TY  - JOUR
A1  - Mukherjee, Rukmini
A1  - Bhattacharya, Anshu
A1  - Bojkova, Denisa
A1  - Mehdipour, Ahmadreza
A1  - Shin, Donghyuk
A1  - Shahed Khan, Khadija
A1  - Cheung, Hayley Hei-Yin
A1  - Wong, Kam-Bo
A1  - Ng, Wai-Lung
A1  - Cinatl, Jindrich
A1  - Geurink, Paul P.
A1  - Heden van Noort, Gerbrand J. van der
A1  - Rajalingam, Krishnaraj
A1  - Ciesek, Sandra
A1  - Hummer, Gerhard
A1  - Đikić, Ivan
T1  - Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection
T2  - The journal of biological chemistry
N2  - 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.
KW  - famotidine
KW  - toll-like receptor
KW  - SARS-CoV-2
KW  - antiviral signaling
KW  - histamine
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63087
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-630871
SN  - 1083-351X
N1  - 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).
VL  - 297.2021
IS  - 2, art. 100925
SP  - 1
EP  - 14
PB  - ASBMB Publications
CY  - Bethesda, Md.
ER  -