Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity.

Abstract

Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.

Authors

Byron W Hayes, Hae Woong Choi, Abhay P S Rathore, Chunjing Bao, Jianling Shi, Yul Huh, Michael W Kim, Qingfeng Chen, Pradeep Bist, Lai Guan Ng, Chang-Ming Shih, Joo Hwan Nho, Aram Kim, Hana Yoon, Donghoon Lim, Johanna L Hannan, J Todd Purves, Francis M Hughes, Ru-Rong Ji, Soman N Abraham

Department of Pathology, Duke University Medical Center, Durham, NC, USA, Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore, Department of Cell Biology, Duke University Medical Center, Durham, NC, USA, Department of Immunology, Duke University Medical Center, Durham, NC, USA, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.