage site in novel bat-borne HKU5-CoV-2 coronavirus
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HKU5-CoV-2 is a new bat-infecting coronavirus phylogenetically related to MERS-CoV. It has recently been confirmed that HKU5-CoV-2 can enter human cells and organoids in vitro via the ACE2 receptor, raising concerns about its pandemic potential due to zoonotic spillover. Whether recombination has an influence on HKU5-CoV-2 infectivity or biological fitness is completely unclear to date. Here, we report the first evidence that the HKU5-CoV-2 receptor-binding domain (RBD) and S1/S2 furin cleavage site (FCS) of the spike protein are recombination hotspots. Using linkage disequilibrium and haploblock analysis, we identified 167 recombination breakpoints and 27 haploblocks. SNP23016/23043/23064/23156/23193/23285 at the RBD and SNP23833/23847 at the FCS are recombinant breakpoints. Our results suggest that recombination may lead to the substitution at RBD residue 498 (Thr498Val/Val498Thr and Thr498Ile/Ile498Thr), which Thr498 directly contacts the ACE2 receptor. Recombination also causes Ser723 deletion/insertion and Ser729Ala substitution at the FCS. These mutations could affect host tropism and change furin cleavage activity. Our results indicate that recombination has played a critical role in HKU5-CoV-2 evolution and infectivity.
IMPORTANCE
HKU5-CoV-2 is a newly discovered bat coronavirus related to MERS-CoV that can infect human cells using the ACE2 receptor, raising concerns about possible transmission from animals to humans. This study provides the first proof that recombination occurs in HKU5-CoV-2 spike protein, which leads to the changes at position 498 in the RBD—which directly interacts with the human ACE2—and at position 722/723 and 729 in the FCS, may impact how efficiently the virus infects people. These mutations might help the virus adapt to animals or humans and spread more effectively. Our research shows that recombination is important in shaping HKU5-CoV-2's ability to infect bats and potentially humans.
