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

Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused significant pathology during respiratory ectromelia virus (ECTV) infection, a surrogate mouse model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those expressing only transmembrane TNF, recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines IL-6, IL-10, TGF-{beta}, and IFN-{gamma}. Blockade of these cytokines reduced lung pathology concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Short-term inhibition of STAT3 activation in ECTV-infected TNF-/- mice with an inhibitor reduced lung pathology. TNF is essential for regulating inflammation and its deficiency exacerbates ECTV infection as a consequence of significant lung pathology caused by dysregulation of inflammatory cytokine production, in part via overactivation of STAT3.