Tuberculosis: The success tale of less explored dormant Mycobacterium tuberculosis

Verma, Akanksha; Ghoshal, Antara; Dwivedi, Ved Prakash; Bhaskar, Ashima

doi:10.3389/fcimb.2022.1079569

Cited by 14 publications

(9 citation statements)

References 119 publications

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“…In contrast to our findings, hypoxia-induced dormant Mycobacterium tuberculosis profoundly alters the transcriptome of Rhesus BMDMs, evoking a broad proinflammatory response to M. tuberculosis marked by TNF expression [79]. Other studies corroborate the correlation between a heightened proinflammatory response and the persistence of dormant M. tuberculosis in host granulomas [80][81][82]. Hence, different strategies for dormancy persistence may occur in the host.…”

Section: Plos Pathogenscontrasting

confidence: 84%

Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis

de Castro,

Marina,

Sturny-Leclère

et al. 2023

PLoS Pathog

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Macrophages play a key role in disseminated cryptococcosis, a deadly fungal disease caused by Cryptococcus neoformans. This opportunistic infection can arise following the reactivation of a poorly characterized latent infection attributed to dormant C. neoformans. Here, we investigated the mechanisms underlying reactivation of dormant C. neoformans using an in vitro co-culture model of viable but non-culturable (VBNC; equivalent of dormant) yeast cells with bone marrow-derived murine macrophages (BMDMs). Comparative transcriptome analysis of BMDMs incubated with log, stationary phase or VBNC cells of C. neoformans showed that VBNC cells elicited a reduced transcriptional modification of the macrophage but retaining the ability to regulate genes important for immune response, such as NLRP3 inflammasome-related genes. We further confirmed the maintenance of the low immunostimulatory capacity of VBNC cells using multiplex cytokine profiling, and analysis of cell wall composition and dectin-1 ligands exposure. In addition, we evaluated the effects of classic (M1) or alternative (M2) macrophage polarization on VBNC cells. We observed that intracellular residence sustained dormancy, regardless of the polarization state of macrophages and despite indirect detection of pantothenic acid (or its derivatives), a known reactivator for VBNC cells, in the C. neoformans-containing phagolysosome. Notably, M0 and M2, but not M1 macrophages, induced extracellular reactivation of VBNC cells by the secretion of extracellular vesicles and non-lytic exocytosis. Our results indicate that VBNC cells retain the low immunostimulatory profile required for persistence of C. neoformans in the host. We also describe a pro-pathogen role of macrophage-derived extracellular vesicles in C. neoformans infection and reinforce the impact of non-lytic exocytosis and the macrophage profile on the pathophysiology of cryptococcosis.

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Section: Plos Pathogenscontrasting

confidence: 84%

Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis

de Castro,

Marina,

Sturny-Leclère

et al. 2023

PLoS Pathog

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“…This notwithstanding, cells with absent CFU capability but quite detectable in MPN tests, which were characterized in this study, can be a useful object for the screening of antibacterial agents. On the one hand, 'non-culturable' or dormant mycobacteria are of clinical relevance, besides actively growing cells, and may occur in clinical specimens [19,36]. On the other hand, dormant mycobacterial cells may escape from routinely used CFU-based tests due to lost ability to form colonies.…”

Section: Discussionmentioning

confidence: 99%

Distinct Effects of Moxifloxacin and Bedaquiline on Growing and ‘Non-Culturable’ Mycobacterium abscessus

Mulyukin,

Recchia,

Kostrikina

et al. 2023

Microorganisms

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Mycobacterium abscessus has recently emerged as the cause of an increasing number of human infections worldwide. Unfortunately, it is highly resistant to existing drugs, and new specific agents to combat M. abscessus have not yet been found. The discovery of antibiotics that are effective not only against replicating but also against dormant and often recalcitrant cells is a daunting challenge. In this study, we developed a model of non-replicating M. abscessus, which represents a valuable screening tool for antibacterial agents. Thus, we demonstrated that, under a deficiency of potassium ions in the growth media and prolonged incubation, M. abscessus entered a ‘non-culturable’ state with a significant loss of colony-forming ability, but it retained viability, as confirmed using the most-probable-number (MPN) assay. The ‘non-culturable’ mycobacteria possessed decelerated cellular metabolism and noticeable differences in cell morphology from actively growing mycobacteria. ‘Non-culturable’ cells were used in a comprehensive screening of the efficacy of antibiotics, along with actively growing cells. Both CFU and MPN tests confirmed the prominent bactericidal effect of moxifloxacin on actively growing and ‘non-culturable’ M. abscessus, as proven by less than 0.01% of cells surviving after antibiotic treatment and prolonged storage. Bedaquiline exhibited a comparable bactericidal effect only on metabolically inactive non-culturable cells aged for 44 days. There were reductions ranging from 1000 to 10,000-fold in CFU and MPN, but it was not so efficient with respect to active cells, resulting in a bacteriostatic effect. The demonstrated specificity of bedaquiline in relation to inert non-replicating M. abscessus offers a new and unexpected result. Based on the findings of this research, moxifloxacin and bedaquiline can be regarded as potential treatments for infections caused by M. abscessus. In addition, a key outcome is the proposal to include the combination of viability assays for comprehensive testing of drug candidates. Relying on CFU-based assays alone resulted in overestimates of antibacterial efficacy, as demonstrated in our experiments.

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“…The immunomodulatory effects of MSCs and their involvement in various infectious diseases result from their interactions with different immune cells in the body. In TB, the granuloma is a well-defined structure composed of macrophages, neutrophils, MSCs, B-lymphocytes, and T-lymphocytes [ 86 ]. There is little knowledge of the interactions of MSCs with different immune cells within the granuloma, which is a major obstacle in understanding the mechanism of the establishment of latency.…”

Section: Interactions Of Mscs With the Host Immune Systemmentioning

confidence: 99%

Revisiting the role of mesenchymal stem cells in tuberculosis and other infectious diseases

et al. 2023

Self Cite

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Mesenchymal stem cells (MSCs) play diverse roles ranging from regeneration and wound healing to immune signaling. Recent investigations have indicated the crucial role of these multipotent stem cells in regulating various aspects of the immune system. MSCs express unique signaling molecules and secrete various soluble factors that play critical roles in modulating and shaping immune responses, and in some other cases, MSCs can also exert direct antimicrobial effects, thereby helping with the eradication of invading organisms. Recently, it has been demonstrated that MSCs are recruited at the periphery of the granuloma containing Mycobacterium tuberculosis and exert “Janus”-like functions by harboring pathogens and mediating host protective immune responses. This leads to the establishment of a dynamic balance between the host and the pathogen. MSCs function through various immunomodulatory factors such as nitric oxide (NO), IDO, and immunosuppressive cytokines. Recently, our group has shown that M.tb uses MSCs as a niche to evade host protective immune surveillance mechanisms and establish dormancy. MSCs also express a large number of ABC efflux pumps; therefore, dormant M.tb residing in MSCs are exposed to a suboptimal dose of drugs. Therefore, it is highly likely that drug resistance is coupled with dormancy and originates within MSCs. In this review, we discussed various immunomodulatory properties of MSCs, their interactions with important immune cells, and soluble factors. We also discussed the possible roles of MSCs in the outcome of multiple infections and in shaping the immune system, which may provide insight into therapeutic approaches using these cells in different infection models.

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Tuberculosis: The success tale of less explored dormant Mycobacterium tuberculosis

Cited by 14 publications

References 119 publications

Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis

Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis

Distinct Effects of Moxifloxacin and Bedaquiline on Growing and ‘Non-Culturable’ Mycobacterium abscessus

Revisiting the role of mesenchymal stem cells in tuberculosis and other infectious diseases

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