Innate Immune Response to Influenza A Virus in Differentiated Human Alveolar Type II Cells

Abstract

Alveolar Type II (ATII) cells are important targets for seasonal and pandemic influenza. To investigate the influenza-induced innate immune response in those cells, we measured the global gene expression profile of highly differentiated ATII cells infected with the influenza A virus at a multiplicity of infection of 0.5 at 4 hours and 24 hours after inoculation. Infection with influenza stimulated a significant increase in the mRNA concentrations of many host defense-related genes, including pattern/pathogen recognition receptors, IFN, and IFN-induced genes, chemokines, and suppressors of cytokine signaling. We verified these changes by quantitative real-time RT-PCR. At the protein level, we detected a robust virus-induced secretion of the three glutamic acid-leucine-arginine (ELR)-negative chemokines CXCL9, CXCL10, and CXCL11, according to ELISA. The ultraviolet inactivation of virus abolished the chemokine and cytokine response. Viral infection did not appear to alter the differentiation of ATII cells, as measured by cellular mRNA and concentrations of surfactant proteins. However, viral infection significantly reduced the secretion of surfactant protein (SP)-A and SP-D. In addition, influenza A virus triggered a time-dependent activation of phosphatidylinositol 3-kinase signaling in ATII cells. The inhibition of this pathway significantly decreased the release of infectious virus and the chemokine response, but did not alter virus-induced cell death. This study provides insights into influenza-induced innate immunity in differentiated human ATII cells, and demonstrates that the alveolar epithelium is a critical part of the initial innate immune response to influenza.

Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant

“…Primary human ATII cells were isolated and cultured as described (14). The human lungs, from de-identified organ donors whose lungs were not suitable for transplantation, were obtained through the International Institute for the Advancement of Medicine (Edison, NJ) and the Center for Organ Recovery (Pittsburgh, PA).…”

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

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Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

“…In cultured primary human alveolar type II pneumocytes (ATII), influenza infection was found to down-regulate LCAD mRNA, whereas other FAO genes were not affected (12). Similarly, based on microarray studies in lung tumors, LCAD was included in a core set of genes whose expression levels distinguish cancerous from normal tissue (13).…”