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Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection.
J Immunol. 2017 05 15; 198(10):4046-4053.JI

Abstract

Pathogenic human coronaviruses (CoVs), such as the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome-CoV, cause acute respiratory illness. Epidemiological data from the 2002-2003 SARS epidemic and recent Middle East respiratory syndrome outbreak indicate that there may be sex-dependent differences in disease outcomes. To investigate these differences, we infected male and female mice of different age groups with SARS-CoV and analyzed their susceptibility to the infection. Our results showed that male mice were more susceptible to SARS-CoV infection compared with age-matched females. The degree of sex bias to SARS-CoV infection increased with advancing age, such that middle-aged mice showed much more pronounced differences compared with young mice. Enhanced susceptibility of male mice to SARS-CoV was associated with elevated virus titers, enhanced vascular leakage, and alveolar edema. These changes were accompanied by increased accumulation of inflammatory monocyte macrophages and neutrophils in the lungs of male mice, and depletion of inflammatory monocyte macrophages partially protected these mice from lethal SARS. Moreover, the sex-specific differences were independent of T and B cell responses. Furthermore, ovariectomy or treating female mice with an estrogen receptor antagonist increased mortality, indicating a protective effect for estrogen receptor signaling in mice infected with SARS-CoV. Together, these data suggest that sex differences in the susceptibility to SARS-CoV in mice parallel those observed in patients and also identify estrogen receptor signaling as critical for protection in females.

Authors+Show Affiliations

Department of Microbiology, University of Iowa, Iowa City, IA 52242.Department of Microbiology, University of Iowa, Iowa City, IA 52242.Department of Internal Medicine, University Hospital Regensburg, Regensburg 93042, Germany.Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242; and.Department of Pathology, University of Iowa, Iowa City, IA 52242.Department of Microbiology, University of Iowa, Iowa City, IA 52242; stanley-perlman@uiowa.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28373583

Citation

Channappanavar, Rudragouda, et al. "Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection." Journal of Immunology (Baltimore, Md. : 1950), vol. 198, no. 10, 2017, pp. 4046-4053.
Channappanavar R, Fett C, Mack M, et al. Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol. 2017;198(10):4046-4053.
Channappanavar, R., Fett, C., Mack, M., Ten Eyck, P. P., Meyerholz, D. K., & Perlman, S. (2017). Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. Journal of Immunology (Baltimore, Md. : 1950), 198(10), 4046-4053. https://doi.org/10.4049/jimmunol.1601896
Channappanavar R, et al. Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol. 2017 05 15;198(10):4046-4053. PubMed PMID: 28373583.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. AU - Channappanavar,Rudragouda, AU - Fett,Craig, AU - Mack,Matthias, AU - Ten Eyck,Patrick P, AU - Meyerholz,David K, AU - Perlman,Stanley, Y1 - 2017/04/03/ PY - 2016/11/07/received PY - 2017/03/10/accepted PY - 2017/4/5/pubmed PY - 2017/9/20/medline PY - 2017/4/5/entrez SP - 4046 EP - 4053 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 198 IS - 10 N2 - Pathogenic human coronaviruses (CoVs), such as the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome-CoV, cause acute respiratory illness. Epidemiological data from the 2002-2003 SARS epidemic and recent Middle East respiratory syndrome outbreak indicate that there may be sex-dependent differences in disease outcomes. To investigate these differences, we infected male and female mice of different age groups with SARS-CoV and analyzed their susceptibility to the infection. Our results showed that male mice were more susceptible to SARS-CoV infection compared with age-matched females. The degree of sex bias to SARS-CoV infection increased with advancing age, such that middle-aged mice showed much more pronounced differences compared with young mice. Enhanced susceptibility of male mice to SARS-CoV was associated with elevated virus titers, enhanced vascular leakage, and alveolar edema. These changes were accompanied by increased accumulation of inflammatory monocyte macrophages and neutrophils in the lungs of male mice, and depletion of inflammatory monocyte macrophages partially protected these mice from lethal SARS. Moreover, the sex-specific differences were independent of T and B cell responses. Furthermore, ovariectomy or treating female mice with an estrogen receptor antagonist increased mortality, indicating a protective effect for estrogen receptor signaling in mice infected with SARS-CoV. Together, these data suggest that sex differences in the susceptibility to SARS-CoV in mice parallel those observed in patients and also identify estrogen receptor signaling as critical for protection in females. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/28373583/full_citation L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=28373583 DB - PRIME DP - Unbound Medicine ER -