Most soil transmitted helminth (STH) species have skin-penetrating larval stages that facilitate chronic human infections causing significant morbidity worldwide. Although these infectious larvae (iL3) are known to release a wide array of excretory-secretory products (ES) that damage skin and mucous membranes human hosts have very little awareness of this process. Rare case reports indicate itch, but otherwise most people do not know they are infected until there are gastrointestinal symptoms or anemia. This suggests that the pain-sensing neurons in the skin may be actively silenced by worm ES. While the activity of transient receptor potential channel vanilloid 1 (TRPV1)-expressing sensory neurons is known to contribute to host protective immunity against microbial and fungal pathogens, it is entirely unknown whether these skin neurons influence immunity against STH infection. This major gap in knowledge is likely because current experimental methods use needle injection to deliver iL3, which bypasses neurons that innervate the epidermal and dermal layers of skin. To address this issue, we have developed a natural model of STH infection where the foot of a mouse is transiently exposed to a saline bath of iL3, allowing natural penetration. Our preliminary studies show that significantly fewer iL3 penetrate the skin of wild-type mice in a second exposure to iL3, indicating that resistance develops. Optogenetics uses blue light to activate the cation channel rhodopsin (CHR2) that is expressed by specific cell populations expressing the cre protein in transgenic mice. When we used this technique to activate TRPV1+ cells, we found a significant reduction in iL3 skin penetration suggesting that sensory neuron activity may contribute to host protective mechanisms. Further, iL3 ES seem to reduce the ability of neurons to respond to the TRPV1 agonist capsaicin. Thus, our overarching goal is to combine this parasite infection model system with sensory neuroscience methods that non-invasively activate specific populations of pain or itch-sensing neurons to investigate how neurons control the ability of iL3 to penetrate the skin. Aim 1 tests whether optogenetic activation of nociceptors or other TRPV1+ cells augments host resistance against STH through induction of skin neuropeptides, inflammatory cells and/or Type 2 and Type 17 cytokines. Also, based on our data showing that treatment with ES products impairs sensory neuron activation, experiments in Aim 2 seek to identify the molecules in ES products that suppress sensory neuron activation and determine whether this equates with blunted behavioral responses to itchy or painful stimuli. Taken together, this R21 stands to break new ground in understanding the neuroimmunology of host protection against parasitic helminths and may reveal novel bioactive molecules with multidisciplinary therapeutic potential.