Abnormal Adaptive Immunity in Bacterial Bladder Infections

Abstract

Bacterial bladder infection, also known as cystitis, is one type of urinary tract infections (UTIs). These infections typically initiate when uropathogens, especially uropathogenic E. coli (UPEC), invade into the bladder through the urethra. Those bacteria could attach to the uroepithelium of the bladder and invade into bladder epithelial cells (BECs). The bladder is critical for the control of these bacteria by activating BECs and recruiting immune cells. If bacteria are not promptly cleared in the bladder, they will further invade ureters and kidneys causing pyelonephritis, which is another common form of UTIs. Nowadays, bacterial bladder infection is one of the most common bacterial infections and a big clinical burden. Its annual incidence rate among human population was estimated to be around 3%-12.6% in female and 0.5%-3% in male. Besides the high incidence rate, the recurrence rate is also very high, up to 44%. As a comparison, the recurrence rate of bacterial infections in the respiratory tract is only around 10% and that rate in the gastrointestinal tract is about 1.5% to 12%. The high incidence rate and high recurrence rate pinpoint the inefficiency of immunity in bladder. However, it is unclear which component of the bladder immunity is inefficient in clearing bacteria and preventing recurrence. By using cutting edge models and techniques, such as genetic knock-out mice, newly developed cytokine reporter mice, optimized flow cytometry and microscopy, I identified that the bladder immunity, especially CD4 T cell mediated adaptive immunity, is focusing on repairing damaged uroepithelium rather than clearing UPEC. This response is modulated by antigen presenting cells (APCs) in bladder. This abnormal bladder immunity also leads to bladder dysfunction featured by urinary frequency. By applying a vaccination strategy, I successfully improved the anti-bacteria ability of CD4 mediated bladder adaptive immunity in mouse model. In summary, this study identified that an abnormal adaptive immunity induced by the uroepithelium-APC-T cell signaling axis is responsible for the suboptimal clearance of bacteria and infection recurrence in bladder. With proper vaccination, the adaptive immunity in bladder can be tuned to be protective against UPEC infections.