Adenovirus 14p1 induced changes in miRNA expression increases lung immunopathogenesis

Abstract

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 around the world of infections with different adenoviral (Ad) serotypes that have resulted in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in some of those infected. Ad14p1, the predominant circulating strain of Ad14 worldwide is one such serotype. The explanations 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. Micro-RNAs (miRNA) are small noncoding RNAs that regulate gene expression at the posttranscriptional level. 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 impact pathogenesis. A549 cells were infected with either Ad14 or Ad14p1 and total RNA samples were collected at 6, 12, 24, 36 and 48 post infection for miRNA sequencing. Cluster analysis revealed that there were 3 temporal changes in miRNA expression profiles following infection. Differential expression analysis showed 8-23 differentially expressed miRNA between Ad14 and Ad14p1 from 6 to 36hpi. However, at 48hpi there were 98 differentially expressed miRNAs in Ad14p1 infected cells compared to those infected by Ad14. Pathway enrichment analysis showed that the differentially expressed miRNA might explain the increased pathogenesis of Ad14p1caused by strain-related loss of modulation of cytokine expression. Overall, the data suggest a role for viral regulation of host miRNA expression in pathogenesis by regulating host inflammatory responses through the delivery of deregulated miRNAs by virally infected cell corpses to macrophages.

Human adenovirus lung disease: outbreaks, models of immune-response-driven acute lung injury and pandemic potential

“…We have reported that immunocompetent Syrian hamsters are permissive for HAdV-14 and HAdV-14p1 infection and that 14p1 infection results in patchy bronchopneumonia in the hamster, in contrast to the minimal lung inflammatory response to infection with the prototype HAdV-14 strain [32 ▪ ]. Additional studies showed that that the lung pathogenesis induced in hamsters by 14p1 is similar to the pathogenesis observed in humans, including increased inflammation as a result of immune cell infiltration and increased cytokine expression in the lungs of 14p1 vs HAdV-14 infected hamsters [33 ▪ ,47 ▪ ]. While none of the 14p1 infected Syrian hamsters died with the infectious doses used in our studies, 14p1 infection induced the early inflammatory responses during ALI that could allow progression to ARDS.…”

“…This loss-of-function activity of HAdV-14p1 could be responsible for driving continued M1 polarization in the lungs of Ad14p1 infected individuals, allowing increased ALI and progression to ARDS. Recently, we have shown that cell corpses infected with the prototype HAdV-14 strain contain cellular microRNAs (miRNAs) that repress signal transduction pathways that would otherwise lead to the activation of pro-inflammatory cytokine expression [33 ▪ ]. Conversely, cell corpses infected with the HAdV14-p1 outbreak strain are not enriched in these same repressive miRNAs.…”