Friday, May 9, 2025
5/9/2025
Contribution of sympathetic nerves to herpes stromal keratitis - PROJECT SUMMARY/ABSTRACT Herpes simplex virus type 1 (HSV-1) corneal infections are leading infectious causes of blindness world-wide. It is well established that the blinding form of HSV-1 infection called herpes stromal keratitis (HSK) is caused by the immune response to the virus rather than by a direct effect of the virus on corneal cells. The disease tends to recur in people because the virus invades and establishes a quiescent (latent) infection in sensory nerves during initial (primary) infection. HSV-1 periodically reactivates from the latent state, travels back down the nerves to the cornea, and triggers recurrent bouts of HSK. A hallmark of HSK is loss of corneal sensitivity that has been associated with loss of corneal sensory nerve endings. However, the role of the neuroimmune axis in pathology is incompletely understood. Our preliminary studies in mice demonstrated that a host factor, Sterile alpha and TIR motif containing 1 (SARM1), acts to prevent HSK as SARM1 deficient mice develop more severe HSK compared to WT controls. While SARM1 is conventionally linked to neuronal cells, it also can function in various immune cell populations. Therefore, we plan to assess the functional consequences of SARM1 during HSK in nerve and immune cells. Specifically, our first aim will investigate how SARM1 deficiency may affect viral control and the generation of the anti-viral immune response over time. Our second aim will focus on defining immune cell intrinsic mechanisms of SARM1 by comparing immune cell functionality, migration, and metabolism of SARM1 deficient immune cells to WT immune cells in vivo and in vitro. Finally, our third aim will investigate how SARM1 deficiency affects sensory and sympathetic nerve growth during steady state and in the context of neurotrophic viral infection. We posit a role that SARM1 limits the activation of inflammatory monocytes while also limiting the outgrowth of sympathetic nerves, which we have found to contribute to pathogenesis in ocular HSV-1 infection. Overall, we anticipate that our studies will identify SARM1 as a host factor that plays an integral role in preventing HSK.
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