Human Herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV) and human herpesvirus (HHV6) are members ofthe herpesvirus family and are included on the NIAID list of Emerging/Re-Emerging pathogens. HHV8/KSHV is associated with three different cancers in the human population including Kaposi's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. In Sub-Saharan Africa, KS is the most common cancer in men. Human herpesvirus type-6 (HHV-6) is the infectious cause of roseola infantum in young children. In response to RFA-AI-12-048, "Immune mechanisms of Viral Control, we propose to determine how DNA herpes viruses are sensed by the host immune system. We propose to determine the interaction of multiple pathogen recognition receptors (PRRs) with these DNA viruses and the mechanisms by which these viruses are sensed by host PRRs to activate the innate immune response. We hypothesize that PRRs involved in nucleic acid sensing of viral genomes are able to detect KSHV and HHV6 and activate innate immune responses. Additionally, the DNA damage response induced by herpes viral infection may also contribute to activation of innate immune pathways. This project advances the overall goals of the program by using cutting edge quantitative proteomic approaches to identify novel paradigm shifting pathways of pathogen sensing, identifying nucleic acid binding by human PRRs, and determining cross-talk between multiple PRRs in the host response to NIAID Emerging/Reemerging viruses.
Human Herpes virus 8 (HHV8), also known as Kaposi sarcoma-associated herpes virus (KSHV), and Human Herpes virus 6 are pathogenic human herpes viruses and are on the NIAID list of Emerging/Re-Emerging pathogens. HHV8/KSHV is associated with three different cancers in the human population including Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. HHV6 causes roseola infantum in children. The work is relevant because it investigates new host innate immune pathways and mechanisms that help detect these pathogenic human viruses.
|Feng, Zongdi; Li, You; McKnight, Kevin L et al. (2015) Human pDCs preferentially sense enveloped hepatitis A virions. J Clin Invest 125:169-76|
|Giguère, Patrick M; Gall, Bryan J; Ezekwe Jr, Ejiofor A D et al. (2014) G Protein signaling modulator-3 inhibits the inflammasome activity of NLRP3. J Biol Chem 289:33245-57|
|Damania, Blossom; Dittmer, Dirk P (2014) What lies within: coinfections and immunity. Cell Host Microbe 16:145-7|
|Zhang, Lu; Mo, Jinyao; Swanson, Karen V et al. (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40:329-41|
|West, John A; Wicks, Megan; Gregory, Sean M et al. (2014) An important role for mitochondrial antiviral signaling protein in the Kaposi's sarcoma-associated herpesvirus life cycle. J Virol 88:5778-87|
|Canna, Scott W; de Jesus, Adriana A; Gouni, Sushanth et al. (2014) An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 46:1140-6|
|Giffin, Louise; Yan, Feng; Ben Major, M et al. (2014) Modulation of Kaposi's sarcoma-associated herpesvirus interleukin-6 function by hypoxia-upregulated protein 1. J Virol 88:9429-41|
|Yamane, Daisuke; McGivern, David R; Wauthier, Eliane et al. (2014) Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med 20:927-35|