IFITM1 expression is crucial to gammaherpesvirus infection, in vivo

Hosni A M Hussein,Shaw M Akula,Katarina Briestenska,Jela Mistrikova

doi:10.1038/s41598-018-32350-0

Abstract

The oncogenic gammaherpesviruses, Epstein–Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV), are etiologically associated with a variety of human cancers, including Burkitt’s lymphoma (BL), Hodgkin lymphoma (HL), Kaposi’s sarcoma (KS), and primary effusion lymphoma (PEL). Recently, we demonstrated KSHV infection of B- and endothelial cells to significantly upregulate the expression of interferon induced transmembrane protein 1 (IFITM1) which in turn enhances virus entry. This is an extension of the above study. In here, we determined EBV infection of cells to trigger IFITM1 expression, in vitro. Silencing IFITM1 expression using siRNA specifically lowered gammaherpesvirus infection of cells at a post binding stage of entry. A natural model system to explore the effect of IFITM1 on gammaherpesvirus infection in vivo is infection of BALB/c mice with murine gammaherpesvirus 68 (MHV-68). Priming mice with siRNA specific to IFITM1 significantly lowered MHV-68 titers in the lung specimens compared to priming with (NS)siRNA or PBS. MHV-68 titers were monitored by plaque assay and qPCR. Taken together, for the first time, this study provides insight into the critical role of IFITM1 to promoting in vivo gammaherpesvirus infections.

Highlights

The oncogenic gammaherpesviruses, Epstein–Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV), are etiologically associated with a variety of human cancers, including Burkitt’s lymphoma (BL), Hodgkin lymphoma (HL), Kaposi’s sarcoma (KS), and primary effusion lymphoma (PEL)
In a recently concluded study, we demonstrated the ability of KSHV to induce interferon induced transmembrane protein 1 (IFITM1) expression during early stages of infection[10]
IFITM1 transcript (Fig. 1A) and protein expression (Fig. 1B) levels were significantly elevated with EBV and KSHV infection of BJAB cells

Summary

Introduction

The oncogenic gammaherpesviruses, Epstein–Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV), are etiologically associated with a variety of human cancers, including Burkitt’s lymphoma (BL), Hodgkin lymphoma (HL), Kaposi’s sarcoma (KS), and primary effusion lymphoma (PEL). We demonstrated KSHV infection of B- and endothelial cells to significantly upregulate the expression of interferon induced transmembrane protein 1 (IFITM1) which in turn enhances virus entry. This is an extension of the above study. We determined that interferon (IFN)-induced transmembrane-1 (IFITM1) expression to significantly enhance KSHV infection of human B and endothelial cells[10]. In opposition to this process, over-expression of microRNA (miRNA)-36 (miR-36) significantly lowered expression of IFITM1 and the virus entry. We provide pioneering evidence to demonstrate a key role for IFITM1 in the in vitro and in vivo infection of γ-herpesviruses

Methods

Results

Conclusion