title: Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection.
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.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Rudragouda
authors.initials: R
authors.lastname: Channappanavar
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Craig
authors.initials: C
authors.lastname: Fett
authors.affiliation: Department of Internal Medicine, University Hospital Regensburg, Regensburg 93042, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242; and.
authors.forename: Patrick P
authors.identifier: 0000-0002-5041-0708
authors.initials: PP
authors.lastname: Ten Eyck
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242; stanley-perlman@uiowa.edu.
authors.forename: Stanley
authors.identifier: 0000-0003-4213-2354
authors.initials: S
authors.lastname: Perlman
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D005260:Female; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000302:isolation & purification / Q000472:pathogenicity; D045169:Severe Acute Respiratory Syndrome / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D012727:Sex Characteristics; D019562:Viral Load
chemical_list: D065171:Estrogen Receptor Antagonists; D011960:Receptors, Estrogen