Mesenchymal stem cells internalize Mycobacterium tuberculosis through scavenger receptors and restrict bacterial growth through autophagy

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.

Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence

“…Previously, we and others have shown that MSCs are associated with nonreplicating M. tuberculosis (9,10,13). Therefore, we sought to determine whether MSCs are a natural reservoir for M. tuberculosis and dormancy that renders nonresponsiveness to antibiotic treatment.…”

“…In contrast, dormant forms of the bacteria generally do not respond to antibiotics, and where and how they evade drugs and detection is incompletely understood. Nevertheless, studies, including our previously published data, have indicated that MSCs represent a major niche for dormant TB (9,10,13). Based on these considerations, we hypothesized that M. tuberculosis acquires dormancy and thereby drug nonresponsiveness in MSCs.…”

Innate immune receptors in development of Mycobacterium tuberculosis infection

“…Мезенхимальные стволовые клетки человека (MSCs) экспрессируют на своей поверхности два типа скавенджер-рецепторов: MARCO и SR-B1, с помощью которых индуцируют фагоцитоз M. tuberculosis. Продемонстрировано, что размножение M. tuberculosis в MSCs не происходит вследствие аутофагии и продукции NO [52].…”

Trained Immunity for Personalized Cancer Immunotherapy: Current Knowledge and Future Opportunities

“…This "trained immunity" does not resemble immunological memory of adaptive immune cells, i.e., T and B cells, but rather pre-programing of cells that will respond with similar effector molecules to subsequent challenge driven by recognition of pathogen-/danger-associated molecular patterns (PAMPs/ DAMPs) by pathogen-recognition receptors (PRRs), such as Toll-like receptors (TLRs) (Gourbal et al, 2018). Stromaassociated mesenchymal stromal cells (MSC) and fibroblasts, which can also harbor pathogens (Das et al, 2013;McCormack et al, 2013;Beamer et al, 2014;Khan et al, 2017), are equipped with the capacity to present antigens to T cells via the human leukocyte antigen (HLA) class I and class II pathways during inflammation (Ilangumaran et al, 2002;Romieu-Mourez et al, 2007;Morandi et al, 2008;Das et al, 2013;Crowley et al, 2018;Hamada et al, 2019), and have been discussed to possess trained immunity characteristics (Hamada et al, 2019).…”