Pseudomonas aeruginosa–induced nociceptor activation increases susceptibility to infection

Abstract

We report a rapid reduction in blink reflexes during in vivo ocular Pseudomonas aeruginosa infection, which is commonly attributed and indicative of functional neuronal damage. Sensory neurons derived in vitro from trigeminal ganglia (TG) were able to directly respond to P. aeruginosa but reacted significantly less to strains of P. aeruginosa that lacked virulence factors such as pili, flagella, or a type III secretion system. These observations led us to explore the impact of neurons on the host’s susceptibility to P. aeruginosa keratitis. Mice were treated with Resiniferatoxin (RTX), a potent activator of Transient Receptor Potential Vanilloid 1 (TRPV1) channels, which significantly ablated corneal sensory neurons, exhibited delayed disease progression that was exemplified with decreased bacterial corneal burdens and altered neutrophil trafficking. Sensitization to disease was due to the increased frequencies of CGRP-induced ICAM-1⁺ neutrophils in the infected corneas and reduced neutrophil bactericidal activities. These data showed that sensory neurons regulate corneal neutrophil responses in a tissue-specific matter affecting disease progression during P. aeruginosa keratitis. Hence, therapeutic modalities that control nociception could beneficially impact anti-infective therapy. Many of the molecular mechanisms behind bacterial keratitis induced nociception activation and specifically, how pathogen-sensing sensory neurons impact the outcome of infection have yet to be discovered, Elucidating the molecular and cellular mechanisms of nociceptor activation during bacterial keratitis can have a profound impact on treatment approaches. In this study, we established that P. aeruginosa can directly induce calcium influx in neurons and this induction is dependent on several virulence factors. Further, we demonstrated that Resiniferatoxin (RTX), a toxin that overactivates TRPV1 channels leading to chemical ablation of neurons, induces significant loss of sensory neurons in the cornea and this improves temporarily local innate responses to P. aeruginosa.