MICRONOME AND KSHV INFECTION: IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF CELLULAR MICRORNAS DURING VIRUS ENTRY

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Hosni Ahmed Mohamed Hussein (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) , is the most recently identified human herpesvirus and causes a variety of human malignancies. KSHV is etiologically associated with Kaposi's sarcoma (KS) , primary effusion lymphoma (PEL) , and multicentric Castleman disease (MCD). MicroRNAs (miRNAs) are small non-coding RNA molecules that play important post transcriptional regulatory roles in gene expression and can greatly influence virus-host cell interactions. KSHV is one of a few examples of viruses that encode their own miRNAs. KSHV encodes 12 pre-miRNAs which are processed to yield 25 mature miRNAs. To date , extensive work has been conducted on the expression and roles of cellular and KSHV-encoded miRNAs during virus latency , replication , and angiogenesis. However , little is currently known about the roles of microRNAs (miRNAs) in KSHV entry. In the following studies , we investigated the induction of cellular miRNA expression in response to initial stages of KSHV infection and their roles in virus entry. We employed deep sequencing to analyze miRNA expression in KSHV infected BJAB cells at 15min post infection (PI) and compared this to uninfected BJAB cells. The expression profile of cellular miRNAs was significantly altered in response to KSHV entry. Interestingly , expression of these KSHV-induced miRNAs noted during early stages of infection does not require virus replication , as UV-inactivated KSHV could induce the expression of cellular miRNAs to comparable levels as live wild-type KSHV. A synthetic mimic for miR-36 , a novel cellular miRNA expressed in response to KSHV infection , was able to significantly inhibit virus entry by targeting the expression of interferon induced transmembrane protein 1 (IFITM1). The effect of miR-36 on KSHV infection of cells was at a post-binding stage of virus entry. Similarly , miR-36 mimic inhibits infection of closely related DNA viruses: Epstein-Barr virus (EBV) , and herpes simplexvirus-2 (HSV-2). IFITM1 was observed to have a crucial role in the in vitro and in vivo infection of gammaherpesviruses. IFITM1-specific siRNA inhibits gammaherpesviruses infection in BJAB cells and BALB/c mice. Taken together , our studies provide new insights and appreciation for the role of the host cellular miRNAs to inhibit internalization of KSHV which may contribute to the development of miRNA-based antiviral therapy.

Additional Information

Publication

Dissertation

Language: English

Date: 2018

Keywords

Kaposi's sarcoma & IFITM1

Subjects

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