Production of amphiregulin and recovery from influenza is greater in males than females
Abstract 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 re...
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BMC
2018-07-01
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Series: | Biology of Sex Differences |
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Online Access: | http://link.springer.com/article/10.1186/s13293-018-0184-8 |
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doaj-4597e7cc17e9456eaaa7c5abe1b54238 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Meghan S. Vermillion Rebecca L. Ursin Denise I. T. Kuok Landon G. vom Steeg Nicholas Wohlgemuth Olivia J. Hall Ashley L. Fink Eric Sasse Andrew Nelson Roland Ndeh Sharon McGrath-Morrow Wayne Mitzner Michael C. W. Chan Andrew Pekosz Sabra L. Klein |
spellingShingle |
Meghan S. Vermillion Rebecca L. Ursin Denise I. T. Kuok Landon G. vom Steeg Nicholas Wohlgemuth Olivia J. Hall Ashley L. Fink Eric Sasse Andrew Nelson Roland Ndeh Sharon McGrath-Morrow Wayne Mitzner Michael C. W. Chan Andrew Pekosz Sabra L. Klein Production of amphiregulin and recovery from influenza is greater in males than females Biology of Sex Differences Epidermal growth factor H1N1 Inflammation Resilience Tolerance Testosterone |
author_facet |
Meghan S. Vermillion Rebecca L. Ursin Denise I. T. Kuok Landon G. vom Steeg Nicholas Wohlgemuth Olivia J. Hall Ashley L. Fink Eric Sasse Andrew Nelson Roland Ndeh Sharon McGrath-Morrow Wayne Mitzner Michael C. W. Chan Andrew Pekosz Sabra L. Klein |
author_sort |
Meghan S. Vermillion |
title |
Production of amphiregulin and recovery from influenza is greater in males than females |
title_short |
Production of amphiregulin and recovery from influenza is greater in males than females |
title_full |
Production of amphiregulin and recovery from influenza is greater in males than females |
title_fullStr |
Production of amphiregulin and recovery from influenza is greater in males than females |
title_full_unstemmed |
Production of amphiregulin and recovery from influenza is greater in males than females |
title_sort |
production of amphiregulin and recovery from influenza is greater in males than females |
publisher |
BMC |
series |
Biology of Sex Differences |
issn |
2042-6410 |
publishDate |
2018-07-01 |
description |
Abstract 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. |
topic |
Epidermal growth factor H1N1 Inflammation Resilience Tolerance Testosterone |
url |
http://link.springer.com/article/10.1186/s13293-018-0184-8 |
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doaj-4597e7cc17e9456eaaa7c5abe1b542382020-11-24T22:17:22ZengBMCBiology of Sex Differences2042-64102018-07-019111210.1186/s13293-018-0184-8Production of amphiregulin and recovery from influenza is greater in males than femalesMeghan S. Vermillion0Rebecca L. Ursin1Denise I. T. Kuok2Landon G. vom Steeg3Nicholas Wohlgemuth4Olivia J. Hall5Ashley L. Fink6Eric Sasse7Andrew Nelson8Roland Ndeh9Sharon McGrath-Morrow10Wayne Mitzner11Michael C. W. Chan12Andrew Pekosz13Sabra L. Klein14W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthDepartment of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public HealthSchool of Public Health, LKS Faculty of Medicine, The University of Hong KongW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthDepartment of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public HealthDepartment of Pediatrics, The Johns Hopkins School of MedicineDepartment of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public HealthDepartment of Environmental Health and Engineering, The Johns Hopkins Bloomberg School of Public HealthSchool of Public Health, LKS Faculty of Medicine, The University of Hong KongW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthW. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public HealthAbstract 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.http://link.springer.com/article/10.1186/s13293-018-0184-8Epidermal growth factorH1N1InflammationResilienceToleranceTestosterone |