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.

尿路感染（urinary tract infection, UTI）是最常见的细菌感染性疾病之一，其频繁复发是当前临床医学面临的主要挑战。由于对介导适应性免疫（adaptive immunity）的分子事件缺乏认知，有效治疗手段的开发一直受到阻碍。本研究首次提供确凿证据表明，UTI感染过程中会触发适应性免疫应答，但该应答无法介导灭菌免疫（sterilizing immunity）。为探究这一免疫缺陷的潜在机制，我们对初始状态下的膀胱免疫细胞区室（naïve bladder immune cell compartment）进行了系统分析，鉴定出驻留巨噬细胞（resident macrophages）为膀胱内数量最多的免疫细胞群体。为评估驻留巨噬细胞对感染后适应性免疫应答建立的影响，我们分别清除了可分化为巨噬细胞的循环单核细胞（circulating monocytes）以及膀胱驻留巨噬细胞，并检测小鼠的细菌清除能力（bacterial clearance）。令人意外的是，初次感染（primary infection）前清除了驻留巨噬细胞的小鼠，在继发攻击（secondary challenge）后的细菌负荷（bacterial burden）较未处理对照组降低了近2个对数级。这种继发感染下细菌清除能力的增强，完全依赖于淋巴细胞（lymphocytes）的参与。巨噬细胞是感染后摄取细菌的主要抗原呈递细胞（antigen presenting cell）；在驻留巨噬细胞缺失的情况下，树突状细胞（dendritic cells）对细菌的摄取量提升了近2倍。上述研究结果表明，组织巨噬细胞对细菌的摄取会阻碍UTI感染过程中适应性免疫应答的建立，这为增强宿主对膀胱细菌感染的免疫应答提供了全新的潜在治疗靶点。