Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India.
FEBS J. 2021 Sep;288(17):5071-5088. doi: 10.1111/febs.16163.
While there is undeniable evidence to link endosomal acid-base homeostasis to viral pathogenesis, the lack of druggable molecular targets has hindered translation from bench to bedside. The recent identification of variants in the interferon-inducible endosomal Na /H exchanger 9 associated with severe coronavirus disease-19 (COVID-19) has brought a shift in the way we envision aberrant endosomal acidification. Is it linked to an increased susceptibility to viral infection or a propensity to develop critical illness? This review summarizes the genetic and cellular evidence linking endosomal Na /H exchangers and viral diseases to suggest how they can act as a broad-spectrum modulator of viral infection and downstream pathophysiology. The review also presents novel insights supporting the complex role of endosomal acid-base homeostasis in viral pathogenesis and discusses the potential causes for negative outcomes of clinical trials utilizing alkalinizing drugs as therapies for COVID-19. These findings lead to a pathogenic model of viral disease that predicts that nonspecific targeting of endosomal pH might fail, even if administered early on, and suggests that endosomal Na /H exchangers may regulate key host antiviral defence mechanisms and mediators that act to drive inflammatory organ injury.
虽然有不可否认的证据表明内体酸碱稳态与病毒发病机制有关，但缺乏可药用的分子靶点阻碍了从实验室到临床的转化。最近发现干扰素诱导的内体 Na+/H 交换器 9 的变异与严重的冠状病毒病 19（COVID-19）有关，这改变了我们对异常内体酸化的看法。这与增加对病毒感染的易感性有关，还是与发展为危重症的倾向有关？本文综述了内体 Na+/H 交换器与病毒疾病相关的遗传和细胞证据，提示它们如何作为病毒感染和下游病理生理学的广谱调节剂。本文还提出了新的见解，支持内体酸碱稳态在病毒发病机制中的复杂作用，并讨论了利用碱化药物作为 COVID-19 治疗方法的临床试验产生阴性结果的潜在原因。这些发现提出了一个病毒疾病的发病模型，该模型预测即使早期进行非特异性靶向内体 pH 也可能失败，并表明内体 Na+/H 交换器可能调节关键的宿主抗病毒防御机制和介质，从而导致炎症性器官损伤。
