Mechanisms of itch and neural regulation of inflammation in S. aureus infection

Project SummaryStaphylococcus aureus is a major human pathogen that causes epicutaneous and subcutaneous skininfections. Evidence shows that S. aureus could be a key contributor to chronic itch conditions, including atopicdermatitis (AD), where over 90% of sufferers are colonized by S. aureus. We hypothesize S. aureus directlyactivates pruriceptor neurons, the itch-mediating sensory neurons densely innervating the epidermis, duringepicutaneous skin infections. In turn, this exacerbates and promotes not only itch, but also skin inflammationand disease pathology in AD. Sensory neuron activation and the subsequent release of neuropeptides causeneurogenic inflammation, resulting in the recruitment/activation of immune cells. The main objective of thisproposal is to determine the mechanisms of itch during S. aureus epicutaneous infection and the contributionof sensory neurons in driving inflammation and skin pathology. In Specific Aim 1, we will establish a mousemodel of epicutaneous S. aureus infection where chronic itch behavior can be quantified. Nerve sprouting andnerve density into the epidermis, key components of AD, will also be analyzed. I have recently shown S.aureus pore-forming toxins (PFTs), such as alpha hemolysin (Hla), are capable of activating sensory neurons.Several recent studies using this model of infection have pointed to the key role of PSM?s, a class of S.aureus PFTs, in inflammation. We have obtained isogenic mutant strains of bacteria lacking these toxins andwill test if the specific PFTs, Hla and PSM?s, contribute to itch-behavior in vivo. In Specific Aim 2, we willdetermine whether these sensory neurons mediate inflammation and host-defense during an epicutaneous S.aureus infection. Sensory neurons will be depleted using chemical and transgenic strategies. Trpv1 expressingneurons will be depleted using resiniferatoxin and by using the transgenic mouse line, Trpv1-Cre/Dta. Inaddition, to target a different, but overlapping set of sensory neurons, the transgenic mouse line Nav1.8-cre/Dta will be used. In these strategies, the subsequent consequences on immune cell recruitment, bacterialclearance, and skin pathology will be determined. The proposed research is novel given the poor mechanisticunderstanding of pathogen-induced itch, particularly in S. aureus infection. The results will not only fill a criticalgap in our knowledge of direct interactions of S. aureus with sensory neurons to drive itch, but also pioneerstudies determining the role of the nervous system in driving inflammation in the skin. Therapeutic strategiestargeting these newfound bacterial-neuron interactions can be developed as novel treatments to alleviate bothAD pathology and its debilitating itch, especially in conjunction with S. aureus infection.