title: Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection.
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 they have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment with Fc-fused interleukin-7 (IL-7-mFc) protects mice from lethal IAV infections. The 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 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. First, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Second, TRM-like cells augment expansion of IAV-specific cytotoxic T lymphocytes (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 the future.
  
  
  OBJECTIVE
  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 naive mice from lethal IAV infections. Intranasal pretreatment with 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 with 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.
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Moon Cheol
authors.initials: MC
authors.lastname: Kang
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Seong Jeong
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Hong
authors.initials: H
authors.lastname: Namkoong
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Ki Seok
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: So-Shin
authors.initials: SS
authors.lastname: Ahn
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Surh
authors.affiliation: Viral Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea.
authors.forename: Sun-Woo
authors.initials: SW
authors.lastname: Yoon
authors.affiliation: Viral Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea.
authors.forename: Doo-Jin
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Molecular Vaccinology Section, Laboratory Science Division, International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Jung-ah
authors.initials: JA
authors.lastname: Choi
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
authors.forename: Yunji
authors.initials: Y
authors.lastname: Park
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea ycsung@postech.ac.kr sw_lee@postech.ac.kr.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Sung
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea ycsung@postech.ac.kr sw_lee@postech.ac.kr.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000235:genetics; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology*; D015851:Interleukin-7 / Q000008:administration & dosage* / Q000235:genetics; D008168:Lung / Q000276:immunology*; D008212:Lymphocyte Depletion; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; D015851:Interleukin-7; D011993:Recombinant Fusion Proteins