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Differential Expression of Host miRNAs During Ad14 and Ad14p1 Infection
Eric R McIndoo1, Ethan Wood1,2, Gina Kuffel3
1Research Section, Boise Veteran Affairs Medical Center and Idaho Veterans Research & Education Foundation, Boise, ID 83702, USA.
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 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.
Insights
Adenovirus type 14p1 (Ad14p1) causes severe lung injury by dysregulating host microRNAs (miRNAs), unlike less pathogenic adenovirus strains. This study reveals how Ad14p1 alters miRNA expression, leading to heightened inflammation in immunocompetent individuals.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Adenovirus infections are typically mild in children but can cause severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in some individuals.
- Adenovirus type 14p1 (Ad14p1) is a globally prevalent strain associated with ARDS, yet the reasons for its severity in immunocompetent hosts remain unclear.
- Previous research indicated that Ad14-infected cells suppress macrophage inflammatory responses, while Ad14p1-infected cells enhance them.
Purpose of the Study:
- To investigate the role of host microRNA (miRNA) expression differences between Ad14 and Ad14p1 infections in modulating macrophage inflammatory responses.
- To elucidate the mechanisms by which Ad14p1 causes more severe illness compared to Ad14 in immunocompetent individuals.
Main Methods:
- Comparative analysis of host miRNA expression profiles in cells infected with Ad14 and Ad14p1 at the stage of full cytopathic effect (CPE).
- Assessment of differential inflammatory responses induced by Ad14 and Ad14p1 CPE corpses in macrophages.
- Pathway enrichment analysis of differentially expressed miRNAs to identify potential pathogenic mechanisms.
Main Results:
- Ninety-eight miRNAs were differentially expressed between Ad14- and Ad14p1-infected cells at full CPE.
- Only 10 enriched miRNAs in Ad14 CPE were found at potentially biologically relevant levels.
- Pathway analysis suggested that differentially expressed miRNAs contribute to Ad14p1's increased pathogenesis by impairing cytokine expression modulation compared to Ad14.
Conclusions:
- Viral regulation of host miRNA expression plays a significant role in adenovirus pathogenesis.
- Ad14p1 infection leads to de-regulated miRNA delivery via CPE corpses to macrophages, resulting in heightened inflammatory responses and increased severity of illness.
- Understanding these miRNA-mediated mechanisms is crucial for explaining Ad14p1's virulence in immunocompetent hosts.
