Globally, the majority of people (>80%) in industrialized countries harbor latent Herpes simplex virus type 1 (HSV1) infections in sensory neurons with trigeminal ganglia that innervate the orofacial region being commonly involved. A variety of stressors can reactivate the virus resulting in asymptomatic shedding of virus or in lesions in the orofacial region including the cornea, eyelids and periocular skin. Curiously, while many people shed HSV1 in tears or develop corneal epithelial lesions that are usually self-healing, recurrent disease in some people involves virus replication and vigorous inflammatory responses in the stroma that cause corneal scarring and impairment of vision ? referred to as herpes stromal keratitis (HSK). Repeated bouts of HSK result in severe scarring and damage to the cornea that can progress to blindness. We speculate that people who suffer from recurrent HSK have gut microbiota dysbiosis that alters host immunity and thereby predisposes to development of HSK. Furthermore, it is conceivable that in these people HSV1 might also reactivate in enteric neurons, resulting in gut barrier malfunction and inflammation, which could cause/exacerbate microbiota dysbiosis. We postulate that as regulators of immunity, the microbiota are important determinants of HSV1 induced inflammatory diseases including HSK and encephalitis (HSE) because oral antibiotic depletion of the gut microbiota prior to ocular HSV1 infection significantly reduced angiogenesis and HSK (4) and our preliminary studies showed that altering the gut microbiota can modulate HSK and HSE development. We propose two specific aims to test this hypothesis.
In Specific Aim 1, the objective is to identify gut bacteria, gut bacterial genes/gene products/pathways, and host immune processes that correlate with varying susceptibilities to and severity of HSK and HSE following HSV1 infection.
In Specific Aim 2, we will causally test bacteria for their abilities to alter the susceptibilities to and severity of HSK and HSE following HSV1 infection, and identify the associated changes in host immunity. By demonstrating that manipulation of the gut microbiota can modulate HSK and HSE severity, we anticipate that this project will change our understanding of the pathophysiology of HSK and HSE. We also envision that by validation of our hypothesis this project will spur research to identify and characterize consortia of bacteria (or individual bacteria) with the potential to function as effective probiotics, providing alternative natural prophylactic therapies for recurrent HSK and HSE
Globally, the majority of people carry latent HSV infections that when reactivated can cause either mild disease as in cold sores or serious eye disease ? herpes stromal keratitis (HSK), which is the leading cause of blindness by an infectious agent. Paradoxically, while many people have recurrent eye infections only some go on to develop HSK, which is an inflammatory disease. We speculate that this disparity might arise from differences in the gut bacteria of people with and without HSK, because recent research has revealed that a balanced gut bacterial community (microbiota) is essential for optimal immune system function and health. Studies in this proposal utilize germfree (GF) mice and transfers of gut bacteria from mouse strains either resistant or susceptible to HSK into GF mice to determine involvement of the microbiota in HSK development after HSV infection. The long-term goal is to identify bacterial strains that when introduced into susceptible (GF) mice prevent HSK, HSE and other viral induced inflammatory diseases, which will provide a framework for future efforts to develop probiotic bacterial strains or prebiotics that can be used prophylatically to treat recurrent HSK.
