Role of Pattern Recognition Receptors in KSHV Infection

Abstract

Kaposi’s sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host’s immune system are crucial to prevent KSHV infection. The host’s immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as ‘pathogen-associated molecular patterns (PAMPs)’. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections.

N6-Methyladenosine and Viral Infection

“…During KSHV latent infection, most of the viral genome is suppressed through DNA methylation, repressive histone modifications and other regulatory mechanisms which negatively regulate gene expression ( Pantry and Medveczky, 2009 ; Gunther and Grundhoff, 2010 ; Lu et al, 2010 ; Toth et al, 2010 ; Purushothaman et al, 2015 ). Changes in the host cell microenvironment could reactivate the virus from latency to the lytic cycle, wherein the inhibitory epigenetic marks are replaced by active ones to allow for transcription of viral lytic genes ( Ye, 2017 ; Uppal et al, 2018 ). Three recent studies revealed that the KSHV life cycle was affected by RNA N 6 -adenosine methylation epigenetic modification ( Ye et al, 2017 ; Hesser et al, 2018 ; Tan et al, 2018 ).…”

Conserved Herpesvirus Kinase ORF36 Activates B2 Retrotransposons during Murine Gammaherpesvirus Infection

“…Due to their activation during herpesvirus infection and broadly acting signaling cascades, we considered that innate immune signaling may be involved upstream of B2 SINE induction. Pattern recognition receptors, namely, the toll-like receptors 2, 3, 7, and 9, RIG-I-like receptors, and AIM2, can become activated during lytic herpesvirus infection (44)(45)(46)(47). To examine the possible upstream involvement of infection-induced innate immune signaling in the induction of B2 SINE transcription, we quantified B2 SINE levels in primary BMDMs derived from WT B6 mice versus mice lacking several canonical innate immune signaling pathways.…”

The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection

“…Due to their activation during herpesvirus infection and broadly acting signaling cascades, we considered that innate immune signaling may be involved upstream of B2 SINE induction. Pattern recognition receptors, namely the toll-like receptors 2, 3, 7, and 9, RIG-I-like receptors, and AIM2, can become activated during lytic herpesvirus infection [43–46]. To examine the possible upstream involvement of infection-induced innate immune signaling in the induction of B2 SINE transcription, we quantified B2 SINE levels in primary BMDMs derived from WT B6 mice versus mice lacking several canonical innate immune signaling pathways.…”