Age and testosterone mediate influenza pathogenesis in male mice

Abstract

Influenza severity increases with age, with hospitalization and mortality rates during seasonal influenza epidemics being higher in older men than age-matched women. As it is known that with age, circulating testosterone levels decline in males, we hypothesized that reduced testosterone contributes to age-associated increases in influenza severity. A murine model was used to test this hypothesis. As in men, testosterone concentrations were lower in aged (18 mo) than young (2 mo) male C57BL/6 mice. Following inoculation with influenza A virus (IAV), aged males experienced greater morbidity, clinical disease, and pulmonary inflammation than young males, and had lower neutralizing and total anti-influenza IgG antibody responses. Peak titers of virus in the lungs did not differ between aged and young males, but virus clearance was delayed in aged males. In young males, removal of the gonads increased-whereas treatment of gonadectomized males with testosterone reduced-morbidity, clinical illness, and pulmonary pathology, but viral replication was not altered by hormone manipulation in young males. Treatment of aged males with testosterone improved survival following infection but did not alter either virus replication or pulmonary pathology. These results indicate that low concentrations of testosterone, whether induced surgically in young males or naturally occurring in aged males, negatively impact the outcome of influenza.

Influenza virus inoculum volume is critical to elucidate age‐dependent mortality in mice

“…The utility of the mice to study how aging affects influenza viral lung infection is somewhat controversial. At least five studies of either C57BL/6 mice or BALB/c mice report that aged mice (16–24 months old) display enhanced morbidity or mortality during influenza A virus (IAV) infection compared to young mice (2–4 months old), similar to humans (Steeg, ; Stout‐Delgado, Vaughan, Shirali, Jaramillo, & Harrod, ; Toapanta & Ross, ; Wong et al, ; Zhao, Zhao, Legge, & Perlman, ). In contrast, two studies of aged C57BL/6 mice (16–30 months old) report that aged mice exhibit reduced mortality during IAV infection compared to young mice (2–4 months old; Lu et al, ; Pillai et al, ).…”

Influenza in High-Risk Hosts—Lessons Learned from Animal Models

“…Testosterone levels can also impact the response to influenza infection, and testosterone decline over the life span contributes to increased severity in the elderly (Vom Steeg et al 2016;Vom Steeg and Klein 2019). As is seen with estrogens and progesterone, testosterone levels do not alter viral load but rather impact immune responses (Vom Steeg et al 2016). Castrated young and intact aged male mice suffer increased pulmonary pathology and edema upon infection because of low testosterone levels (Vom Steeg et al 2016).…”

“…As is seen with estrogens and progesterone, testosterone levels do not alter viral load but rather impact immune responses (Vom Steeg et al 2016). Castrated young and intact aged male mice suffer increased pulmonary pathology and edema upon infection because of low testosterone levels (Vom Steeg et al 2016). Testosterone also plays a role in the recovery and remodeling stage of infection.…”

“…Low estrogen levels in prepubertal children-especially females-are protective against severe influenza infection (Suber and Kobzik 2017). Testosterone decline over the life span increases susceptibility to influenza in aging males, and the dynamic interaction between aging and sex hormones impacts influenza pathogenesis as well as host responses to infection and vaccination, as discussed below (Vom Steeg et al 2016;Potluri et al 2019).…”

“…Despite numerous exposures to influenza virus via infection and vaccination, morbidity and mortality increase with age in the elderly, likely because of immunosenescence and increasing incidence of comorbidities (Talbot 2017). Older mice infected with influenza virus have increased morbidity and mortality associated with increased virus replication, decreased naive T-cell receptor repertoire, and delayed resolution of inflammation (Yager et al 2008;Gil et al 2015;Vom Steeg et al 2016; Nikolich-Žugich 2018; Vom Steeg and Klein 2019). Furthermore, immunosenescence during influenza virus infection is associated with lung macrophage alterations, resulting in decreased phagocytosis and increased pulmonary fibrosis (Samy and Lim 2015;Wong et al 2017).…”