Differential Immunomodulatory Properties of Langya and Nipah Virus Proteins

Langya virus (LayV) is a shrew-borne emerging parahenipavirus first identified in 2018 in 35 febrile patients in China. The closely related Nipah virus (NiV) is a highly pathogenic emerging bat-borne henipavirus that has caused numerous outbreaks with public health concerns in Asia. Among other symptoms, NiV causes severe acute respiratory syndrome and encephalitis, leading to high lethality. Thus, although closely related, infections with these two emerging and zoonotic viruses have distinct pathogenicity. Since the interplay with the hosts immune system is a key determinant of species barrier crossing and pathogenicity, we aimed at deciphering the ability of LayV to counteract the human intrinsic immunity using the better-characterised NiV as a prototype. NiV expresses the P, V, and W proteins, known to hinder the hosts innate immune response during infection. We thus compared the immunomodulatory properties of LayV and NiV proteins in human cells and showed that, similarly to NiV, the C-terminal domain of LayV V proteins inhibits the response to the activation of the pattern recognition receptor MDA5. However, although the N-terminal region of LayV P can inhibit the interferon signalling, it is not as efficient as its NiV counterpart. Moreover, only NiV W inhibits MDA5 and RIG-I signalling pathways. Similarly, unlike NiV, LayV W cannot efficiently block the activation of the NF-{kappa}B promoter after stimulation with IL-1{beta}. These results suggest that LayV is less efficient than NiV in counteracting the human intrinsic immunity, which may contribute to the difference in severity observed between NiV and LayV-infected patients. IMPORTANCELangya virus (LayV) is a shrew-borne emerging parahenipavirus recently identified in patients in China with symptoms such as fever, fatigue, cough, anorexia, headache, and vomiting. Since the interaction between a virus and its hosts immune system is an essential parameter influencing host adaptation and disease severity, we investigated the interplay between LayV and the human intrinsic immunity using as a prototype the better-characterized and closely related Nipah virus (NiV), a highly pathogenic henipavirus. We compared the immunomodulatory properties of LayV and NiV proteins in human cells and showed that, similarly to NiV, some of LayV proteins can inhibit human signalling pathways, while, unlike NiV, LayV W protein is unable to block essential immune pathways. This suggests that LayV is less efficient than NiV in counteracting the human intrinsic immunity, which may contribute to the difference in severity between NiV and LayV-infected patients.