Concurrent Control of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle through Chromatin Modulation and Host Hedgehog Signaling: a New Prospect for the Therapeutic Potential of Lipoxin A4

Abstract

Lipoxin A4 (LXA4) is an endogenous lipid mediator with compelling anti-inflammatory and proresolution properties. Studies done to assess the role of arachidonic acid pathways of the host in Kaposi's sarcoma-associated herpesvirus (KSHV) biology helped discover that KSHV infection hijacks the proinflammatory cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) pathways and concurrently reduces anti-inflammatory LXA4 secretion to maintain KSHV latency in infected cells. Treatment of KSHV-infected cells with LXA4 minimizes the activation of inflammatory and proliferative signaling pathways, including the NF-κB, AKT, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, but the exact mechanism of action of LXA4 remains unexplored. Here, using mass spectrometry analysis, we identified components from the minichromosome maintenance (MCM) protein and chromatin-remodeling complex SMARCB1 and SMARCC2 to be LXA4-interacting host proteins in KSHV-infected cells. We identified a higher level of nuclear aryl hydrocarbon receptor (AhR) in LXA4-treated KSHV-infected cells than in untreated KSHV-infected cells, which probably facilitates the affinity interaction of the nucleosome complex protein with LXA4. We demonstrate that SMARCB1 regulates both replication and transcription activator (RTA) activity and host hedgehog (hh) signaling in LXA4-treated KSHV-infected cells. Host hedgehog signaling was modulated in an AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-S6 kinase-dependent manner in LXA4-treated KSHV-infected cells. Since anti-inflammatory drugs are beneficial as adjuvants to conventional and immune-based therapies, we evaluated the potential of LXA4 treatment in regulating programmed death-ligand 1 (PD-L1) on KSHV-carrying tumor cells. Overall, our study identified LXA4-interacting host factors in KSHV-infected cells, which could help provide an understanding of the mode of action of LXA4 and its therapeutic potential against KSHV. IMPORTANCE The latent-to-lytic switch in KSHV infection is one of the critical events regulated by the major replication and transcription activator KSHV protein called RTA. Chromatin modification of the viral genome determines the phase of the viral life cycle in the host. Here, we report that LXA4 interacts with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter. SMARCB1 has also been recognized to be a tumor suppressor protein which controls many tumorigenic events associated with the hedgehog (hh) signaling pathway. We also observed that LXA4 treatment reduces PD-L1 expression and that PD-L1 expression is an important immune evasion strategy used by KSHV for its survival and maintenance in the host. Our study underscores the role of LXA4 in KSHV biology and emphasizes that KSHV is strategic in downregulating LXA4 secretion in the host to establish latency. This study also uncovers the therapeutic potential of LXA4 and its targetable receptor, AhR, in KSHV’s pathogenesis.

Targeting Host Cellular Factors as a Strategy of Therapeutic Intervention for Herpesvirus Infections

“…Mass spectrometry analysis from our experiment also suggested LXA4 be interacting with factors associated with metabolic and signaling pathways, immune response, cell proliferation, angiogenesis, transport-related proteins, and nuclear protein related to KSHV replication and life cycle ( Asha et al., 2020 ). In the study, we identified that during the KSHV infection, RTA (replication and transcription activator) protein regulating the latent-lytic switch, recruits SWI/SNF chromatin remodeling complex and other cofactors to the viral promoter to facilitate RTA dependent KSHV gene expression.…”

“…Ex vivo studies have established romidepsin as an effective inhibitor that works against lymphoproliferative diseases ( Smolewski and Robak, 2017 ) and is a better agent for viral reactivation ( Wei et al., 2014 ) than other HDAC inhibitors. Likewise, a recent study from our lab has shown anti-inflammatory lipoxin A4 (LXA4) as a promising candidate for lytic induction therapy ( Asha et al., 2020 ). LXA4 treatment regulates KSHV reactivation and life cycle through chromatin modification ( Asha et al., 2020 ) and the host’s hedgehog signaling pathway ( Asha et al., 2020 ).…”

“…Likewise, a recent study from our lab has shown anti-inflammatory lipoxin A4 (LXA4) as a promising candidate for lytic induction therapy ( Asha et al., 2020 ). LXA4 treatment regulates KSHV reactivation and life cycle through chromatin modification ( Asha et al., 2020 ) and the host’s hedgehog signaling pathway ( Asha et al., 2020 ).…”

Role of specialized pro-resolving lipid mediators and their receptors in virus infection: a promising therapeutic strategy for SARS-CoV-2 cytokine storm

“…Recently, it has been reported that LXA4 binds to the nuclear aryl hydrocarbon receptor (AhR) (Fig. 2 ) (Asha et al 2020 ).…”

“…For example, among SPMs, LXA4 modulates Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) life cycle through chromatin modulation and hedgehog signalling to destabilize the latency of herpes virus and decreases the expression of programmed death-ligand 1 (PD-L1) in Kaposi’s Sarcoma, thereby reducing immune evasion (Fig. 3 ) (Asha et al 2020 ). On the other hand, there are not a few reports that the receptors mentioned above for SPMs act as receptors in virus infection (see below).…”