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J Virol. 2015 Dec 9. pii: JVI.02768-15. [Epub ahead of print]
Intranasal introduction of Fc-fused interleukin-7 provides long-lasting prophylaxis from lethal influenza infection.
Kang MC1, Choi DH2, Choi YW1, Park SJ2, Namkoong H2, Park KS2, Ahn SS2, Surh CD1, Yoon SW3, Kim DJ3, Choi JA4, Park Y1, Sung YC5, Lee SW5.
Author information
Abstract
Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment of Fc-fused interleukin-7 (IL-7-mFc) protect mice from lethal IAV infections. Protective activity of IL-7-mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7-mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as the tissue-resident memory-like T (TRM-like) cells. IL-7-mFc-primed pulmonary TRM-like cells contribute to protection upon IAV infection by dual modes. Firstly, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Secondly, TRM-like cells augment expansion of IAV-specific CTLs, in particular at the late phase of infection, which directly control viruses. Thus, accelerated viral clearance facilitated by pulmonary T cells, which are either antigen-specific or not, alleviates immunopathology in the lung and mortality from IAV infection. Depleting a subset of pulmonary T cells indicates that both CD4 and CD8 T cells contribute to protection from IAV, although IL-7-primed CD4 T cells have a more prominent role. Collectively, we propose intranasal IL-7-mFc pretreatment as an effective means for generating protective immunity against IAV infections, which could be applied to a potential prophylaxis for influenza pandemics in future.
IMPORTANCE:
The major consequence of a highly-pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7-mFc pretreatment protected immunologically na?ve mice from lethal IAV infections. Intranasal pretreatment of IL-7-mFc induced an infiltration of T cells in the lung, which reside as effector/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology, while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment of IL-7-mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7-mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26656713 [PubMed - as supplied by publisher]
Intranasal introduction of Fc-fused interleukin-7 provides long-lasting prophylaxis from lethal influenza infection.
Kang MC1, Choi DH2, Choi YW1, Park SJ2, Namkoong H2, Park KS2, Ahn SS2, Surh CD1, Yoon SW3, Kim DJ3, Choi JA4, Park Y1, Sung YC5, Lee SW5.
Author information
Abstract
Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment of Fc-fused interleukin-7 (IL-7-mFc) protect mice from lethal IAV infections. Protective activity of IL-7-mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7-mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as the tissue-resident memory-like T (TRM-like) cells. IL-7-mFc-primed pulmonary TRM-like cells contribute to protection upon IAV infection by dual modes. Firstly, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Secondly, TRM-like cells augment expansion of IAV-specific CTLs, in particular at the late phase of infection, which directly control viruses. Thus, accelerated viral clearance facilitated by pulmonary T cells, which are either antigen-specific or not, alleviates immunopathology in the lung and mortality from IAV infection. Depleting a subset of pulmonary T cells indicates that both CD4 and CD8 T cells contribute to protection from IAV, although IL-7-primed CD4 T cells have a more prominent role. Collectively, we propose intranasal IL-7-mFc pretreatment as an effective means for generating protective immunity against IAV infections, which could be applied to a potential prophylaxis for influenza pandemics in future.
IMPORTANCE:
The major consequence of a highly-pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7-mFc pretreatment protected immunologically na?ve mice from lethal IAV infections. Intranasal pretreatment of IL-7-mFc induced an infiltration of T cells in the lung, which reside as effector/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology, while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment of IL-7-mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7-mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26656713 [PubMed - as supplied by publisher]