Reduced DPP4 Binding Confers Resistance to Soluble DPP4 While Preserving MERS-CoV Entry into Cells Expressing High Levels of DPP4
Year: 2026
Type: preprint
Abstract: ABSTRACT The Middle East respiratory syndrome coronavirus uses DPP4/CD26 as receptor for cell entry. Soluble recombinant DPP4 can block MERS-CoV infection in cell culture and in animal models and might hold promise as antiviral. Furthermore, endogenous soluble DPP4 in plasma might reduce MERS-CoV dissemination in infected individuals. Therefore, we addressed whether and how MERS-CoV can acquire resistance against soluble DPP4 (sDPP4), employing a vesicular stomatitis virus (VSV) encoding the MERS-CoV spike (S) protein (VSV-MERS-S). Passaging of VSV-MERS-S in the presence of sDPP4 selected for viral variants with mutations L507I and L507H in the receptor binding domain (RBD) of the S protein. These mutations reduced sDPP4 binding, were compatible with robust entry into cell lines expressing high levels of DPP4 and conferred sDPP4 resistance. In contrast, entry into cell lines expressing low levels of DPP4 was reduced. Furthermore, polymorphisms L507F/R/P, which were detected in MERS-CoV sequences from patients, exhibited an even more pronounced phenotype, with L507R and L507P conferring complete sDPP4 resistance. Collectively, our results show that naturally occurring polymorphisms in the MERS-CoV S protein can confer sDPP4 resistance by reducing sDPP4 binding but might still be compatible with robust viral spread in cells and tissues expressing high levels of DPP4. IMPORTANCE DPP4 is the cellular receptor used by MERS-CoV for entry into target cells. A soluble form of DPP4 (sDPP4) blocks MERS-CoV infection and has been proposed as a potential antiviral. Here, using surrogate systems, we show that MERS-CoV can acquire resistance to sDPP4 through spike protein mutations that reduce DPP4 binding. These mutations remain compatible with efficient entry into cells expressing high levels of DPP4 and were also identified in patient-derived MERS-CoV. Our findings suggest that MERS-CoV can balance receptor engagement with resistance to a soluble receptor decoy, with implications for antiviral strategies targeting virus-receptor interactions.
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7213753470