Abstract
Human mesenchymal stem cells (MSCs) express scavenger receptors that internalize lipids, including oxidized low-density lipoprotein (oxLDL). We report that MSCs phagocytose Mycobacterium tuberculosis (Mtb) through two types of scavenger receptors (SRs; MARCO and SR-B1), as blockade of the receptors with antibodies or siRNA knockdown decreased the uptake of Mtb. MSCs also expressed mannose receptor (MR) that was found to endocytose rhodamine-labeled mannosylated BSA (rMBSA), though the receptor was not involved in the uptake of Mtb. Dil-oxLDL and rMBSA taken up into MSC endosomes colocalized with Mtb phagosomes, thus suggesting that the latter were fusion competent. Phagocytosed Mtb did not replicate within MSCs, thus suggesting an intrinsic control of bacterial growth. Indeed, MSCs exhibited intrinsic autophagy, which was up-regulated after activation with rapamycin. SiRNA knockdown of autophagy initiator beclin-1 enhanced Mtb survival, whereas rapamycin-induced autophagy increased intracellular killing of Mtb. In addition, MSCs secreted nitric oxide after Mtb infection, and inhibition of NO by N(G)-monomethyl-L-arginine enhanced intracellular survival of Mtb. MSCs can be grown in large numbers in vitro, and autologous MSCs transfused into tuberculosis patients have been found to be safe and improve lung immunity. Thus, MSCs are novel phagocytic cells with a potential for immunotherapy in treating multidrug-resistant tuberculosis.
Highlights
Tuberculosis is responsible for 2 million deaths each year and is a major cause of mortality from a single infectious disease worldwide[1]
Mycobacterium tuberculosis (Mtb) is phagocytosed by macrophages and DCs through a variety of receptors such as Fc, complement receptor CR-1, C-type lectin receptors (DC-SIGN, dectin-1, Mincle and mannose receptor or MR) and scavenger receptors (SRs)[23,24,25]
Since Mesenchymal stem cells (MSCs) were present in Mtb containing granulomas of mice and humans, these cells have been thought to play a role during the pathogenesis of tuberculosis[19,20]
Summary
Tuberculosis is responsible for 2 million deaths each year and is a major cause of mortality from a single infectious disease worldwide[1]. Th1 immunity against Mtb is generated through degradation of Mtb in lysosomes, producing peptides that are routed via MHC-II to CD4 T cells. These cells secrete Th1 cytokines, which in turn activate macrophages and increase the secretion of oxidants, which kill Mtb. In addition, Th1 cytokines such as IFN-γ enhance phagosome-lysosome fusion[4]. Peptides cleaved by proteasomes are loaded through MHC-I and activate CD8 T cells These cells secrete IFN-γ and are able to lyse Mtb-infected macrophages through perforin and granzyme. The cell biology of MSCs during infection has remained largely unclear[11,12]
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