Dataset Information

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters.

ABSTRACT: Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double-stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-complementary adeno-associated virus (scAAV) vectors for treatment of hAd5 infections in immunosuppressed Syrian hamsters. In vitro evaluation of amiRs targeting the E1A, pTP, IVa2, and hexon genes of hAd5 revealed that two scAAV vectors containing three copies of amiR-pTP and three copies of amiR-E1A, or six copies of amiR-pTP, efficiently inhibited hAd5 replication and improved the viability of hAd5-infected cells. Prophylactic application of amiR-pTP/amiR-E1A- and amiR-pTP-expressing scAAV9 vectors, respectively, to immunosuppressed Syrian hamsters resulted in the reduction of hAd5 levels in the liver of up to two orders of magnitude and in reduction of liver damage. Concomitant application of the vectors also resulted in a decrease of hepatic hAd5 infection. No side effects were observed. These data demonstrate anti-adenoviral RNAi as a promising new approach to combat hAd5 infection.

SUBMITTER: Schaar K

PROVIDER: S-EPMC5537171 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters.

Schaar Katrin K Geisler Anja A Kraus Milena M Pinkert Sandra S Pryshliak Markian M Spencer Jacqueline F JF Tollefson Ann E AE Ying Baoling B Kurreck Jens J Wold William S WS Klopfleisch Robert R Toth Karoly K Fechner Henry H

Molecular therapy. Nucleic acids 20170708

Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double-stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-com ...[more]

PMID: 28918031

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Project description: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. Infection with Ad14p1 results in increased expression of pro-inflammatory genes in the lungs of Syrian hamsters than infection with 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 deregulated miRNAs by virally infected cell corpses to macrophages.

Dataset Information

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters.

Publications

Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters.

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