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Porphyromonas gingivalis coinfects with KSHV in oral cavities of HIV+ patients and induces viral lytic reactivation.

ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) infection causes several human cancers, including Kaposi's sarcoma (KS), one of the most common AIDS-associated tumors. The involvement of the oral cavity represents one common clinical manifestation of AIDS-KS individuals with periodontal diseases and an oral carriage of a variety of pathogenic bacteria, including Porphyromonas gingivalis. In the current study, we report the clinical relevance of P. gingivalis and KSHV coinfection in the oral cavity of a cohort of HIV+ patients. Furthermore, we found that P. gingivalis conditioned medium or derived lipopolysaccharide effectively induced KSHV lytic reactivation from infected oral cells. This reactivation requires TLR4 as well as the activities of p38 and Jun N-terminal kinase- mitogen-activated protein kinase signaling pathways. Our findings reveal the mechanisms through which coinfected periodontal pathogens potentially promote oncogenic virus pathogenesis in the unique niche of immunocompromised patients.

SUBMITTER: Dai L

PROVIDER: S-EPMC7679274 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Porphyromonas gingivalis coinfects with KSHV in oral cavities of HIV+ patients and induces viral lytic reactivation.

Dai Lu L Barrett Lindsey L Plaisance-Bonstaff Karlie K Post Steven R SR Qin Zhiqiang Z

Journal of medical virology 20200602 12

Kaposi's sarcoma-associated herpesvirus (KSHV) infection causes several human cancers, including Kaposi's sarcoma (KS), one of the most common AIDS-associated tumors. The involvement of the oral cavity represents one common clinical manifestation of AIDS-KS individuals with periodontal diseases and an oral carriage of a variety of pathogenic bacteria, including Porphyromonas gingivalis. In the current study, we report the clinical relevance of P. gingivalis and KSHV coinfection in the oral cavit ...[more]

PMID: 32436999

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Project description:The immediate early viral protein replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential for activating the lytic cycle of KSHV. RTA induces the KSHV lytic cycle by several mechanisms, acting as a viral transcription factor that directly induces viral and host genes and acting as a viral E3 ubiquitin ligase by degrading host proteins that block viral lytic replication. Recently, we have characterized the global gene expression changes in primary effusion lymphoma (PEL) upon lytic reactivation of KSHV, which also led to the identification of rapidly downregulated genes such as ID2, an inhibitor of basic helix-loop-helix transcription factors. Here, we demonstrate that ID2 overexpression in PEL ablates KSHV lytic reactivation, indicating that ID2 inhibits the KSHV lytic cycle. Furthermore, we show that while ID2 is highly expressed during latency, its protein level is rapidly reduced by 4 h postinduction during lytic reactivation. Our results indicate that RTA binds to ID2 and induces its degradation during the KSHV lytic cycle by N-terminal ubiquitination through the ubiquitin-proteasome pathway. Importantly, we found that not only KSHV RTA but also its Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) homologs interact with ID2, and they can induce the degradation of all four members of the ID protein family, suggesting an evolutionarily conserved interplay between gammaherpesvirus RTAs and ID proteins. Taken together, we propose that ID2 acts as a repressor of the KSHV lytic cycle, which is counteracted by its RTA-mediated degradation. We also predict that ID proteins may act as restriction factors of the lytic phase of the other gammaherpesviruses as well. IMPORTANCE In addition to its transcription regulatory role, RTA is also known to have an E3 ubiquitin ligase activity, which RTA utilizes for inducing protein degradation. However, it is still largely unknown what host factors are downregulated during KSHV lytic reactivation by RTA-mediated protein degradation and what the biological significance of the degradation of these host factors is. In this study, we discovered that RTA employs N-terminal ubiquitination to induce degradation of ID2, a potent transcription repressor of host genes, via the ubiquitin-proteasome pathway to promote KSHV lytic reactivation in PEL cells. Furthermore, we found that not only KSHV RTA but also RTA of EBV and MHV68 gammaherpesviruses can induce the degradation of all four human ID proteins, indicating that the interplay between gammaherpesvirus RTAs and ID proteins is evolutionarily conserved.

Project description:SUMOylation is associated with epigenetic regulation of chromatin structure and transcription. Epigenetic modifications of herpesviral genomes accompany the transcriptional switch of latent and lytic genes during the virus life cycle. Here, we report a genome-wide comparison of SUMO paralog modification on the KSHV genome. Using chromatin immunoprecipitation in conjunction with high-throughput sequencing, our study revealed highly distinct landscape changes of SUMO paralog genomic modifications associated with KSHV reactivation. A rapid and widespread deposition of SUMO-2/3, compared with SUMO-1, modification across the KSHV genome upon reactivation was observed. Interestingly, SUMO-2/3 enrichment was inversely correlated with H3K9me3 mark after reactivation, indicating that SUMO-2/3 may be responsible for regulating the expression of viral genes located in low heterochromatin regions during viral reactivation. RNA-sequencing analysis showed that the SUMO-2/3 enrichment pattern positively correlated with KSHV gene expression profiles. Activation of KSHV lytic genes located in regions with high SUMO-2/3 enrichment was enhanced by SUMO-2/3 knockdown. These findings suggest that SUMO-2/3 viral chromatin modification contributes to the diminution of viral gene expression during reactivation. Our previous study identified a SUMO-2/3-specific viral E3 ligase, K-bZIP, suggesting a potential role of this enzyme in regulating SUMO-2/3 enrichment and viral gene repression. Consistent with this prediction, higher K-bZIP binding on SUMO-2/3 enrichment region during reactivation was observed. Moreover, a K-bZIP SUMO E3 ligase dead mutant, K-bZIP-L75A, in the viral context, showed no SUMO-2/3 enrichment on viral chromatin and higher expression of viral genes located in SUMO-2/3 enriched regions during reactivation. Importantly, virus production significantly increased in both SUMO-2/3 knockdown and KSHV K-bZIP-L75A mutant cells. These results indicate that SUMO-2/3 modification of viral chromatin may function to counteract KSHV reactivation. As induction of herpesvirus reactivation may activate cellular antiviral regimes, our results suggest that development of viral SUMO E3 ligase specific inhibitors may be an avenue for anti-virus therapy.

Dataset Information

Porphyromonas gingivalis coinfects with KSHV in oral cavities of HIV+ patients and induces viral lytic reactivation.

Publications

Porphyromonas gingivalis coinfects with KSHV in oral cavities of HIV+ patients and induces viral lytic reactivation.

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