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

  • 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.
Author:Rukmini MukherjeeORCiD, Anshu BhattacharyaORCiD, Denisa BojkovaORCiDGND, Ahmadreza MehdipourORCiDGND, Donghyuk ShinORCiD, Khadija Shahed KhanORCiD, Hayley Hei-Yin CheungORCiD, Kam-Bo Wong, Wai-Lung NgORCiD, Jindrich CinatlORCiD, Paul P. GeurinkORCiD, Gerbrand J. van der Heden van NoortORCiD, Krishnaraj RajalingamORCiDGND, Sandra CiesekORCiDGND, Gerhard HummerORCiD, Ivan ĐikićORCiDGND
Parent Title (English):The journal of biological chemistry
Publisher:ASBMB Publications
Place of publication:Bethesda, Md.
Document Type:Article
Date of Publication (online):2021/06/30
Date of first Publication:2021/06/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/06/15
Tag:SARS-CoV-2; antiviral signaling; famotidine; histamine; toll-like receptor
Issue:2, art. 100925
Article Number:100925
Page Number:14
First Page:1
Last Page:14
I. D. acknowledges funding support from the grants from Else Kroener Fresenius Stiftung; Dr Rolf M. Schwiete Stiftung and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project number 259130777 – SFB 1177, LYSFOR2625 (DFG) to A.B, WLN acknowledges funding support from CUHK (a seed fund from the Faculty of Medicine and a PIEF grant), and W. L. N. from CUHK (a seed fund, "Faculty Innovation Award," from the Faculty of Medicine and a PIEF grant) and Croucher Foundation (start-up fund). G. J. v. d. H. v. N. was funded by NWO (Vidi) and ZonMw (Off-road). A. R. M and G. H. thank the Max Planck Society for support. D. S. was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1C1C1003961) and the Yonsei University Research Fund of 2021 (2021-22-0050).
Biochemie, Chemie und Pharmazie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 53 Physik / 530 Physik
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0