Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:297 |
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| Enthalten in: |
The Journal of biological chemistry - 297(2021), 2 vom: 22. Aug., Seite 100925 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mukherjee, Rukmini [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.09.2021 Date Revised 03.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2021.100925 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM327611723 |
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| 100 | 1 | |a Mukherjee, Rukmini |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection |
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| 500 | |a Date Completed 13.09.2021 | ||
| 500 | |a Date Revised 03.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a antiviral signaling | |
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| 700 | 1 | |a Bojkova, Denisa |e verfasserin |4 aut | |
| 700 | 1 | |a Mehdipour, Ahmad Reza |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Donghyuk |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Khadija Shahed |e verfasserin |4 aut | |
| 700 | 1 | |a Hei-Yin Cheung, Hayley |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Kam-Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Ng, Wai-Lung |e verfasserin |4 aut | |
| 700 | 1 | |a Cinatl, Jindrich |e verfasserin |4 aut | |
| 700 | 1 | |a Geurink, Paul P |e verfasserin |4 aut | |
| 700 | 1 | |a van der Heden van Noort, Gerbrand J |e verfasserin |4 aut | |
| 700 | 1 | |a Rajalingam, Krishnaraj |e verfasserin |4 aut | |
| 700 | 1 | |a Ciesek, Sandra |e verfasserin |4 aut | |
| 700 | 1 | |a Hummer, Gerhard |e verfasserin |4 aut | |
| 700 | 1 | |a Dikic, Ivan |e verfasserin |4 aut | |
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