The Role of Scavenger Receptor B1 in Infection with Mycobacterium tuberculosis in a Murine Model Georgia Scha¨ fer1, Reto Guler1,2, Graeme Murray3, Frank Brombacher1,2, Gordon D. Brown1,4* 1 Division of Immunology, Institute for Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, Cape Town, South Africa, 2 International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa, 3 Section of Translational Medicine, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, United Kingdom, 4 Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, United Kingdom Abstract Background: The interaction between Mycobacterium tuberculosis (Mtb) and host cells is complex and far from being understood. The role of the different receptor(s) implicated in the recognition of Mtb in particular remains poorly defined, and those that have been found to have activity in vitro were subsequently shown to be redundant in vivo. Methods and Findings: To identify novel receptors involved in the recognition of Mtb, we screened a macrophage cDNA library and identified scavenger receptor B class 1 (SR-B1) as a receptor for mycobacteria. SR-B1 has been well-described as a lipoprotein receptor which mediates both the selective uptake of cholesteryl esters and the efflux of cholesterol, and has also recently been implicated in the recognition of other pathogens. We show here that mycobacteria can bind directly to SR-B1 on transfected cells, and that this interaction could be inhibited in the presence of a specific antibody to SR-B1, serum or LDL. We define a variety of macrophage populations, including alveolar macrophages, that express this receptor, however, no differences in the recognition and response to mycobacteria were observed in macrophages isolated from SR- B12/2 or wild type mice in vitro. Moreover, when wild type and SR-B12/2 animals were infected with a low dose of Mtb (100 CFU/mouse) there were no alterations in survival, bacterial burdens, granuloma formation or cytokine production in the lung. However, significant reduction in the production of TNF, IFNc, and IL10 were observed in SR-B12/2 mice following infection with a high dose of Mtb (1000 CFU/mouse), which marginally affected the size of inflammatory foci but did not influence bacterial burdens. Deficiency of SR-B1 also had no effect on resistance to disease under conditions of varying dietary cholesterol. We did observe, however, that the presence of high levels of cholesterol in the diet significantly enhanced the bacterial burdens in the lung, but this was independent of SR-B1. Conclusion: SR-B1 is involved in mycobacterial recognition, but this receptor plays only a minor role in anti-mycobacterial immunity in vivo. Like many other receptors for these pathogens, the loss of SR-B1 can be functionally compensated for under normal conditions. Citation: Scha¨fer G, Guler R, Murray G, Brombacher F, Brown GD (2009) The Role of Scavenger Receptor B1 in Infection with Mycobacterium tuberculosis in a Murine Model. PLoS ONE 4(12): e8448. doi:10.1371/journal.pone.0008448 Editor: Ludovic Tailleux, Institut Pasteur, France Received September 18, 2009; Accepted November 20, 2009; Published December 24, 2009 Copyright: 2009 Scha¨fer 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. Funding: This work was supported by funding from the Deutsche Forschungsgemeinschaft (DFG), Germany, to GS (grant SCHA 1470/1-1), the Claude Leon Foundation, South Africa, to GS and RG, the National Research Foundation (NRF), South Africa, to FB, the South African Research Chair Initiative of the Department of Science and Technology (DST) to FB, and the Wellcome Trust to GDB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: gordon.brown@abdn.ac.uk Introduction Tuberculosis is the leading cause of death worldwide from a single infectious disease. The causative agent, Mycobacterium tuberculosis (Mtb), enters the host typically via aerosols, and alveolar macrophages are considered the first cells to engulf Mtb and become infected. Although the initial interaction of the pathogen with the host macrophage is considered a critical step in the pathogenesis of Mtb, the role of the receptors that play a role in mediating the entry of Mtb into macrophages and in transducing intracellular signals is very controversial and far from being understood. Over the years, more than a dozen receptors have been shown to recognize and bind mycobacteria (reviewed in [1]). However, the role of these receptors has been mostly based on in vitro examination in transfected cells; studies using inhibitors or animals deficient for specific receptors have indicated that these receptors are dispensable [2–7]. Since no direct functional-based search for the macrophage receptors involved in mycobacterial recognition has been performed, here we utilised a generalized screening method [8] with which we identified scavenger receptor B class 1 (SR-B1) as a novel macrophage receptor involved in the recognition of Mtb. Scavenger receptors belong to a family of cell surface transmembrane glycoproteins with broad ligand-binding abilities and important roles in atherogenesis, innate immunity and macrophage regulation (reviewed in [9]). Although their impact for recognition of Mtb has not been extensively studied, there are a few reports that show the general involvement of scavenger PLoS ONE | www.plosone.org 1 December 2009 | Volume 4 | Issue 12 | e8448