Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.
Department of Infectious Diseases, Singapore General Hospital, Singapore.
FEBS J. 2021 Sep;288(17):5055-5070. doi: 10.1111/febs.15613. Epub 2020 Nov 17.
The ongoing coronavirus disease 2019 (COVID-19) crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a large-scale pandemic that is afflicting millions of individuals in over 200 countries. The clinical spectrum caused by SARS-CoV-2 infections can range from asymptomatic infection to mild undifferentiated febrile illness to severe respiratory disease with multiple complications. Elderly patients (aged 60 and above) with comorbidities such as cardiovascular diseases and diabetes mellitus appear to be at highest risk of a severe disease outcome. To protect against pulmonary immunopathology caused by SARS-CoV-2 infection, the host primarily depends on two distinct defense strategies: resistance and disease tolerance. Resistance is the ability of the host to suppress and eliminate incoming viruses. By contrast, disease tolerance refers to host responses that promote host health regardless of their impact on viral replication. Disruption of either resistance or disease tolerance mechanisms or both could underpin predisposition to elevated risk of severe disease during viral infection. Aging can disrupt host resistance and disease tolerance by compromising immune functions, weakening of the unfolded protein response, progressive mitochondrial dysfunction, and altering metabolic processes. A comprehensive understanding of the molecular mechanisms underlying declining host defense in elderly individuals could thus pave the way to provide new opportunities and approaches for the treatment of severe COVID-19.
由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的持续的 2019 年冠状病毒病（COVID-19）危机引发了一场大规模的大流行，影响了 200 多个国家的数百万人。SARS-CoV-2 感染引起的临床谱可从无症状感染到轻度非特异性发热疾病到伴有多种并发症的严重呼吸道疾病不等。患有心血管疾病和糖尿病等合并症的老年患者（60 岁及以上）似乎面临最严重疾病结局的高风险。为了防止 SARS-CoV-2 感染引起的肺部免疫病理，宿主主要依赖于两种截然不同的防御策略：抵抗和疾病耐受。抵抗是宿主抑制和消除传入病毒的能力。相比之下，疾病耐受是指宿主反应，无论其对病毒复制的影响如何，都能促进宿主健康。抵抗或疾病耐受机制的破坏，或两者兼而有之，都可能导致病毒感染期间严重疾病风险增加。衰老可通过损害免疫功能、削弱未折叠蛋白反应、进行性线粒体功能障碍和改变代谢过程来破坏宿主的抵抗和疾病耐受。因此，全面了解老年人宿主防御能力下降的分子机制，可为治疗严重 COVID-19 提供新的机会和方法。
