Macrophages Subvert Adaptive Immunity to Urinary Tract Infection

Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder.
Author Summary Urinary tract infection is a common infection with a high propensity for recurrence. The majority of infections are caused by uropathogenic E. coli, a growing public health concern with increasing prevalence of antibiotic resistant strains. Finding therapeutic options that circumvent the need for antibiotics, while boosting patients’ immune response to infection is desirable to counteract further increases in antibiotic resistance and to provide long-lasting resistance to infection. Currently, little is known about how adaptive immune responses, which typically prevent recurrent infection in other organs, arise from the bladder during urinary tract infection. Here, we investigated the initial interactions between immune cell populations of the bladder and uropathogenic E. coli, finding that macrophages are the principal cell population to engulf bacteria. Interestingly, these same cells appear to inhibit the development of adaptive immunity to the bacteria, as their depletion, prior to primary infection, results in a stronger immune response during bacterial challenge. We found that in the absence of macrophages, dendritic cells, which are the most potent initiators of adaptive immunity, are able to take up more bacteria for presentation. Our study has revealed a mechanism in which specific immune cells may act in a manner detrimental to host immunity.