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Local induction of bladder Th1 responses to combat urinary tract infections

Jianxuan Wu,Chunjing Bao,R. Reinhardt,S. Abraham

Published 2021 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Urinary tract infections (UTIs) are the second most common bacterial infections. Caring for UTI patients is very difficult and often perplexing. We typically view our immune system as an adaptive line of defense that becomes more responsive to specific pathogens after episodes of infection. However, the opposite is seen in these patients, in whom each infection actually increases the risk of a subsequent infection. Our group recently identified the underlying basis as a highly Th2-biased response in bladder that inhibits Th1-mediated bacterial clearance. To resolve this situation, we investigated whether immunizing mice intravesically with bacterial antigens combined with a Th1-skewing adjuvant (CpG) would evoke a more balanced and protective immune response. Given the high frequency of urinary tract infections (UTIs) and their recurrence, there is keen interest in developing effective UTI vaccines. Currently, most vaccine studies, including those in humans, involve parenteral vaccination aimed at evoking and sustaining elevated levels of systemic antibody directed at the uropathogens. In view of recent reports of aberrant Th2-biased bladder immune responses to infection, we hypothesized that immunizing mice intravesically with antigens from uropathogenic Escherichia coli (UPEC) combined with a Th1-skewing adjuvant could correct this defect and promote protection against UTIs. Here we report that compared with mice immunized subcutaneously with this vaccine combination, intravesically immunized mice were markedly more protected from UTIs because of their distinctive ability to recruit Th1 cells into the bladder. This mode of vaccination was effective even in mice that experienced multiple UTIs and displayed pronounced aberrant bladder immune responses. Thus, intravesical vaccination with one or more UPEC antigens to induce bladder Th1 responses represents a superior strategy to combat UTIs, especially in UTI-prone subjects.

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