Mesenchymal stem cells (MSCs) offer a drug tolerant and immune- privileged niche to Mycobacterium tuberculosis

Mycobacterium tuberculosis (M.tb) is an intracellular pathogen that predominantly affects the alveolar macrophages in the respiratory tract. Upon infection, the activation of TLR2 and TLR4- mediated signaling pathways leads to lysosomal degradation of the bacteria. However, bacterium counteracts the host immune cells and utilizes them as a cellular niche for its survival. One distinctive mechanism of M.tb to limit the host stress responses such as hypoxia and nutrient starvation is induction of dormancy. As the environmental conditions become favorable, the bacteria resuscitate, resulting in a relapse of clinical symptoms. Different bacterial proteins play a critical role in maintaining the state of dormancy and resuscitation, namely, DevR (DosS), Hrp1, DATIN and RpfA-D, RipA, etc., respectively. Existing knowledge regarding the key proteins associated with dormancy and resuscitation can be employed to develop novel therapies. In this review we aim to highlight the current knowledge of bacterial progression from dormancy to resuscitation and the gaps in understanding the transition from dormant to active state. We have also focused on elucidating a few therapeutic strategies employed to prevent M.tb resuscitation.

Section: Host-pathogen Interactions During Dormancymentioning

confidence: 99%

Tuberculosis: The success tale of less explored dormant Mycobacterium tuberculosis

Verma

Ghoshal

Dwivedi

et al. 2022

“…Since the median percentage of persisters were significantly different between CytD-and BafA1-treated groups, highlights mechanisms whereby M. tuberculosis may differentially modulate macrophage metabolic processes and antimicrobial functions (or vice versa), thus affecting the capacity of the host to resolve infection (Gleeson et al, 2016;Martin et al, 2017). The pharmacokinetics of anti-M. tuberculosis drugs may furthermore be influenced following BafA1 treatment, as drugs that accumulate in acidic vacuoles possessed a reduced killing capacity (Schump et al, 2017), whilst treatment with isoniazid or rifampicin led to a rapid decrease in drug tolerant M. tuberculosis (Mishra et al, 2019;Jain et al, 2020). It would thus be intriguing to determine the influence of these host processes on M. tuberculosis gene regulation to provide insight into how M. tuberculosis manipulates host immune signals and cytokines to evade immune detection and clearance.…”

Section: Discussionmentioning

confidence: 99%

Persistence of Mycobacterium tuberculosis in response to infection burden and host-induced stressors

Parbhoo

Schurz²,

Mouton³

et al. 2022

IntroductionAs infection with Mycobacterium tuberculosis progresses, the bacilli experience various degrees of host stressors in the macrophage phagosome such as low pH, nutrient deprivation, or exposure to toxic agents, which promotes cell-to-cell phenotypic variation. This includes a physiologically viable but non- or slowly replicating persister subpopulation, which is characterised by a loss of growth on solid media, while remaining metabolically active. Persisters additionally evade the host immune response and macrophage antimicrobial processes by adapting their metabolic pathways to maintain survival and persistence in the host.MethodsA flow cytometry-based dual-fluorescent replication reporter assay, termed fluorescence dilution, provided a culture-independent method to characterize the single-cell replication dynamics of M. tuberculosis persisters following macrophage infection. Fluorescence dilution in combination with reference counting beads and a metabolic esterase reactive probe, calcein violet AM, provided an effective approach to enumerate and characterize the phenotypic heterogeneity within M. tuberculosis following macrophage infection.ResultsPersister formation appeared dependent on the initial infection burden and intracellular bacterial burden. However, inhibition of phagocytosis by cytochalasin D treatment resulted in a significantly higher median percentage of persisters compared to inhibition of phagosome acidification by bafilomycin A1 treatment.DiscussionOur results suggest that different host factors differentially impact the intracellular bacterial burden, adaptive mechanisms and entry into persistence in macrophages.

“…In recent years, many researchers have suggested that this change significantly reduces the virulence factors mannose-capped lipoarabinomannan (Man-LAM) and trehalose-6,6'-dimycolate (TDM) on the surface of MTB (Tuladhar and Kanneganti, 2020). For example, MTBsecreted ESAT-6 protein can improve the permeability of phagosomes in host phagocytes and activate NLRP3 (Jain et al, 2020). Thus, after thousands of years of development, MTB has coevolved with humans.…”

Section: Mechanisms Of Interaction Between Mtb Effector Proteins and ...mentioning

confidence: 99%

Emerging advances in identifying signal transmission molecules involved in the interaction between Mycobacterium tuberculosis and the host

Wang

Shi

Chen

et al. 2022

Tuberculosis caused by Mycobacterium tuberculosis (MTB) is an ancient chronic infectious disease and is still the leading cause of death worldwide due to a single infectious disease. MTB can achieve immune escape by interacting with host cells through its special cell structure and secreting a variety of effector proteins. Innate immunity-related pattern recognition receptors (PPR receptors) play a key role in the regulation of signaling pathways.In this review, we focus on the latest research progress on related signal transduction molecules in the interaction between MTB and the host. In addition, we provide new research ideas for the development of new anti-tuberculosis drug targets and lead compounds and provide an overview of information useful for approaching future tuberculosis host-oriented treatment research approaches and strategies, which has crucial scientific guiding significance and research value.