Abstract
Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes which results in significant morbidity and mortality, especially in women, worldwide. HSV-2 is transmitted primarily through infection of epithelial cells at skin and mucosal surfaces. Our earlier work to examine interactions between HSV-2 and vaginal epithelial cells demonstrated that infection of the human vaginal epithelial cell line (VK2) with HSV-2 resulted in increased expression of TRIM26, a negative regulator of the Type I interferon pathway. Given that upregulation of TRIM26 could negatively affect anti-viral pathways, we decided to further study the role of TRIM26 in HSV-2 infection and replication. To do this, we designed and generated two cell lines derived from VK2s with TRIM26 overexpressed (OE) and knocked out (KO). Both, along with wildtype (WT) VK2, were infected with HSV-2 and viral titres were measured in supernatants 24 h later. Our results showed significantly enhanced virus production by TRIM26 OE cells, but very little replication in TRIM26 KO cells. We next examined interferon-β production and expression of two distinct interferon stimulated genes (ISGs), MX1 and ISG15, in all three cell lines, prior to and following HSV-2 infection. The absence of TRIM26 (KO) significantly upregulated interferon-β production at baseline and even further after HSV-2 infection. TRIM26 KO cells also showed significant increase in the expression of MX1 and ISG15 before and after HSV-2 infection. Immunofluorescent staining indicated that overexpression of TRIM26 substantially decreased the nuclear localization of IRF3, the primary mediator of ISG activation, before and after HSV-2 infection. Taken together, our data indicate that HSV-2 utilizes host factor TRIM26 to evade anti-viral response and thereby increase its replication in vaginal epithelial cells.
Highlights
We found that Herpes simplex virus type 2 (HSV-2) infection upregulated TRIM26 gene expression 200-fold after 12 h of infection and 150fold after 24 h post infection, as compared to mock controls (Figure 1A)
Using TRIM26 transgenic cell lines, we demonstrated that HSV-2 infection is altered with changes in expression of TRIM26
We have shown that TRIM26 serves as a regulator of the antiviral response to HSV-2 by demonstrating that modulation of TRIM26 expression alters the activity of interferon regulatory factor 3 (IRF3) and the outcome of HSV-2 replication (Figure 7B)
Summary
Transmitted infections (STI) constitute a significant global burden as they are responsible for significant morbidity and mortality, in women, marginalized communities, and those who engage in high-risk sexual behavior. Herpes simplex virus type 2 (HSV-2), the virus responsible for genital herpes, is one of the most prevalent sexually transmitted infections [1]. Women constitute nearly 60 percent of infected individuals and the disease is reported to have the highest burden in Africa [2]. The epithelium that lines the female reproductive tract (FRT), is one of the primary physical barriers to pathogen entry and can be subdivided into three major compartments: lower, upper, and transitional. The lower compartment of the FRT, consisting of the vagina and the ectocervix, acts as the first line of defense of the mucosal immune system against
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