NDLI: Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness

Content Provider	Springer Nature : BioMed Central
Author	Yates, Abi G. Weglinski, Caroline M. Ying, Yuxin Dunstan, Isobel K. Strekalova, Tatyana Anthony, Daniel C.
Abstract	Background The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. Methods CD-1 mice received an intraperitoneal injection of R848 (200 μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 μL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. Results R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. Conclusions Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.
Related Links	https://jneuroinflammation.biomedcentral.com/counter/pdf/10.1186/s12974-021-02357-y.pdf
Ending Page	16
Page Count	16
Starting Page	1
File Format	HTM / HTML
ISSN	17422094
DOI	10.1186/s12974-021-02357-y
Journal	Journal of Neuroinflammation
Issue Number	1
Volume Number	19
Language	English
Publisher	BioMed Central
Publisher Date	2022-01-06
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Neurobiology Immunology Nafamostat Viral infection Inflammation Sickness behaviour COVID-19
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology Cellular and Molecular Neuroscience Neurology
Journal Impact Factor	9.3/2023
5-Year Journal Impact Factor	9.8/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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