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We examined this pathway using EjCoV-3, a recently identified bat merbecovirus. Exogenous PS, but not phosphatidylcholine, reduced viral infectivity in a concentration-dependent manner, suggesting competitive inhibition of receptor binding by virion-associated PS. T-cell immunoglobulin and mucin domain 1 (TIM-1) knockout (KO) in Vero\/TMPRSS2 (transmembrane protease, serine 2) cells markedly reduced early viral infection. TIM-1 KO cells also showed markedly reduced virion attachment, indicating that TIM-1 acts as a PS-dependent attachment factor. Growth kinetics further revealed that TIM-1 contributes to efficient EjCoV-3 replication under conditions without exogenous protease and accelerates early viral growth in the presence of exogenous protease. A549 cells and A549\/hACE2 cells are not susceptible to EjCoV-3 infection in the absence of exogenous proteases, and sustained viral replication was observed only when TIM-1 and TMPRSS2 were co-expressed, indicating that the two proteins synergistically promote infection. However, the expression of either factor alone was insufficient to sustain sustained viral replication. In contrast, in A549\/EnACE2 cells, an EjCoV-3-susceptible cell line expressing a more compatible bat angiotensin-converting enzyme 2 (ACE2) orthologue, even in the absence of exogenous proteases, the expression of TMPRSS2 enhanced infection, whereas the expression of TIM-1 had no effect. These findings indicate that in environments where only low-affinity receptors are present, TIM-1 promotes EjCoV-3 infection primarily through PS-mediated attachment and functions in concert with TMPRSS2-dependent spike activation. This cooperative mechanism may reduce receptor barriers and enhance the potential for cross-species transmission of bat-derived coronaviruses, thereby contributing to their emergence as zoonotic pathogens.<\/jats:p>","DOI":"10.1099\/jgv.0.002299","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:16:13Z","timestamp":1786119373000},"source":"Crossref","is-referenced-by-count":0,"title":["T-cell immunoglobulin and mucin domain 1 and transmembrane serine protease 2 synergistically enhance entry of a bat-derived merbecovirus"],"prefix":"10.1099","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3546-1985","authenticated-orcid":false,"given":"Misa","family":"Katayama","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 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