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Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection

Al Rumaih, Z, Kels, MJT, Ng, E, Pandey, P, Pontejo, SM, Alejo, A, Alcami, A, Chaudhri, G and Karupiah, G ORCID: 0000-0001-6306-4405 2020 , 'Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection' , National Academy of Sciences of The United States of America. Proceedings, vol. 117, no. 43 , pp. 26885-26894 , doi: 10.1073/pnas.2004688117.

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Abstract

Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both orthopoxviruses encode tumor necrosis factor receptor (TNFR) homologs or viral TNFR (vTNFR). These homologs are termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain called smallpox virus-encoded chemokine receptor (SECRET) domain. ECTV encodes one vTNFR known as CrmD. Infection of ECTV-resistant C57BL/6 mice with a CrmD deletion mutant virus resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production. CrmD dampened pathology, leukocyte recruitment, and inflammatory cytokine production in lungs including TNF, IL-6, IL-10, and IFN-γ. Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung pathology and provided 60 to 100% protection from otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were absent. Presence of the SECRET domain alone induced significantly higher levels of IL-1β, IL-6, and IL-10, likely overcoming any protective effects that might have been afforded by anti–IFN-γ treatment. The use of TNF-deficient mice and those that express only membrane-associated but not secreted TNF revealed that CrmD is critically dependent on host TNF for its function. In vitro, recombinant Crm proteins from different orthopoxviruses bound to membrane-associated TNF and dampened inflammatory gene expression through reverse signaling. CrmD does not affect virus replication; however, it provides the host advantage by enabling survival. Host survival would facilitate virus spread, which would also provide an advantage to the virus.

Item Type: Article
Authors/Creators:Al Rumaih, Z and Kels, MJT and Ng, E and Pandey, P and Pontejo, SM and Alejo, A and Alcami, A and Chaudhri, G and Karupiah, G
Keywords: TNF, Immune evasion, inflammation
Journal or Publication Title: National Academy of Sciences of The United States of America. Proceedings
Publisher: Natl Acad Sciences
ISSN: 0027-8424
DOI / ID Number: 10.1073/pnas.2004688117
Copyright Information:

Copyright 2020 the authors

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