Ronco, I. | Search bioRxiv

bioRxiv2026

Noncanonical P gene mRNA editing in Cedar virus generates a V-like protein that is required for efficient virion production

Highly pathogenic Hendra and Nipah viruses encode accessory P gene products (C, V and W) that antagonize innate immunity and contribute to pathogenicity. Cedar virus (CedV), an apathogenic bat-borne henipavirus, is presumed to lack P gene mRNA editing and therefore is unable to express V and W proteins. Here, we identify CedV peptides originating from a frameshifted P gene open reading frame and demonstrate a previously unrecognized, noncanonical editing site at a homopolymeric adenine tract that introduces single-nucleotide A or G insertion. This mRNA editing produces a protein that we refer to as U protein, whose C-terminal domain shares sequence and predicted structural features with those of the henipavirus V protein. Recombinant CedV mutants defective in mRNA editing were only recoverable by trans-complementation and showed markedly reduced release of infectious virus in cell culture and attenuated replication in mice lacking type I interferon receptor. Our data revise the CedV gene expression models and reveal a noncanonical editing mechanism that supports the production of a U protein critical for efficient infectious virus release. These results expand the fundamental concepts of paramyxovirus gene expression and reveal an unexpected requirement for P-gene editing in efficient infectious-virus production, with implications for the evaluation of potentially high-consequence paramyxoviruses.

microbiology↗

bioRxiv2025

Nipah virus Malaysia and Bangladesh strain-induced pathogenesis in mice lacking type I interferon receptor signaling

Nipah virus (NiV) is a zoonotic highly pathogenic Paramyxovirus inducing lethal outbreaks of encephalitis and severe acute respiratory syndrome (SARS) with an average case-fatality rate of 75%. Two viral strains, NiV-Malaysia (NiV-Mal) and NiV-Bangladesh (NiV-Ban), associated to distinct geographical distribution, route of transmission, symptoms and lethality have been described. Due to the permanent threat of these emerging infections and the lack of approved therapeutics, it is crucial to improve our understanding regarding NiV-associated pathogenesis. Mice represent a small and accessible animal model, provided with numerous biological tools for the functional assessment of different genes related to antiviral response. Here, we analyze the susceptibility of mice deficient for type I interferon receptor (IFNAR KO) to infection with either NiV-Mal or NiV-Ban through intraperitoneal or intranasal routes. Our results show that IFNAR KO mice are susceptible to NiV-Ban infection via intraperitoneal route, although to a lesser extent than NiV-Mal, and develop encephalitis and pulmonary syndrome with viral propagation to different organs and lethal outcome in 60% of infected animals. In addition, intranasal administration of both viral strains led to a subclinical infection with viral replication in brain and lungs and production of virus-specific neutralizing antibodies. These results indicate IFNAR KO mice as a small animal model permitting comparative studies of the immunopathogenesis perpetrated by both NiV-Mal and NiV-Ban infections. Author summaryAvailability of small animal models represents a major issue to characterize virus-associated pathogenesis to further implement therapeutic strategies. Previous studies performed with NiV-Mal and NiV-Ban strains in wild-type (WT) mice did not indicate signs of NiV disease. However, when challenged with NiV-Mal, IFNAR KO mice suffered fatal outcomes, thus providing useful information on viral immunopathogenesis. Surprisingly, while being the more frequently re-emerging virus strain, no infection studies with NiV-Ban have been performed in IFNAR KO mice so far. Here, we sought comparing pathogenesis after NiV-Mal- and NiV-Ban-infection following IP and IN inoculations in IFNAR KO mice. Indeed, our results highlighted that contrary to fatal IP challenge, IN inoculation lead to a subclinical infection with both NiV strains. Moreover, we determined that NiV-Mal is more pathogenic than NiV-Ban following IP infection. Finally, distinct histopathological manifestations and tropism were associated with each viral strain and specific route of infection. Overall, our study implies that IFNAR KO mice represent a useful animal model to study strain-specific NiV pathophysiology.

microbiology↗