RESUMO
Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.
Assuntos
Necroptose , Infecções por Orthomyxoviridae , Proteína Serina-Treonina Quinases de Interação com Receptores , Animais , Necroptose/efeitos dos fármacos , Camundongos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/complicações , Feminino , Masculino , Humanos , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/virologia , Lesão Pulmonar/patologia , Lesão Pulmonar/tratamento farmacológico , Vírus da Influenza A/fisiologia , Vírus da Influenza A/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/virologia , Células Epiteliais Alveolares/metabolismo , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Influenza Humana/virologia , Influenza Humana/tratamento farmacológico , Síndrome do Desconforto Respiratório/virologia , Síndrome do Desconforto Respiratório/prevenção & controle , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/tratamento farmacológicoRESUMO
Astroviruses are a global cause of pediatric diarrhea, but they are largely understudied, and it is unclear how and where they replicate in the gut. Using an in vivo model, here we report that murine astrovirus preferentially infects actively secreting small intestinal goblet cells, specialized epithelial cells that maintain the mucus barrier. Consequently, virus infection alters mucus production, leading to an increase in mucus-associated bacteria and resistance to enteropathogenic E. coli colonization. These studies establish the main target cell type and region of the gut for productive murine astrovirus infection. They further define a mechanism by which an enteric virus can regulate the mucus barrier, induce functional changes to commensal microbial communities, and alter host susceptibility to pathogenic bacteria.