RESUMEN
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 (TH) cell polarization, composed of TH1, TH2, and TH17 T cells, among T cells infiltrating the bladder during primary infection. Thus, we hypothesized that reducing antigen load altered TH cell polarization, leading to poor memory. Unexpectedly, however, TH 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 naïve 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 with unmanipulated mice against a second UTI. Thus, we uncovered an unappreciated key role for TRM cells in the memory response to bacterial infection in the bladder mucosa, providing a target for non-antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI.
Asunto(s)
Infecciones Urinarias , Vacunas , Humanos , Animales , Ratones , Células T de Memoria , Inmunidad Mucosa , VacunaciónRESUMEN
Bacterial prostatitis affects 1% of men, with increased incidence in the elderly. Acute bacterial prostatitis frequently progresses to chronicity, marked by recurrent episodes interspersed with asymptomatic periods of variable duration. Antibiotic treatment is standard of care; however, dissemination of antimicrobially resistant uropathogens threatens therapy efficacy. Thus, development of nonantibiotic-based approaches to treat chronic disease is a priority. Currently, why chronic prostatitis arises is unclear, as the immune response to prostate infection is incompletely understood. As 80% of prostatitis cases are caused by Gram-negative uropathogenic Escherichia coli (UPEC) or Gram-positive Enterococcus faecalis, we used a mouse transurethral instillation model to address the hypothesis that an innate immune response fails to develop following prostate infection with these uropathogens, leading to chronic disease. Surprisingly, infection induced robust proinflammatory cytokine expression and myeloid cell infiltration. Following a second infection, cytokine responses and innate cell infiltration were largely comparable to primary infection. Characteristic of memory responses, more lymphoid cells infiltrated the prostate in a second infection compared with a first, suggesting that adaptive immunity develops to eliminate the pathogens. Unexpectedly, bacterial burden in prostates challenged with either UPEC or E. faecalis was equal or greater than primary infection despite that a protective adaptive response to UPEC infection was evident in the bladder of the same animals. Our findings support that chronic or recurrent prostatitis develops despite strong innate immune responses and may be the result of a failure to develop immune memory to infection, pointing to actionable targets for immunotherapy.
Asunto(s)
Infecciones por Escherichia coli/inmunología , Infecciones por Bacterias Grampositivas/inmunología , Prostatitis/inmunología , Infecciones Urinarias/inmunología , Animales , Enfermedad Crónica , Citocinas/metabolismo , Modelos Animales de Enfermedad , Enterococcus faecalis/inmunología , Enterococcus faecalis/patogenicidad , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/terapia , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacterias Grampositivas/terapia , Humanos , Inmunidad Innata , Memoria Inmunológica , Inmunoterapia , Masculino , Ratones , Próstata/inmunología , Próstata/microbiología , Prostatitis/microbiología , Prostatitis/terapia , Recurrencia , Vejiga Urinaria/inmunología , Vejiga Urinaria/microbiología , Infecciones Urinarias/microbiología , Infecciones Urinarias/terapia , Escherichia coli Uropatógena/inmunología , Escherichia coli Uropatógena/patogenicidadRESUMEN
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 γδ T cells and group 3 innate lymphoid cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying a 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.