Abstract
BackgroundThe 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 FindingsTo 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-B1−/− or wild type mice in vitro. Moreover, when wild type and SR-B1−/− 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, IFNγ, and IL10 were observed in SR-B1−/− 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.ConclusionSR-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.
Highlights
Tuberculosis is the leading cause of death worldwide from a single infectious disease
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 Mycobacterium tuberculosis (Mtb)
Positive cells were isolated and enriched in culture until almost pure colonies of bacilli Calmette-Guerin (BCG)-binding cells were obtained. After isolation of their genomic DNA and re-amplification of the stably inserted cDNA fragments originating from the RAW264.7 library, a 2.5kb cDNA fragment corresponding to the full-length murine scavenger receptor B class 1 (SR-B1) was obtained that was tested positive for bacillus Calmette-Guerin expressing Green Fluorescent Protein (BCG-GFP) binding when re-inserted into NIH3T3 cells (Fig. 1A)
Summary
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. 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. 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. 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
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