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


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, 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, 117, (43) pp. 26885-26894. ISSN 0027-8424 (2020) [Refereed Article]

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Copyright 2020 the authors

DOI: doi:10.1073/pnas.2004688117


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 Details

Item Type:Refereed Article
Keywords:TNF, Immune evasion, inflammation
Research Division:Biomedical and Clinical Sciences
Research Group:Medical microbiology
Research Field:Medical virology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Prevention of human diseases and conditions
UTAS Author:Pandey, P (Mrs Pratikshya Pandey)
UTAS Author:Karupiah, G (Associate Professor Guna Karupiah)
ID Code:142701
Year Published:2020
Web of Science® Times Cited:3
Deposited By:Medicine
Deposited On:2021-02-07
Last Modified:2022-08-25

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