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

Abstract

<jats:p>Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF<jats:sup>−/−</jats:sup>) also caused substantial pathology during respiratory ectromelia virus (ECTV) infection, a surrogate model for smallpox. TNF<jats:sup>−/−</jats:sup>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<jats:sup>−/−</jats:sup>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<jats:sup>−/−</jats:sup>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.</jats:p>

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

“…Disease and Increases Survival Rates. The increased production of a number of inflammatory cytokines in mice infected with mutant ECTV possibly contributed to the increased morbidity and mortality, as shown previously in ECTV-infected TNF −/− mice (41). We postulated that the in vivo blockade of some of these cytokines might reduce the severity of the clinical symptoms and lung pathology and possibly allow the recovery of mice infected with ECTV ΔCrmD or ECTV Rev.SECRET .…”

“…WT and TNF −/− mice do not express detectable levels of IFNγ, IL-6, IL-10, TGF-β, and TNF (WT mice only) (41). The cytokine responses to ECTV WT infection in WT and TM lungs were similar, whereas the levels of most mRNA transcripts were significantly higher in TNF −/− lungs compared to WT or TM lungs (Fig.…”

“…Mice were inoculated intranasally (i.n.) with virus and monitored for changes in body weight and disease signs, which are presented as clinical scores using a scoring system (SI Appendix, Table S3) (41).…”

“…We semiquantified the histopathological changes in the lungs using a scoring system (SI Appendix, Table S4) (41). Five distinct observations were made from the analysis.…”

Proposed Mechanisms of Targeting COVID-19 by Delivering Mesenchymal Stem Cells and Their Exosomes to Damaged Organs

“…It has been shown that TNF- α did not play a pivotal role in the clearance of viral infections such as influenza and poxvirus, while TNF-α depletion dysregulates antiviral inflammation. Highly expressed TNF-α results in lung tissue fibrotic remodeling by inducing uncontrolled recruitment of immune cells and decreased level of antioxidant molecules in parenchymal and endothelial cells of lung tissue [ 34 , 35 ]. TNF- α activates the host cells' extrinsic apoptotic pathway by activating death receptors TNFR1, Fas, and TNF-related apoptosis-inducing ligand (TRAIL) [ 36 , 37 ].…”