W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Biol Sex Differ. 2018 Jul 17;9(1):24. doi: 10.1186/s13293-018-0184-8.
Amphiregulin (AREG) is an epidermal growth factor that is a significant mediator of tissue repair at mucosal sites, including in the lungs during influenza A virus (IAV) infection. Previous research illustrates that males of reproductive ages experience less severe disease and recover faster than females following infection with IAV.
Whether males and females differentially produce and utilize AREG for pulmonary repair after IAV infection was investigated using murine models on a C57BL/6 background and primary mouse and human epithelial cell culture systems.
Following sublethal infection with 2009 H1N1 IAV, adult female mice experienced greater morbidity and pulmonary inflammation during the acute phase of infection as well as worse pulmonary function during the recovery phase of infection than males, despite having similar virus clearance kinetics. As compared with females, AREG expression was greater in the lungs of male mice as well as in primary respiratory epithelial cells derived from mouse and human male donors, in response to H1N1 IAVs. Internalization of the epidermal growth factor receptor (EGFR) was also greater in respiratory epithelial cells derived from male than female mice. IAV infection of Areg knock-out (Areg) mice eliminated sex differences in IAV pathogenesis, with a more significant role for AREG in infection of male compared to female mice. Deletion of Areg had no effect on virus replication kinetics in either sex. Gonadectomy and treatment of either wild-type or Areg males with testosterone improved the outcome of IAV as compared with their placebo-treated conspecifics.
Taken together, these data show that elevated levels of testosterone and AREG, either independently or in combination, improve resilience (i.e., repair and recovery of damaged tissue) and contribute to better influenza outcomes in males compared with females.
Amphiregulin（AREG）是一种表皮生长因子，是包括流感病毒（IAV）感染时肺部在内的黏膜部位组织修复的重要介质。先前的研究表明，处于生殖年龄的男性在感染 IAV 后，其疾病严重程度较轻，恢复速度较快。
使用 C57BL/6 背景下的鼠模型和原代鼠和人上皮细胞培养系统，研究了男性和女性在 IAV 感染后是否通过不同的方式产生和利用 AREG 进行肺部修复。
在感染 2009 年 H1N1 IAV 后，成年雌性小鼠在感染急性期的发病率和肺部炎症比雄性小鼠更高，在感染恢复期的肺功能也更差，尽管病毒清除动力学相似。与雌性相比，雄性小鼠的肺部以及源自雄性鼠和人供体的原代呼吸上皮细胞中 AREG 的表达更高，对 H1N1 IAV 也有更高的反应性。表皮生长因子受体（EGFR）的内化在源自雄性而非雌性小鼠的呼吸上皮细胞中也更高。IAV 感染 Areg 敲除（Areg）小鼠消除了 IAV 发病机制中的性别差异，AREG 在感染雄性小鼠中的作用比感染雌性小鼠更为显著。在两性中，Areg 的缺失对病毒复制动力学均无影响。无论雌雄，性腺切除术和用睾酮处理野生型或 Areg 雄性，均改善了 IAV 的结果，与接受安慰剂治疗的同性别相比。
综上所述，这些数据表明，升高的睾酮和 AREG 水平，无论是单独还是联合使用，都能提高雄性的抵抗力（即受损组织的修复和恢复），并有助于改善男性的流感结局，优于女性。
