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

Significance Excessive tumor necrosis factor (TNF) production during some respiratory viral infections is associated with lung pathology and death. We show here that deficiency in TNF also causes significant pathology during respiratory poxvirus infection of mice but has no effect on viral load. TNF deficiency causes increased production of interleukin (IL)-6, IL-10, transforming growth factor beta, and interferon gamma and overactivation of STAT3 signaling. Cytokine blockade, or STAT3 inactivation, ameliorates lung pathology in TNF-deficient mice. The membrane form of TNF alone is necessary and sufficient for regulating inflammation and the prevention of lung pathology. Targeting specific cytokines or cytokine signaling pathways to can ameliorate lung inflammation during respiratory viral infections but the timing and duration of the interventive measures are critical.