McFadden, M. I. | bioRxiv Science

bioRxiv2025

Accelerated Adaptation of SARS-CoV-2 Variants in Mice Lacking IFITM3 Preserves Distinct Tropism and Pathogenesis

Here we investigated whether interferon induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. Enhancements associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enabled comparative studies of variants in mice. Beta caused lung dysfunction and altered cilia-associated gene programs, consistent with broad viral antigen distribution in lungs. Omicron, which shows low pathogenicity and upper respiratory tract preference in humans, replicated to high nasal titers while showing restrained spatial distribution in lungs and diminished lung inflammatory responses compared to Beta. Our findings demonstrate that IFITM3 deficiency accelerates coronavirus adaptation and reveal that intrinsic SARS-CoV-2 variant traits shape tropism, immunity, and pathogenesis across hosts. HIGHLIGHTSO_LIIFITM3 is a critical barrier to SARS-CoV-2 adaptation in new host species C_LIO_LIMouse-adapted SARS-CoV-2 strains enable comparative pathology C_LIO_LIOmicron favors nose and large airways, leading to mild lung pathology C_LIO_LIBeta exhibits broad lung replication, driving severe inflammation and dysfunction C_LI

immunology↗

bioRxiv2024

ERK5 Signaling is Required for Type III IFN-mediated Mucosal Antiviral Responses

Type III interferons (IFN{lambda}) are innate immune cytokines that limit viral replication and coordinate tissue repair through the induction of interferon stimulated genes (ISGs). This response must be tightly regulated to avoid excessive responses that result in the disruption of tissue barrier integrity or inefficient responses that allow for pathogen escape. Here we examine the contribution of Mitogen Activated Protein Kinase (MAPK) signaling on IFN{lambda}-mediated antiviral activity. We find that extracellular-signal-regulated kinase 5 (ERK5), a poorly characterized member of the conventional MAPK family, potentiates the antiviral efficacy of IFN{lambda}. Chemical inhibition and genetic targeting of ERK5 during IFN{lambda} treatment of cells results in a decrease in ISG induction and impaired control of viral infections. This decrease in IFN{lambda} antiviral efficacy in the absence of ERK5 kinase activity corresponded to lowered STAT1 phosphorylation, revealing a noncanonical role for ERK5 in STAT1 activation downstream of IFN{lambda}. In contrast, type I IFN antiviral signaling is largely resistant to ERK5 modulation. Altogether, we identify ERK5 as a potentiator of STAT1 activation, ISG expression, and antiviral activity following type III IFN stimulation. SIGNIFICANCERegulation of type III interferons (IFN{lambda}) at mucosal barriers in response infection to mitigate viral replication and support barrier integrity. The specific mechanistic requirements for MAPK signaling to sustain IFN{lambda}-mediated gene expression have remained elusive. Amongt the least characterized members of the MAPK family, the role of ERK5 in regulating host inflammatory responses has been hampered by off-target effects of kinase inhibitors. Here, we combine pharmacological and genetic approaches to specifically demonstrate that ERK5 promotes antiviral immunity in epithelial cells. Mechanistically, ERK5 enhances the activation of STAT1 in response to IFN stimulation to augment the transcription of IFN-stimulated genes. Our work demonstrates that therapeutic modulation of MAPK and IFN signaling pathway co-integration could distinguish between the protective and deleterious outcomes of IFN expression. One-sentence summaryERK5 potentiates IFN lambda responses.

immunology↗