Age and testosterone effects on responses to influenza infection and vaccination

描述（由申请人提供）：随着年龄的增长，男性的循环睾酮水平下降，导致从性功能下降到认知能力下降、代谢紊乱和心血管疾病风险增加的疾病。因此，老年男性，在某些情况下，临床睾酮浓度低的年轻男性，被规定长期睾酮替代疗法。在初步研究中，我们发现免疫系统也是睾酮的靶点，影响包括流感在内的传染病的结果。使用小鼠模型，我们表明低睾酮浓度，无论是内源性发生在老年男性还是由手术去势（即，与具有高循环睾酮浓度的年轻男性相比，年轻男性中的性腺机能减退症（hypogonadism）增加炎症并导致流感病毒感染后更高的发病率和死亡率。在这个R21应用中，我们建议严格检验以下假设：低循环睾酮浓度通过改变男性的免疫应答，导致与年龄相关的流感易感性变化和疫苗有效性变化。我们进一步预测，睾酮水平低的年轻或老年男性的睾酮替代将防止流感感染，并改善疫苗接种的结果。在目标1中，我们将确定男性中睾酮的年龄依赖性降低是否会影响病毒复制的动力学和幅度，以及对流感感染的炎症、细胞介导和体液免疫应答。我们还将确定睾酮治疗是否可以预防疾病，特别是在老年男性中。接种流感疫苗是减少流感的最有效手段，但疫苗的效力随着年龄的增长而下降，尤其是在男性中。目标2将检验低睾酮水平 减少男性对流感疫苗的抗体反应和对流感病毒致命攻击的保护。在睾酮水平较低的年轻或老年男性中替代睾酮，可以通过直接改变肱骨免疫应答来提高疫苗效力。在季节性流感流行期间以及最近的H7N9疫情期间，绝大多数死亡发生在65岁以上的人群中，男性死亡的可能性是女性的两倍。如果睾酮替代疗法为男性提供了显著的流感保护，那么这可以提供一种廉价的补充治疗方法，用于在流感流行和大流行期间挽救生命和减少疾病负担。

DESCRIPTION (provided by applicant): With age, circulating testosterone levels decline in males, resulting in conditions ranging from decreased sexual function to cognitive decline, metabolic disorders, and increased cardiovascular disease risk. As a result, aged males, and in some cases young males with clinically low testosterone concentrations, are prescribed long-term testosterone replacement therapy. In preliminary studies, we found that the immune system also is a target of testosterone, affecting the outcome of infectious diseases, including influenza. Using a murine model, we show that low testosterone concentrations, either endogenously occurring in aged male or caused by surgical castration (i.e., hypogonadism) in young males, increase inflammation and result in greater morbidity and mortality following influenza virus infection as compared with young males that have high circulating concentrations of testosterone. In this R21 application, we propose to critically test the hypothesis that low circulating testosterone concentrations contribute to age-associated changes in susceptibility to influenza and in vaccine efficacy by altering immune responses in males. We further predict that testosterone replacement in either young or aged males with low testosterone levels will protect against influenza infection and improve the outcome of vaccination. In Aim 1, we will determine whether age-dependent reduced testosterone in males affects the kinetics and magnitude of virus replication as well as inflammatory, cell-mediated, and humeral immune responses to influenza infection. We will also establish whether treatment with testosterone protects against disease, particularly in older males. Vaccination against influenza is the most effective means for reducing influenza, yet the efficacy of vaccines declines with age, especially in males. Aim 2 will test the hypothesis that low testosterone levels reduce antibody responses to influenza vaccination and protection against lethal challenge with influenza viruses in males. Replacement of testosterone in either young or aged males with low testosterone levels should improve vaccine efficacy by directly altering humeral immune responses. During seasonal epidemics of influenza as well as during the recent H7N9 outbreak, a significant majority of the deaths occur in people over 65 years of age, with men being 2-times more likely to die than women. If testosterone replacement therapy provides significant protection for males against influenza, then this could provide an inexpensive supplemental therapeutic approach for saving lives and reducing disease burden during influenza epidemics and pandemics.