Differential Expression of Host miRNAs During Ad14 and Ad14p1 Infection.

Adenovirus is a frequent cause of mild, usually self-limited infections in infants and young children. Severe infections occur in immunocompromised patients but are rarely observed in healthy, immunocompetent adults. However, there have been outbreaks of infections with different adenoviral (Ad) types around the world that have resulted in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in some of those infected. Ad14p1 is the predominant circulating strain of Ad14 worldwide that has caused ARDS. An explanation for the severity of illness caused by Ad14p1 infection in immunocompetent patients is unknown. Previously, we have shown that A549 cells infected with Ad14 repress macrophage pro-inflammatory responses, whereas cells infected with Ad14p1 fail to repress macrophages and instead can increase pro-inflammatory responses. Adenoviral infection has been shown to modulate host miRNA expression, and we hypothesized that differences in miRNA expression between Ad14- and Ad14p1-infected cells might explain the differential responses of macrophages to Ad14- and Ad14p1-infected cells. Analysis of host miRNA showed that 98 miRNAs are differentially expressed when infection reaches full cytopathic effect (CPE), the same point at which Ad14 and Ad14p1 CPE corpses induce differential inflammatory responses in macrophages. Only 10 of the miRNAs that were enriched in Ad14 CPE corpses were expressed at levels that are potentially biologically relevant. Pathway enrichment analysis showed that the differentially expressed miRNAs might explain the increased pathogenesis of Ad14p1 through strain-related loss of modulation of cytokine expression when compared with prototype Ad14. Overall, the data suggest a role for viral regulation of host miRNA expression in pathogenesis by regulating host inflammatory responses through the delivery of de-regulated miRNAs by viral CPE corpses to macrophages.