Immune system response could be undermining ability to fight urinary tract infections
New findings in mice about immune system responses to urinary tract infections (UTIs) could help explain the high rates of UTI recurrence in humans and suggest novel ways to treat them. UTIs are very common, especially in women, many of whom suffer repeated infections with symptoms such as painful urination and a frequent or intense urge to urinate. The most common cause of UTIs is a bacterium normally found in the human intestines, called Escherichia coli (E. coli); uropathogenic E. coli, or UPEC, are those able to infect the urinary tract and sometimes the kidneys. While UTIs can be treated with antibiotics, the threat of increasing bacterial antibiotic resistance is driving research to identify new therapeutic approaches.
To gain insights that could lead to potential therapeutic targets, researchers are examining not only bacterial factors that enhance UPEC infectivity, but also factors and responses in human and animal model hosts that can either help or hamstring the ability to ward off UTI-causing microbes. For example, one way both humans and mice respond to UTIs is to shed infected cells lining the inside of the bladder—an early, innate response to UTIs that is mediated by certain immune system cells residing in the bladder. Though drastic, as it damages the bladder lining, cell shedding reduces infection in the bladder wall. Simultaneously, other cells of the immune system begin to organize so-called adaptive responses to the invading microbes that are supposed to help fight the bladder infection in a more targeted fashion, such as through developing antibodies. However, humans and mice appear not to develop a robust antibody response against UPEC that would help kill residual bacteria and protect against subsequent infections. Instead, researchers have now uncovered evidence in mice strongly suggesting that, rather than being balanced, the adaptive immune response to bladder infection by UPEC is highly biased toward aiding repair of the bladder lining and inhibits responses that would clear UPEC. The researchers used mouse models deficient in different adaptive immune responses and/or genetically engineered to enable detection of cells involved in these responses. Studying these mice, the scientists were able to identify distinct subsets of immune system cells responsible for initiating and executing this biased response and the steps involved in establishing it in the bladder. Moreover, when the scientists exposed mice to multiple rounds of UPEC infection, they observed that the bias toward tissue repair was reinforced over time and, in fact, led to a thickening of the bladder lining that ultimately reduced mouse bladder capacity.
Repair of the bladder lining is critical for protecting underlying cells from noxious waste molecules present in urine—a unique challenge posed by the innate response to UTIs. However, the high bias toward repair and consequent inhibition of a robust companion antibody response could be contributing not only to recurrent infection but also to development of bladder dysfunction, such as urinary urgency or incontinence. This possible connection can now be explored, along with methods to reestablish balance in the host response to UTIs that could improve outcomes and prevent recurrence.
Wu J, Hayes BW, Phoenix C,…Abraham SN. A highly polarized TH2 bladder response to infection promotes epithelial repair at the expense of preventing new infections. Nat Immunol 21: 671-683, 2020.