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，男性血液中的睾丸素水平下降，导致从性功能下降到认知能力下降、代谢障碍和心血管疾病风险增加等各种情况。因此，老年男性，在某些情况下，临床上睾酮浓度较低的年轻男性，会被开出长期的睾酮替代疗法。在初步研究中，我们发现免疫系统也是睾酮的靶子，影响包括流感在内的传染病的结局。使用小鼠模型，我们发现低浓度的睾酮，无论是发生在老年男性体内，还是由手术切除年轻男性引起的(即性腺功能减退)，都会增加炎症，并导致流感病毒感染后更高的发病率和死亡率，与循环中睾酮浓度较高的年轻男性相比。在R21的应用中，我们建议对这一假设进行批判性检验，即低循环睾酮浓度通过改变男性的免疫反应，导致与年龄相关的流感易感性和疫苗效力的变化。我们进一步预测，无论是对睾酮水平较低的年轻男性还是老年男性进行睾酮替代，都将预防流感感染，并改善疫苗接种的结果。在目标1中，我们将确定男性中与年龄相关的睾酮水平降低是否会影响病毒复制的动力学和大小，以及对流感感染的炎症、细胞介导和体液免疫反应。我们还将确定睾丸素治疗是否可以预防疾病，特别是在老年男性。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，特别是在男性中。目标2将检验这样一种假设，即低睾丸激素水平 减少男性接种流感疫苗后的抗体反应，保护男性免受流感病毒的致命攻击。在睾酮水平较低的年轻或老年男性中替换睾酮，应该会通过直接改变体液免疫反应来提高疫苗效力。在流感季节性流行期间以及最近的H7N9疫情期间，大多数死亡病例发生在65岁以上的人中，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预防流感提供了显著的保护，那么这可以提供一种廉价的补充治疗方法，在流感流行和大流行期间拯救生命和减轻疾病负担。

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.