Abstract
The molecular initiators of infection-associated pain are not understood. We recently found that uropathogenic E. coli (UPEC) elicited acute pelvic pain in murine urinary tract infection (UTI). UTI pain was due to E. coli lipopolysaccharide (LPS) and its receptor, TLR4, but pain was not correlated with inflammation. LPS is known to drive inflammation by interactions between the acylated lipid A component and TLR4, but the function of the O-antigen polysaccharide in host responses is unknown. Here, we examined the role of O-antigen in pain using cutaneous hypersensitivity (allodynia) to quantify pelvic pain behavior and using sacral spinal cord excitability to quantify central nervous system manifestations in murine UTI. A UPEC mutant defective for O-antigen biosynthesis induced chronic allodynia that persisted long after clearance of transient infections, but wild type UPEC evoked only acute pain. E. coli strains lacking O-antigen gene clusters had a chronic pain phenotype, and expressing cloned O-antigen gene clusters altered the pain phenotype in a predictable manner. Chronic allodynia was abrogated in TLR4-deficient mice, but inflammatory responses in wild type mice were similar among E. coli strains spanning a wide range of pain phenotypes, suggesting that O-antigen modulates pain independent of inflammation. Spinal cords of mice with chronic allodynia exhibited increased spontaneous firing and compromised short-term depression, consistent with centralized pain. Taken together, these findings suggest that O-antigen functions as a rheostat to modulate LPS-associated pain. These observations have implications for an infectious etiology of chronic pain and evolutionary modification of pathogens to alter host behaviors.
Highlights
The mechanisms by which infections induce pain are not understood
NU14DwaaL is highly attenuated in murine urinary tract infection (UTI) and represents a convenient strain to test the role of O-antigen in pain
We previously reported that DwaaL is rapidly cleared from the bladder after an initial infection [16], and the waaL mutant was undetectable at 14 days following a third infection, whereas the majority of NU14-infected mice retained detectable bladder colonization despite resolution of pain (Fig. 1B)
Summary
The mechanisms by which infections induce pain are not understood. Inflammation may cause or contribute to pain [1,2], few studies have examined infection-associated pain. Most UTIs are caused by UPEC and result in pelvic pain and voiding dysfunction [5]. Interactions between UPEC and the urothelium that lines the bladder lumen result in local cytokine/chemokine production and accumulation of urinary IL-6 and IL-8 [6,7]. IL-8 secretion, in turn, drives a robust innate immune response characterized by an influx of neutrophils that clear bacteria from the bladder. It remains unclear how these events relate to pain
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