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A new study published January 8, 2026, in PLoS Pathogens reveals how feline coronavirus (FCoV) strategically utilizes a variety of host serine proteases to activate its spike protein, optimizing its ability to infect intestinal cells. This research sheds light on the mechanisms behind FCoV infection and could inform future antiviral strategies.
Coronaviruses are notorious for their ability to hijack host cells, turning them into viral replication factories. A crucial step in this process is the activation of the virus’s spike (S) protein, which mediates both receptor binding and membrane fusion – essential for viral entry. This activation isn’t a spontaneous event; it relies on host cell proteases, enzymes that cleave proteins at specific sites.
FCoV’s Adaptable Cleavage Strategy
FCoV, which primarily infects the intestinal tract, has evolved to exploit the proteolytic environment of the gut. Researchers identified two key regions on the FCoV S protein known as cleavage sites (CSs) – S1/S2 CS and S2′ CS – where these proteases act. Through a extensive protease screen, the team discovered that serine proteases play a particularly critical role in FCoV infection.
“We observed that several serine proteases significantly enhanced FCoV infection and promoted the formation of syncytia, which are fused cells created by viral infection,” explained one senior researcher involved in the study.
Notably, three pancreatic serine proteases – chymotrypsin, trypsin, and elastase – all boosted infection rates despite their differing cleavage specificities. this suggests FCoV possesses a flexible activation strategy, capable of utilizing a range of available enzymes. Moreover, membrane-bound serine proteases TMPRSS2 and TMPRSS11D were also found to facilitate infection, though their effectiveness varied depending on the viral strain.
Identifying key Cleavage Sites and a Compensatory Mechanism
By analyzing the cleavage profiles of these proteases, the researchers confirmed the existence of the previously proposed S1/S2 CS and S2′ CS on the FCoV S protein, and identified additional cleavage sites as well. A particularly significant finding was the discovery of a compensatory cleavage mechanism at the S2′ CS.
“Our analysis revealed that even when mutations disrupt the canonical cleavage motif, the S2′ CS maintains spike activation,” stated a lead author of the study. “This underscores the central role of the S2′ CS in viral infection and highlights the virus’s remarkable adaptability.”
The role of an Acidic Environment
The study also revealed that an acidic microenvironment is crucial for efficient FCoV infection, further optimizing the conditions for protease activity and viral entry.
Implications for Future Research
These findings illustrate how FCoV cleverly adapts to the locally available serine proteases within the intestinal tract to maximize S protein priming and gain entry into host cells. Understanding these mechanisms could pave the way for the progress of novel antiviral therapies targeting these proteases or disrupting the virus’s ability to exploit them. further research is needed to fully elucidate the interplay between FCoV, host proteases, and the intestinal microenvironment.
