Protons to Patients: targeting endosomal Na+/H+ exchangers against COVID-19 and other viral diseases

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.

Automated summary

This review explores the connection between endosomal acid-base homeostasis, endosomal Na+/H+ exchangers, and viral diseases, suggesting a potential role of the exchangers as a modulator of viral infection and pathophysiology. It also discusses the potential negative outcomes of clinical trials utilizing alkalinizing drugs for COVID-19 and the complexity of targeting endosomal pH in viral disease pathogenesis.