Biology subjects

Canton, T.

Publications and source records attributed to Canton, T..

5 recordsLinked to original sources

bioRxiv2025

Oral OM-89 in combination with antibiotics prevents recurrent infection in a mouse model of urinary tract infection

Urinary tract infection (UTI) is a very common infection. Approximately 25% of all women will experience recurrent infection, defined by 2 UTI in 6 months or 3 UTI in a 12 month period. Recurrent infection is thought to be due in part to the development of local bacterial reservoirs in the bladder after an infection. These reservoirs are undetected by the host immune system and may re-emerge after resolution of the primary infection. Frequently, recurrent UTI require repeated antibiotic use, leading to the development of resistance, and negatively impacting the quality of life of the patient. Given the rise in multidrug resistant uropathogens, treatments that do not rely upon antibiotics are urgently needed for this patient population. We assessed the capacity of a lyophilized E. coli extract, OM-89(R), as a preventive measure to reduce the incidence of spontaneous recurrence in a mouse cystitis model. Administration of OM-89 per os after the initiation of an acute UTI significantly reduced the number of spontaneous recurrent UTI in female mice over a 1 month follow-up period only when the animals were also treated with antibiotics. Protection against recurrent UTI arose quickly and without changes in any adaptive immune response parameter measured, ruling out a role for OM-89 in augmenting adaptive immunity to protect against spontaneous recurrent UTI in the first month of use.

immunology↗

bioRxiv2021

Bladder tissue-resident memory T cells are necessary and sufficient to mediate immunity to recurrent UTI

Urinary tract infection (UTI) is one of the most prevalent human bacterial infections. New therapeutic approaches, including vaccination and immunotherapy, are urgently needed to combat the rapid global dissemination of multidrug-resistant uropathogens. Development of therapies is impeded by an incomplete understanding of memory development during UTI. Here, we found that reducing bacterial load early in infection, by reducing the inoculum or with antibiotics after infection, completely abrogated the protective memory response. We observed a mixed T helper cell polarization, comprised of Th1, Th2, and Th17 T cells, among T cells infiltrating the bladder during primary infection. Thus, we hypothesized that reducing antigen load altered T helper cell polarization leading to poor memory. Surprisingly, however, T helper cell polarization was unchanged in these scenarios. Instead, we uncovered a population of tissue resident memory (TRM) T cells that was significantly reduced in the absence of sufficient antigen. Demonstrating that TRM cells are necessary for immune memory, transfer of lymph node or spleen-derived infection-experienced T cells to naive animals did not confer protection against infection. Supporting that TRM cells are sufficient to protect against recurrent UTI, animals depleted of systemic T cells, or treated with FTY720 to block memory lymphocyte migration from lymph nodes to infected tissue, were equally protected compared to unmanipulated mice against a second UTI. Thus, we uncovered an unappreciated key role for TRM cells in the memory response to bacterial infection in this mucosa, providing a target for non-antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI. One Sentence SummaryTRM are necessary and sufficient for memory to recurrent UTI

immunology↗

bioRxiv2020

Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumor-specific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model. We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations. Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8+ T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy and that these cells had the highest levels of the exhaustion marker PD-1. We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men.

immunology↗

bioRxiv2020

The immune system fails to mount a protective response to Gram-positive or Gram-negative bacterial prostatitis

Bacterial prostatitis affects 1% of men, with increased incidence in the elderly. It is defined by the frequency and urgency to urinate, localized pain, and positive bacterial cultures in expressed seminal fluids. Acute bacterial prostatitis frequently progresses to chronicity, which is marked by recurrent acute episodes interspersed with asymptomatic periods of variable duration. Up to 80% of bacterial prostatitis cases are caused by Gram-negative uropathogenic E. coli (UPEC) or Gram-positive E. faecalis. Antibiotic treatment is standard of care, however, global dissemination of antimicrobial resistant uropathogens threatens efficacy of therapy. Thus, development of non-antibiotic-based approaches to treat bacterial prostatitis is a priority. One challenge is that the immune response to infection in the prostate is incompletely understood. We used a mouse model of transurethral bacterial instillation to study the immune response to UPEC or E. faecalis prostate infection. Both uropathogens exhibited tropism for the prostate over the bladder early post-infection. UPEC infection induced greater proinflammatory cytokine expression and neutrophil and monocyte infiltration compared to E. faecalis infection. Following challenge infection, cytokine responses and myeloid cell infiltration were largely comparable to primary infection. Characteristic of memory responses, more lymphoid cells infiltrating the prostate in the second infection compared to the primary infection. Unexpectedly, however, bacterial burden in prostates challenged with either UPEC or E. faecalis was equal or greater than in primary infection, despite that an adaptive response to UPEC infection was evident in the bladder of the same animals. Thus, an immune response to primary infection is initiated, however it does not protect against reinfection. Our findings support the idea that chronic or recurrent prostatitis develops in the absence of efficacious immunity to infection. A greater understanding of the mechanisms underlying this observation may point to actionable targets for immunotherapy.

immunology↗

bioRxiv2018

Sex differences in IL-17 determine chronicity in male versus female urinary tract infection

Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased {gamma}{delta} T and LTi-like cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying the cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non-antibiotic-based immune targeting to improve the response to UTI.\n\nOne Sentence SummaryWe investigated mechanisms underlying the clinical observation that while urinary tract infection is more prevalent in women, it is more severe in men, observing that in contrast to robust immune responses characterized by IL-17 in female animals, male mice develop chronic infection, following a failure to initiate innate immunity.

immunology↗