DNA RECOGNITION · Recognition of viral DNA by the innate immune system

Herpes simplex virus 1 and 2 (HSV1/2) are important human pathogens, causing both acute and recurrent infections leading to serious diseases such as encephalitis, herpes keratitis, genital herpes, and potentially fatal disseminated disease in newborns. Pathogen recognition by the innate immune system is mediated via host-encoded pattern recognition receptors, which recognize conserved pathogen-associated molecular patterns (PAMPs) and trigger the production of pro-inflammatory cytokines and chemokines, including the type I interferons and interleukin 1. Recent studies have demonstrated that DNA may be an important PAMP. However, very little is known about the physiological role of viral DNA recognition in the innate immune response. The proposed project will utilise state-of-the-art technology in cell biology, bioimaging and animal models to investigate the physiologic role of virally delivered DNA in immune activation, and identify and classify the pathways and receptors involved, establishing the host laboratory as a world leader in the field. The overall hypothesis of the project is that HSV infection leads to release of DNA in the cytoplasm of host cells, which recognize the DNA through specific receptors, and initiate a protective innate immune response. Specific aims:Aim 1 – Describe the role of cytosolic viral DNA in initiating the innate immune response to HSV and characterise the mechanism of DNA release from the virion into the cytosol.Aim 2 – Determine the contribution of cytosolic DNA receptors to the immune response against HSV in vivo.Results from the proposed project may aid in (i) identifying potential novel drug targets, (ii) improving vaccine efficacy, (iii) and allowing control of the potential side effects of viral gene delivery systems.