Disulfiram attenuates MCMV-Induced pneumonia by inhibition of NF-κB/NLRP3 signaling pathway in immunocompromised mice

Abstract

Cytomegalovirus (CMV) pneumonia in immunocompromised individuals is associated with damaging hyperinflammation and leads to high morbidity and mortality. It is urgently needed to develop new strategies to treat CMV-induced pneumonia. As disulfiram (DSF) reportedly inhibits inflammatory responses in different disease models, its therapeutic effects in CMV-induced pneumonia are proposed. In this study, we demonstrated that DSF effectively attenuated pulmonary injury and improved survival in murine CMV (MCMV) pneumonia model. DSF treatment inhibited lung inflammatory responses, e.g. reducing pro-inflammatory cytokines, upregulating anti-inflammatory cytokine, and lowering the accumulation of leukocytes in the lung. Similar to the in vivo results, DSF attenuated inflammatory responses and modulated NF-κB/NLRP3 inflammasome activation in MCMV-infected BMDMs. Furthermore, DSF reduced pulmonary fibrosis and viral loads in MCMV pneumonia mice and BMDMs. The mechanism of anti-inflammatory effects of DSF may due to its regulating NF-κB signaling and NLRP3 inflammasome activation. Collectively, our results suggest that DSF-mediated anti-hyperinflammatory effects have potentials for therapy of human CMV pneumonia.

Keywords: Cytomegalovirus; Disulfiram; Inflammatory response; NF-κB; NLRP3 inflammasome; Pneumonia.