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TNF deficiency dysregulates inflammatory cytokine production, leading to lung pathology and death during respiratory poxvirus infection

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Tuazon Kels, MJ, Ng, E, Al Rumaih, Z, Pandey, P, Ruuls, SR, Korner, H ORCID: 0000-0003-4610-2814, Newsome, TP, Chaudhri, G and Karupiah, G ORCID: 0000-0001-6306-4405 2020 , 'TNF deficiency dysregulates inflammatory cytokine production, leading to lung pathology and death during respiratory poxvirus infection' , Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 27 , 15935–15946 , doi: 10.1073/pnas.2004615117.

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Abstract

Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused substantial pathology during respiratory ectromelia virus (ECTV) infection, a surrogate model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those engineered to express only transmembrane TNF (mTNF), fully recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines interleukin (IL)-6, IL-10, transforming growth factor beta (TGF-β), and interferon gamma (IFN-γ). Short-term blockade of these cytokines significantly reduced lung pathology in TNF-/- mice concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Consequently, inhibition of STAT3 activation with an inhibitor reduced lung pathology. Long-term neutralization of IL-6 or TGF-β protected TNF-/- mice from an otherwise lethal infection. Thus, mTNF alone is necessary and sufficient to regulate lung inflammation but it has no direct antiviral activity against ECTV. The data indicate that targeting specific cytokines or cytokine-signaling pathways to reduce or ameliorate lung inflammation during respiratory viral infections is possible but that the timing and duration of the interventive measure are critical.

Item Type: Article
Authors/Creators:Tuazon Kels, MJ and Ng, E and Al Rumaih, Z and Pandey, P and Ruuls, SR and Korner, H and Newsome, TP and Chaudhri, G and Karupiah, G
Keywords: STAT3 dysregulation, dysregulated cytokine response, lung inflammation and pathology, respiratory poxvirus infection, tumor necrosis factor deficiency
Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
Publisher: Natl Acad Sciences
ISSN: 0027-8424
DOI / ID Number: 10.1073/pnas.2004615117
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Copyright 2020 PNAS

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