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A comprehensive study on cellular RNA editing activity in response to infections with different subtypes of influenza a viruses.

ABSTRACT: RNA editing is an important mechanism that expands the diversity and complexity of genetic codes. The conversions of adenosine (A) to inosine (I) and cytosine (C) to uridine (U) are two prominent types of RNA editing in animals. The roles of RNA editing events have been implicated in important biological pathways. Cellular RNA editing activity in response to influenza A virus infection has not been fully characterized in human and avian hosts. This study was designed as a big data analysis to investigate the role and response of RNA editing in epithelial cells during the course of infection with various subtypes of influenza A viruses.Using a bioinformatics pipeline modified from our previous study, we characterized the profiles of A-to-I and C-to-U RNA editing events in human epithelial cells during the course of influenza A virus infection. Our results revealed a striking diversity of A-to-I RNA editing activities in human epithelial cells in responses to different subtypes of influenza A viruses. The infection of H1N1 and H3N2 significantly up-regulated normalized A-to-I RNA editing levels in human epithelial cells, whereas that of H5N1 did not change it and H7N9 infection significantly down-regulated normalized A-to-I editing level in A549 cells. Next, the expression levels of ADAR and APOBEC enzymes responsible for A-to-I and C-to-U RNA editing during the course of virus infection were examined. The increase of A-to-I RNA editing activities in infections with some influenza A viruses (H1N1 and H3N2) is linked to the up-regulation of ADAR1 but not ADAR2. Further, the pattern recognition receptors of human epithelial cells infected with H1N1, H3N2, H5N1 and H7N9 were examined. Variable responsive changes in gene expression were observed with RIG-I like receptors and Toll like receptors. Finally, the effect of influenza A virus infection on cellular RNA editing activity was also analyzed in avian hosts.This work represents the first comprehensive study of cellular RNA editing activity in response to different influenza A virus infections in human and avian hosts, highlighting the critical role of RNA editing in innate immune response and the pathogenicity of different subtypes of influenza A viruses.

SUBMITTER: Cao Y

PROVIDER: S-EPMC5780764 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A comprehensive study on cellular RNA editing activity in response to infections with different subtypes of influenza a viruses.

Cao Yingying Y Cao Ruiyuan R Huang Yaowei Y Zhou Hongxia H Liu Yuanhua Y Li Xuan X Zhong Wu W Hao Pei P

BMC genomics 20180119 Suppl 1

<h4>Background</h4>RNA editing is an important mechanism that expands the diversity and complexity of genetic codes. The conversions of adenosine (A) to inosine (I) and cytosine (C) to uridine (U) are two prominent types of RNA editing in animals. The roles of RNA editing events have been implicated in important biological pathways. Cellular RNA editing activity in response to influenza A virus infection has not been fully characterized in human and avian hosts. This study was designed as a big ...[more]

PMID: 29363430

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Project description:Adenosine-to-Inosine (A-to-I) RNA editing is catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes, which induces alterations in mRNA sequence. It has been shown that A-to-I RNA editing events are of significance in the cell's innate immunity and cellular response to viral infections. However, whether RNA editing plays a role in cellular response to microorganism/fungi infection has not been determined. Candida albicans, one of the most prevalent human pathogenic fungi, usually act as a commensal on skin and superficial mucosal, but has been found to cause candidiasis in immunosuppression patients. Previously, we have revealed the up-regulation of A-to-I RNA editing activity in response to different types of influenza virus infections. The current work is designed to study the effect of microorganism/fungi infection on the activity of A-to-I RNA editing in infected hosts.We first detected and characterized the A-to-I RNA editing events in oral epithelial cells (OKF6) and primary human umbilical vein endothelial cells (HUVEC), under normal growth condition or with C. albicans infection. Eighty nine thousand six hundred forty eight and 60,872 A-to-I editing sites were detected in normal OKF6 and HUVEC cells, respectively. They were validated against the RNA editing databases, DARNED, RADAR, and REDIportal with 50, 80, and 80% success rates, respectively. While over 95% editing sites were detected in Alu regions, among the rest of the editing sites in non repetitive regions, the majority was located in introns and UTRs. The distributions of A-to-I editing activity and editing depth were analyzed during the course of C. albicans infection. While the normalized editing levels of common editing sites exhibited a significant increase, especially in Alu regions, no significant change in the expression of ADAR1 or ADAR2 was observed. Second, we performed further analysis on data from in vivo mouse study with C. albicans infection. One thousand one hundred thirty three and 955 A-to-I editing sites were identified in mouse tongue and kidney tissues, respectively. The number of A-to-I editing events was much smaller than in human epithelial or endothelial cells, due to the lack of Alu elements in mouse genome. Furthermore, during the course of C. albicans infection we observed stable level of A-to-I editing activity in 131 and 190 common editing sites in the mouse tongue and kidney tissues, and found no significant change in ADAR1 or ADAR2 expression (with the exception of ADAR2 displaying a significant increase at 12 h after infection in mouse kidney tissue before returning to normal).This work represents the first comprehensive analysis of A-to-I RNA editome in human epithelial and endothelial cells. C. albicans infection of human epithelial and endothelial cells led to the up-regulation of A-to-I editing activities, through a mechanism different from that of viral infections in human hosts. However, the in vivo mouse model with C. albicans infection did not show significant changes in A-to-I editing activities in tongue and kidney tissues. The different results in the mouse model were likely due to the presence of more complex in vivo environments, e.g. circulation and mixed cell types.

Project description:BackgroundInnate immunity provides first line of defense against viral infections. The interactions between hosts and influenza A virus and the response of host innate immunity to viral infection are critical determinants for the pathogenicity or virulence of influenza A viruses. This study was designed to investigate global changes of gene expression and detailed responses of innate immune systems in human and avian hosts during the course of infection with various subtypes of influenza A viruses, using collected and self-generated transcriptome sequencing data from human bronchial epithelial (HBE), human tracheobronchial epithelial (HTBE), and A549 cells infected with influenza A virus subtypes, namely H1N1, H3N2, H5N1 HALo mutant, and H7N9, and from ileum and lung of chicken and quail infected with H5N1, or H5N2.ResultsWe examined the induction of various cytokines and chemokines in human hosts infected with different subtypes of influenza A viruses. Type I and III interferons were found to be differentially induced with each subtype. H3N2 caused abrupt and the strongest response of IFN-β and IFN-λ, followed by H1N1 (though much weaker), whereas H5N1 HALo mutant and H7N9 induced very minor change in expression of type I and III interferons. Similarly, differential responses of other innate immunity-related genes were observed, including TMEM173, MX1, OASL, IFI6, IFITs, IFITMs, and various chemokine genes like CCL5, CX3CL1, and chemokine (C-X-C motif) ligands, SOCS (suppressors of cytokine signaling) genes. Third, the replication kinetics of H1N1, H3N2, H5N1 HALo mutant and H7N9 subtypes were analyzed, H5N1 HALo mutant was found to have the highest viral replication rate, followed by H3N2, and H1N1, while H7N9 had a rate similar to that of H1N1 or H3N2 though in different host cell type.ConclusionOur study illustrated the differential responses of innate immunity to infections of different subtypes of influenza A viruses. We found the influenza viruses which induced stronger innate immune responses replicate slower than those induces weaker innate immune responses. Our study provides important insight into links between the differential innate immune responses from hosts and the pathogenicity/ virulence of different subtypes of influenza A viruses.

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A comprehensive study on cellular RNA editing activity in response to infections with different subtypes of influenza a viruses.

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A comprehensive study on cellular RNA editing activity in response to infections with different subtypes of influenza a viruses.

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