KSHV infection results in inflammation associated malignancies such as Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma (PEL). Cytokines and viral gene products play roles in KSHV associated malignancies. In vitro KSHV infected endothelial cells secrete cytokines that are identical to the cytokines detected in KSHV associated KS and PEL lesions. Our overall hypothesis is that KSHV utilizes and/or subverts host molecules to regulate its own and host gene expression to create an environment that is conducive for the establishment and maintenance of a latent infection. Our overall objectives are to decipher the molecular mechanism by which KSHV utilizes the host molecules for its infection with a rationale that such knowledge will lead into designing therapeutic strategies to eliminate KSHV latency, inflammation and the associated malignancies. KSHV utilizes COX-2/PGE2, the target molecules of IL-1 beta, to maintain its latent gene expression in latently infected cells. Mature IL-1 beta is formed due to the action of an inflammasome that is composed of a sensor protein, adaptor ASC protein and effector procaspase-1 protein. While defining the mechanism of IL-1 beta induction by KSHV, we made the novel discovery that KSHV DNA entering the nucleus induces the innate inflammasome response via the nuclear resident interferon gamma-inducible protein 16 (IFI16). Our studies also showed evidence of IFI16 inflammasome activation in human PEL and KS lesions. Only the IFI16-inflammasome is activated in KSHV latently infected endothelial and PEL cells. We also discovered that KSHV latency persists despite the IFI16-inflammasome induction and IFI16 associates with the KSHV genome very early during infection in the nucleus of infected cells and in the nuclei of latently infected endothelial and PEL cells. We hypothesize that KSHV utilizes IFI16 for its latent gene expression. This hypothesis will be tested by studies proposed here. These studies are significant as they address a fundamental gap in our knowledge regarding how KSHV utilizes a host cell innate response in the nucleus to maintain its gene expression and explore the link between innate response and epigenetic modifications of viral DNA. These studies will facilitate the development of novel therapies to eliminate KSHV latent infection and ameliorate the associated diseases.
KSHV is etiologically associated with Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma (PEL or BCBL). The proposed studies will decipher how KSHV utilizes host proteins for its advantage to maintain latent infection. These studies are significant as they will lead into the development of effective strategies to eliminate KSHV latency and the associated malignancies.
| Roy, Arunava; Dutta, Dipanjan; Iqbal, Jawed et al. (2016) Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency. J Virol 90:8822-41 |
| Ansari, Mairaj Ahmed; Dutta, Sujoy; Veettil, Mohanan Valiya et al. (2015) Herpesvirus Genome Recognition Induced Acetylation of Nuclear IFI16 Is Essential for Its Cytoplasmic Translocation, Inflammasome and IFN-? Responses. PLoS Pathog 11:e1005019 |
| Dutta, Dipanjan; Dutta, Sujoy; Veettil, Mohanan Valiya et al. (2015) BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-? Responses. PLoS Pathog 11:e1005030 |
