Macrophages Subvert Adaptive Immunity to Urinary Tract Infection

Abstract

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.

Proteus mirabilis fimbriae- and urease-dependent clusters assemble in an extracellular niche to initiate bladder stone formation

“…3E). We did not detect neutrophils in naive bladders, consistent with other reports (26,27). Taken together, these data suggest that P. mirabilis clusters elicit a specific immune response that is robust and distinct from UPEC.…”

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

“…To gain greater insight into the kinetics and composition of the predicted immune cell infiltration, we analyzed cellular migration into the bladder from 1 hour to 1 week after catheter implantation by spectral flow cytometry. Bladders from naive or catheterized mice were digested to a single-cell suspension and immunostained for predefined immune cell markers (21). We chose to use spectral analysis, which permitted investigation of a greater number of parameters than possible using conventional flow cytometry, including natural autofluorescent signals, without the need for compensation (22).…”

“…We chose to use spectral analysis, which permitted investigation of a greater number of parameters than possible using conventional flow cytometry, including natural autofluorescent signals, without the need for compensation (22). We incorporated the strongest autofluorescent signal emitted from inflamed bladder tissue into the deconvolution algorithm to exclude autofluorescent nonimmune cells, whose signal typically spills over into the channels used to identify CD45 + immune cells (21).…”

“…To quantify immune cell infiltration, we gated CD45 + immune cells and identified distinct populations based on previously defined protein expression (21) (Figure 2, B-E). Catheterized bladders had increased numbers of CD45 + cells, which included robust neutrophil accumulation that started at 1 hpc and was statistically significantly increased over the naive cohort from 6 hpc ( Figure 2C).…”

“…Bladders were prepared as previously described (21). At indicated time points, bladders were removed, catheters were recovered, and tissue was minced into digestion buffer containing 0.34 U/ml of Liberase TM (Roche) in PBS at 4°C.…”