PMID- 30012205 OWN - NLM STAT- MEDLINE DCOM- 20190320 LR - 20190320 IS - 2042-6410 (Electronic) IS - 2042-6410 (Linking) VI - 9 IP - 1 DP - 2018 Jul 17 TI - Production of amphiregulin and recovery from influenza is greater in males than females. PG - 24 LID - 10.1186/s13293-018-0184-8 [doi] LID - 24 AB - BACKGROUND: Amphiregulin (AREG) is an epidermal growth factor that is a significant mediator of tissue repair at mucosal sites, including in the lungs during influenza A virus (IAV) infection. Previous research illustrates that males of reproductive ages experience less severe disease and recover faster than females following infection with IAV. METHODS: Whether males and females differentially produce and utilize AREG for pulmonary repair after IAV infection was investigated using murine models on a C57BL/6 background and primary mouse and human epithelial cell culture systems. RESULTS: Following sublethal infection with 2009 H1N1 IAV, adult female mice experienced greater morbidity and pulmonary inflammation during the acute phase of infection as well as worse pulmonary function during the recovery phase of infection than males, despite having similar virus clearance kinetics. As compared with females, AREG expression was greater in the lungs of male mice as well as in primary respiratory epithelial cells derived from mouse and human male donors, in response to H1N1 IAVs. Internalization of the epidermal growth factor receptor (EGFR) was also greater in respiratory epithelial cells derived from male than female mice. IAV infection of Areg knock-out (Areg(-/-)) mice eliminated sex differences in IAV pathogenesis, with a more significant role for AREG in infection of male compared to female mice. Deletion of Areg had no effect on virus replication kinetics in either sex. Gonadectomy and treatment of either wild-type or Areg(-/-) males with testosterone improved the outcome of IAV as compared with their placebo-treated conspecifics. CONCLUSIONS: Taken together, these data show that elevated levels of testosterone and AREG, either independently or in combination, improve resilience (i.e., repair and recovery of damaged tissue) and contribute to better influenza outcomes in males compared with females. FAU - Vermillion, Meghan S AU - Vermillion MS AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. AD - Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Ursin, Rebecca L AU - Ursin RL AD - Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Kuok, Denise I T AU - Kuok DIT AD - School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. FAU - Vom Steeg, Landon G AU - Vom Steeg LG AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Wohlgemuth, Nicholas AU - Wohlgemuth N AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Hall, Olivia J AU - Hall OJ AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Fink, Ashley L AU - Fink AL AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Sasse, Eric AU - Sasse E AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Nelson, Andrew AU - Nelson A AD - Department of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Ndeh, Roland AU - Ndeh R AD - Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - McGrath-Morrow, Sharon AU - McGrath-Morrow S AD - Department of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. AD - Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Mitzner, Wayne AU - Mitzner W AD - Department of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Chan, Michael C W AU - Chan MCW AD - School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. FAU - Pekosz, Andrew AU - Pekosz A AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. AD - Department of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. FAU - Klein, Sabra L AU - Klein SL AUID- ORCID: 0000-0002-0730-5224 AD - W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. sklein2@jhu.edu. AD - Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. sklein2@jhu.edu. LA - eng GR - T32 AI007417/AI/NIAID NIH HHS/United States GR - T32 CA009110/CA/NCI NIH HHS/United States GR - R01 HL114800/HL/NHLBI NIH HHS/United States GR - HHSN272201400007C/National Institute of Allergy and Infectious Diseases/International GR - T32 OD011089/OD/NIH HHS/United States GR - HHSN272201400006C/National Institute of Allergy and Infectious Diseases/International GR - T32 GM008752/GM/NIGMS NIH HHS/United States GR - HHSN272201400007C/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20180717 PL - England TA - Biol Sex Differ JT - Biology of sex differences JID - 101548963 RN - 0 (Amphiregulin) RN - 3XMK78S47O (Testosterone) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Amphiregulin/*metabolism MH - Animals MH - Cells, Cultured MH - Epithelial Cells/metabolism/virology MH - ErbB Receptors/metabolism MH - Female MH - Humans MH - *Influenza A Virus, H1N1 Subtype MH - Lung/metabolism MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Orthomyxoviridae Infections/*metabolism MH - Severity of Illness Index MH - *Sex Characteristics MH - Testosterone/metabolism PMC - PMC6048771 OTO - NOTNLM OT - Epidermal growth factor OT - H1N1 OT - Inflammation OT - Resilience OT - Testosterone OT - Tolerance COIS- ETHICS APPROVAL: Not applicable. CONSENT FOR PUBLICATION: All authors read and approved the final draft. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/07/18 06:00 MHDA- 2019/03/21 06:00 PMCR- 2018/07/17 CRDT- 2018/07/18 06:00 PHST- 2018/01/08 00:00 [received] PHST- 2018/05/30 00:00 [accepted] PHST- 2018/07/18 06:00 [entrez] PHST- 2018/07/18 06:00 [pubmed] PHST- 2019/03/21 06:00 [medline] PHST- 2018/07/17 00:00 [pmc-release] AID - 10.1186/s13293-018-0184-8 [pii] AID - 184 [pii] AID - 10.1186/s13293-018-0184-8 [doi] PST - epublish SO - Biol Sex Differ. 2018 Jul 17;9(1):24. doi: 10.1186/s13293-018-0184-8.