Macrophages Subvert Adaptive Immunity to Urinary Tract Infection

RESEARCH ARTICLE Macrophages Subvert Adaptive Immunity to Urinary Tract Infection Gabriela Mora-Bau1, Andrew M. Platt2, Nico van Rooijen3, Gwendalyn J. Randolph2¤, Matthew L. Albert1, Molly A. Ingersoll1* 1 Unité d’Immunobiologie des Cellules Dendritiques, Department of Immunology, Institut Pasteur and INSERM U818, Paris, France, 2 Department of Gene and Cell Medicine and the Immunology Institute, Mount Sinai School of Medicine, New York, New York, United States of America, 3 Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands a11111 ¤ Current Address: Department of Pathology, Washington University Medical School, St. Louis, Missouri, United States of America * Abstract OPEN ACCESS Citation: Mora-Bau G, Platt AM, van Rooijen N, Randolph GJ, Albert ML, Ingersoll MA (2015) Macrophages Subvert Adaptive Immunity to Urinary Tract Infection. PLoS Pathog 11(7): e1005044. doi:10.1371/journal.ppat.1005044 Editor: William C Gause, University of Medicine & Dentistry New Jersey, UNITED STATES Received: March 5, 2015 Accepted: June 23, 2015 Published: July 16, 2015 Copyright: © 2015 Mora-Bau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This project was supported in part by funding from a Ruth Chemers Neustein Postdoctoral Fellowship award, European Union Seventh Framework Programme Marie Curie Action (PCIG11GA- 2012-3221170, and the Immuno-Oncology LabEx (MAI). GMB is a scholar from the PasteurParis University (PPU) International PhD program. GJR was supported by National Institutes of Health AI049653. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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 longlasting resistance to infection. Currently, little is known about how adaptive immune PLOS Pathogens | DOI:10.1371/journal.ppat.1005044 July 16, 2015 1 / 23 Macrophages Limit Adaptive Immunity to UTI Competing Interests: The authors have declared that no competing interests exist. 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. Introduction Urinary tract infection (UTI) is one of the most common bacterial infections, impacting more than 130 million people annually worldwide [1,2]. The principal causative agent is uropathogenic Escherichia coli (UPEC), accounting for more than 75% of all community acquired infections, particularly among a seemingly healthy population (e.g., premenopausal women) [1]. In uncomplicated UTI (i.e., cystitis), nearly half of all women infected will experience recurrence [3]. Currently, there is little consensus in the field regarding the underlying causes of the high rate of recurrence. Mechanisms previously proposed to explain this phenomenon include that UPEC forms protected reservoirs in the bladder, remerging at later time points after initial infection [4,5]; that UPEC strains colonize the gut and periodically migrate to the urinary tract [6]; or that the immune response to infection is suppressed by mast cell-derived IL-10 in the bladder [7]. The innate immune response to UPEC infection is characterized by robust cytokine and chemokine expression, leading to rapid neutrophil and monocyte infiltration and subsequent bacterial clearance [8–12]. Depletion of both neutrophils and monocytes, by Gr1 antibody treatment [13], leads to increased bacterial burden, whereas a reduction in circulating neutrophils alone decreases bacterial burden, suggesting that monocytes help eliminate bacteria in the bladder [10,11]. A recent study demonstrated that innate immune cell crosstalk is necessary for a coordinated innate response, whereby resident macrophages, responding to signals from infiltrating monocytes, induce MMP9 expression in neutrophils, in turn facilitating their transurothelial migration [14]. This mechanism likely works in concert with cytokine and chemokine expression from infected urothelium that mediates neutrophil recruitment and transurotheli (...truncated)