Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against acute viral infection

The pulmonary immune system consists of a network of tissue-resident cells as well as immune cells that are recruited to the lungs during infection and/or inflammation. How these immune components communicate during an acute DNA viral infection is not well understood. Intranasal infection of mice with vaccinia virus causes lethal pneumonia and systemic dissemination. Here we report that vaccinia host range protein C7 is a critical virulence factor. We provide evidence that lung type II alveolar epithelial cells (AECIIs) provide first-line of defense against viral infection by inducing IFN-b and IFN-stimulated genes via the activation of the MDA5 and STING-mediated nucleic acid-sensing pathways and the type I IFN positive feedback loop. This leads to the recruitment and activation of CCR2+ inflammatory monocytes in the lungs, which are indispensable to fight against viral dissemination. Our data provide novel insights into how the lung AECIIs orchestrate innate immune responses to defend pulmonary viral infection. RNAseq of delta C7 vaccinia virus infection in lung AECII cells from WT or MDA5/STING KO mice; RNAseq of lung AECII cells treated with interferon beta; RNAseq of lung monocytes with WT or delta C7 vaccinia virus