RESUMO
Lambda interferons (IFNλs) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFNλs are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1-/- mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFNλ potently suppresses these effects. IFNλs therefore constitute the front line of antiviral defense in the lung without compromising host fitness.
Assuntos
Aptidão Genética , Interações Hospedeiro-Patógeno , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Influenza Humana/metabolismo , Interferon gama/metabolismo , Animais , Análise por Conglomerados , Citocinas/biossíntese , Modelos Animais de Doenças , Resistência à Doença/genética , Resistência à Doença/imunologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes Reporter , Humanos , Mediadores da Inflamação/metabolismo , Vírus da Influenza A/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Interferon gama/genética , Interferon gama/farmacologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/virologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Carga Viral , Replicação ViralRESUMO
Influenza A viruses (IAVs) are common respiratory viruses. Mouse models of IAV infection are valuable to study the mechanisms of IAV infection and pathology. Here, we present a detailed protocol for IAV infection of mice via intranasal administration. We detail the processing of mouse lung tissue and then describe the determination of viral load by several approaches including RNA, protein, or plaque-forming unit assays. This protocol may be adapted to other influenza strains or respiratory viruses. For complete details on the use and execution of this protocol, please refer to Galani et al. (2017).