University Of Tasmania
TNF deficiency and Immunopathology.full.pdf (2.87 MB)

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

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journal contribution
posted on 2023-05-20, 16:09 authored by Tuazon Kels, MJ, Ng, E, Al Rumaih, Z, Pratikshya PandeyPratikshya Pandey, Ruuls, SR, Heinrich KornerHeinrich Korner, Newsome, TP, Chaudhri, G, Gunasegaran KarupiahGunasegaran Karupiah
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.


Publication title

Proceedings of the National Academy of Sciences of the United States of America










Tasmanian School of Medicine


Natl Acad Sciences

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2101 Constitution Ave Nw, Washington, USA, Dc, 20418

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Copyright 2020 PNAS

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  • Open

Socio-economic Objectives

Clinical health not elsewhere classified