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

Abstract

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.