Biology subjects

Pöhlmann, S. H.

Publications and source records attributed to Pöhlmann, S. H..

3 recordsLinked to original sources

bioRxiv2026

Reduced DPP4 Binding Confers Resistance to Soluble DPP4 While Preserving MERS-CoV Entry into Cells Expressing High Levels of DPP4

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.

microbiology↗

bioRxiv2026

The conserved QTQTX motif in the SARS-CoV-2 spike protein is dispensable for cleavage and lung cell entry of the emerging variant BA.3.2

The furin motif in the SARS-CoV-2 spike (S) protein is important for lung cell entry. It is embedded in an extended loop structure and preceded by a highly conserved QTQTX motif that is required for efficient furin cleavage of the SARS-CoV-2 WA-1 S protein. BA.3.2 is an emerging SARS-CoV-2 saltation variant that is spreading globally in April 2026 and encodes for a highly mutated S protein. Here, we analyzed whether the QTQTX motif is also required for spike protein cleavage and lung cell entry of BA.3.2. We report that two patient-derived spike sequences of the BA.3.2 subvariant BA.3.2.2 lack the first QT repeat of the QTQTX motif and show that this motif is largely dispensable for both cleavage and lung cell entry of BA.3.2.2, which we found to depend on TMPRSS2. Our results suggest that the reconfiguration of the BA.3.2 S protein during persistent infection may have significantly altered the determinants of furin cleavage. IMPORTANCEThe furin motif in the SARS-CoV-2 spike (S) protein is unique among sarbecoviruses and constitutes a virulence determinant. A QTQTX motif located immediately upstream of the furin motif is required for furin cleavage of the S protein of the virus that circulated early in the pandemic. Here, we show that the QTQTX motif is largely dispensable for S protein processing and S protein-driven lung cell entry of the emerging saltation variant BA.3.2, which is currently spreading globally. Thus, BA.3.2 evolution within immunocompromised individuals may have relaxed the requirements for furin processing of the spike protein.

microbiology↗

bioRxiv2021

Interferon induction and not replication interference mainly determines anti-influenza virus activity of defective interfering particles

Defective interfering (DI) RNAs arise during influenza virus replication, can be packaged into particles (DIPs) and suppress spread of wildtype (WT) virus. However, the molecular signatures of DI RNAs and the mechanism underlying antiviral activity are incompletely understood. Here, we show that any central deletion is sufficient to convert a viral RNA into a DI RNA and that antiviral activity of DIPs is inversely correlated with DI RNA length when induction of the interferon (IFN) system is disfavored. When induction of the IFN system was allowed, it was found to be the major contributor to DIP antiviral activity. Finally, while both DIPs and influenza virus triggered expression of IFN-stimulated genes (ISG) only virus stimulated robust expression of IFN. These results suggest a key role of innate immune activation in DIP antiviral activity and point towards previously unappreciated differences in DIP- and influenza virus-mediated activation of the effector functions of the IFN system. ImportanceDefective interfering (DI) RNAs naturally arise during RNA virus infection. They can be packaged into defective interfering particles (DIPs) and exert antiviral activity by suppressing viral genome replication and inducing the interferon (IFN) system. However, inhibition of influenza virus infection by DI RNAs has been incompletely understood. Here, we show that induction of the IFN system and not suppression of genome replication is the major determinant of DIP antiviral activity. Moreover, we demonstrate that DIPs induce IFN-stimulated genes (ISG) but not IFN with high efficiency. Our results reveal unexpected major differences in influenza virus and DIP activation of the IFN system, a key barrier against viral infection, and provide insights into how to design DIPs for antiviral therapy.

molecular biology↗