Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

Abstract

Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155. (Am J Pathol 2017, 187: 851e863; http://dx

Down-regulation of miR-155 inhibits inflammatory response in human pulmonary microvascular endothelial cells infected with influenza A virus by targeting sphingosine-1-phosphate receptor 1

“…[ 15 ] miR-155 knockout mice have been found to recover from influenza infection faster than wide type mice. [ 26 ] Similar to this, another study found that knocking out of miR-155 could protect mice from influenza and Staphylococcus aureus superinfection. [ 24 ] These findings suggest a crucial role of miR-155 in the pathogenesis of influenza infection, which was confirmed in this study.…”

Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection

“…As such, we measured influenza burden by real-time qPCR for the viral M1 gene as we have previously described. 5,23 We found that despite the differences in weight loss, there were no significant differences in viral burden between Il22ra2 −/− and WT mice at 6 dpi (days post infection) and both groups cleared the virus by day 10 (Fig. 2b).…”

Integrative Physiology of Pneumonia

“…Presumably because of the infections experienced, the co-housing of laboratory mice with mice purchased from pet stores is sufficient to thereafter increase the numbers of innate lymphocyte populations in the lungs, including ILC1, ILC2, ILC3, and ␥␦-T cells (34). Infection with influenza virus is capable of altering the phenotypes of alveolar macrophages and epithelial cells in the mouse lung for months afterwards (107,247,394). The degrees to which BALT, innate lymphocyte accumulation, and such remodeling of epithelial cells and macrophages reflects chronic inflammation, trained immunity (363), aberrant repair, or all of the above, and the factors influencing these and other long-term changes in the lung occasionally observed after respiratory infection, are largely unclear.…”