Mx1揭示了抗病毒耐药性和致命流感疾病的先天途径
Padmini S Pillai1, Ryan D Molony1, Kimberly Martinod2
1Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
概括
患有甲型流感病毒 (IAV) 耐药性减弱的老年人面临更多的细菌感染. 在这些脆弱群体中,死亡率与酶依赖的病理有关,而不是病毒载量.
科学领域:
- 免疫学
- 病毒学
- 老年学
背景情况:
- 甲型流感病毒 (IAV) 导致每年显著的死亡率,不成比例地影响老年人.
- 老年人感染IAV的单细胞表现出干扰素的产生受损,但炎症体反应保持完整.
- 了解与年龄相关的IAV脆弱性需要检查宿主-病原体相互作用.
研究的目的:
- 在IAV感染的背景下调查抗病毒反应受损的体内后果.
- 确定IAV感染期间老年人死亡率增加的机制.
- 阐明细菌共感染和炎症酶激活在IAV病变中的作用.
主要方法:
- 使用表达功能Mx基因的小鼠,这是人类干扰素诱导的关键抗病毒效应剂.
- 使用Mavs和Tlr7缺陷的小鼠模型来模拟弱化的抗病毒抵抗力.
- 评估病毒载量,细菌负担,炎症酶激活 (caspase-1/11) 和中性粒细胞依赖的组织损伤.
主要成果:
- 抗药性减弱的小鼠 (Mavs 和 Tlr7 缺陷) 的呼吸道细菌负担增加.
- 死亡率独立于病毒载量或MyD88依赖的信号.
- 死亡率严重依赖于细菌负担,-1/11激活和中性粒细胞介导的组织损伤.
结论:
- 在抗病毒防御受损的个体中,严重的IAV疾病的易感性是由酶依赖的病理学驱动的,由细菌共感染加剧.
- 这突显了炎症酶激活和二次细菌感染在易受感染群体中与IAV相关的死亡率中的关键作用.
- 针对卡斯巴酶依赖性途径可能提供治疗策略,以减轻流感爆发期间老年人的严重后果.
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