Abstract Title

Ad 14 VA RNA Encoded MiRNAs Regulate Host's Transcription

Additional Funding Sources

The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant No. P20GM103408, COBRE IVREF, and INBRE- Nevada.

Abstract

Human adenoviruses (Ad) encode numerous genes that regulate the innate immune response to viral infection. Virus-associated RNA (VA RNA) is a non-coding RNA found in all human Ad genomes. VA RNA is required for efficient viral replication and plays a role in modulating the cellular innate immune response to infection. The stem-loop structure of VA RNA resembles human precursor-microRNAs (pre-miRNA) and like pre-miRNA, VA RNA is processed by Dicer into small RNAs (mivaRNA) analogous to human miRNA. Ad14 is a human respiratory virus that induces self-limiting infections in immunocompetent patients. Ad14p1 is an emergent strain of Ad14 that can induce acute respiratory distress syndrome (ARDS) in otherwise healthy individuals. Patients that develop ARDS have a 50% mortality rate. In the Syrian hamster we have shown that Ad14p1 induces early ARDS-like responses while infection with Ad14 does not. To date there is no known role of VA RNA in Ad pathogenesis. Recent studies in our laboratory have identified the mivaRNAs produced during infection and bioinformatic analysis has identified over 1900 potential cellular targets. The objective of these studies was to understand the role of mivaRNA in regulating host gene expression. Bioinformatic analysis showed that overall host gene expression was similar between Ad14 and Ad14p1 infection. Analysis of predicted mivaRNA target gene expression showed that Ad14 downregulates expression of more predicted genes than Ad14p1. To directly assess the ability of mivaRNA to alter gene expression a reporter vector was constructed that contained sequences complementary to the mivaRNA seed sequence in the 3′ UTR of luciferase. Our data shows that Ad14 infection results in luciferase activity that is 50% lower than uninfected A549 cells. The data show that Ad14/Ad14p1 mivaRNA regulates host gene expression.

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Ad 14 VA RNA Encoded MiRNAs Regulate Host's Transcription

Human adenoviruses (Ad) encode numerous genes that regulate the innate immune response to viral infection. Virus-associated RNA (VA RNA) is a non-coding RNA found in all human Ad genomes. VA RNA is required for efficient viral replication and plays a role in modulating the cellular innate immune response to infection. The stem-loop structure of VA RNA resembles human precursor-microRNAs (pre-miRNA) and like pre-miRNA, VA RNA is processed by Dicer into small RNAs (mivaRNA) analogous to human miRNA. Ad14 is a human respiratory virus that induces self-limiting infections in immunocompetent patients. Ad14p1 is an emergent strain of Ad14 that can induce acute respiratory distress syndrome (ARDS) in otherwise healthy individuals. Patients that develop ARDS have a 50% mortality rate. In the Syrian hamster we have shown that Ad14p1 induces early ARDS-like responses while infection with Ad14 does not. To date there is no known role of VA RNA in Ad pathogenesis. Recent studies in our laboratory have identified the mivaRNAs produced during infection and bioinformatic analysis has identified over 1900 potential cellular targets. The objective of these studies was to understand the role of mivaRNA in regulating host gene expression. Bioinformatic analysis showed that overall host gene expression was similar between Ad14 and Ad14p1 infection. Analysis of predicted mivaRNA target gene expression showed that Ad14 downregulates expression of more predicted genes than Ad14p1. To directly assess the ability of mivaRNA to alter gene expression a reporter vector was constructed that contained sequences complementary to the mivaRNA seed sequence in the 3′ UTR of luciferase. Our data shows that Ad14 infection results in luciferase activity that is 50% lower than uninfected A549 cells. The data show that Ad14/Ad14p1 mivaRNA regulates host gene expression.