Abstract
Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host’s antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.
Highlights
Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent in the human population worldwide [1]
We found that inhibition of the endonuclease activity of IRE1a in HSV-1- or HSV-2-infected dendritic cells (DCs) significantly increases the viability of these cells infected with either of these two viruses, as well as their capacity to migrate to lymph nodes in vivo and to activate virus-specific T cells
Based on our previous finding that wild-type (WT) HSV-2 triggers significant splicing of the XBP1 splicing (XBP1s) mRNA transcript in virus-infected DCs, as well as cell death [17], we sought to assess the contribution of Inositol-Requiring Enzyme 1 alpha (IRE-1a) activation of the unfolded protein response (UPR) over DC viability and function during HSV-1 and HSV-2 infection
Summary
Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent in the human population worldwide [1]. The global prevalence of HSV-1 and HSV-2 infection is estimated at 66.6% and 13.2%, respectively, in young adults with lifelong persistent infections and the occurrence of reactivation episodes throughout life with the possibility of viral shedding regardless of clinical symptoms [2]. There are no vaccines available to date against these viruses and current therapies need improvement [4] These viruses encode numerous molecular determinants to evade and escape the host’s innate and adaptive immune responses [7, 8]. These viruses modulate early and late antiviral cellular processes, such as negative modulation of interferon production, inhibition of innate immune components, and hamper the function of adaptive immune cells [8,9,10]
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