Staphylococcus aureus activates sensory neurons in the skin to cause pain or itch during infection

Abstract

Specialized sensory neurons innervating barrier tissues, such as the skin, are designed to detect and alert the body to a variety of noxious stimuli. Pain, an unpleasant sensation, is mediated by nociceptive neurons and results in protective behavioral avoidance responses. Itch, mediated by pruriceptive neurons, is mainly felt in the skin’s outermost layers and produces scratching behaviors. Staphylococcus aureus is a major skin and soft tissue human pathogen that causes both painful and itchy infections; the mechanisms leading to these distinct sensations are poorly understood. Recent studies show that sensory neurons possess receptors for bacterial products and toxins; damaging pathogens may therefore be necessary “dangers” that sensory neurons detect. Whether skin innervating sensory neurons detect S. aureus during infection to cause pain or itch is unknown. Here, I investigated the mechanisms of pain and itch during live S. aureus infections utilizing mouse models of either subcutaneous hind paw infections or epicutaneous skin infections to target these sensations, respectively. In chapters 1-2, I broadly introduce S. aureus pathogenesis, together with the role of sensory neurons and their functions in regulating immunity at barrier tissues. Next, in chapter 3, I explore mechanisms of pain during subcutaneous S. aureus infection. I found spontaneous pain was dependent on the agr quorum sensing locus and bacterial pore-forming toxins (PFTs). Using genetic strategies targeting the TRPV1 ion channel in mice, I determined that TRPV1 was necessary for heat hyperalgesia during S. aureus infection. I tested the hypothesis that both pore-formation in neurons and the TRPV1 ion channel would allow delivery of the membrane-impermeable sodium channel blocker QX-314 into nociceptors to block pain during infection. Finally, in chapter 4, I adapted an epicutaneous S. aureus mouse infection model to measure resultant itch behaviors and to quantify skin inflammation. I found that agr mediated both itch and inflammation during infection. However, unlike in our pain model, PFTs did not mediate itch, but rather S. aureus proteases. In conclusion, S. aureus PFTs and S. aureus proteases are novel mechanisms to produce pain or itch during infection. It would be interesting to determine if similar mechanisms exist for other pathogens.