Famotidine inhibits inflammatory signaling mediated by toll-like receptor 3 in SARS-CoV-2 infected cells.

Key Messages

In this laboratory study, an explanation for the beneficial role of famotidine in treating COVID-19 was investigated by studying SARS-CoV-2 infected cells using biochemical, cellular, and functional methods.

The results indicate that famotidine does not affect the activity of viral proteases or inhibit viral replication.

Instead, it was shown that in cells infected with the SARS-CoV-2 virus and exposed to histamine, treating with famotidine decreased the levels of the toll-like receptor 3 (TLR3).

This decrease suppressed TLR3-dependent inflammatory pathways, and is proposed to be the mechanism responsible for famotidine’s ability to prevent exaggerated inflammatory responses in COVID-19 patients.

Journal of Biological Chemistry

Publication Date: August 1, 2021
Peer Reviewed: Yes
Publication Type: Original | Preclinical
DOI: https://www.doi.org/10.1016/j.jbc.2021.100925

Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection

Rukmini Mukherjee, Anshu Bhattacharya, Denisa Bojkova, Ahmad Reza Mehdipour, Donghyuk Shin, Khadija Shahed Khan, Hayley Hei-Yin Cheung, Kam-Bo Wong, Wai-Lung Ng, Jindrich Cinatl, Paul P. Geurink, Gerbrand J. van der Heden van Noort, Krishnaraj Rajalingam, Sandra Ciesek, Gerhard Hummer, Ivan Dikic

Abstract

Apart from prevention using vaccinations, the management options for COVID-19 remain limited. In retrospective cohort studies, use of famotidine, a specific oral H2 receptor antagonist (antihistamine), has been associated with reduced risk of intubation and death in patients hospitalized with COVID-19. In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19.