Tolerance and Persistence to Drugs: A Main Challenge in the Fight Against Mycobacterium tuberculosis

Boldrin, Francesca; Provvedi, Roberta; Mazzabò, Laura Cioetto; Segafreddo, Greta; Manganelli, Riccardo

doi:10.3389/fmicb.2020.01924

Cited by 42 publications

(45 citation statements)

References 88 publications

(124 reference statements)

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“…Intriguingly, we found that expression of CD11c in the host cell correlates inversely with the expression levels of hspx9::GFP (Fig. 4 Drug tolerance is defined as an increase in the survival times of bacterial cells toward a bactericidal drug without any change in the minimum inhibitory concentration and this phenomenon is frequently associated with a reduction of bacterial metabolism upon encountering specific environmental conditions (Boldrin et al, 2020). We had shown previously that the drug tolerance phenotype in Mtb can be induced through classical activation of macrophages in vitro and that nitrosative stress is the most potent single inducer of drug tolerance in Mtb in a murine infection in vivo (Liu et al, 2016).…”

Section: Expression Of the Surface Marker Cd11c Is Inversely Associated With Drug-tolerant Bacteriamentioning

confidence: 86%

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Pisu

Huang

Narang

et al. 2021

Journal of Experimental Medicine

107

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In this study, we detail a novel approach that combines bacterial fitness fluorescent reporter strains with scRNA-seq to simultaneously acquire the host transcriptome, surface marker expression, and bacterial phenotype for each infected cell. This approach facilitates the dissection of the functional heterogeneity of M. tuberculosis–infected alveolar (AMs) and interstitial macrophages (IMs) in vivo. We identify clusters of pro-inflammatory AMs associated with stressed bacteria, in addition to three different populations of IMs with heterogeneous bacterial phenotypes. Finally, we show that the main macrophage populations in the lung are epigenetically constrained in their response to infection, while inter-species comparison reveals that most AMs subsets are conserved between mice and humans. This conceptual approach is readily transferable to other infectious disease agents with the potential for an increased understanding of the roles that different host cell populations play during the course of an infection.

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Section: Expression Of the Surface Marker Cd11c Is Inversely Associated With Drug-tolerant Bacteriamentioning

confidence: 86%

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Pisu

Huang

Narang

et al. 2021

Journal of Experimental Medicine

107

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“…This frameshift mutations are particularly enriched in MDR- and XDR- M.tb strains, and suggest that variation in GlpK might contribute to the development of drug resistance. Thus, limited efficacy of current TB treatments suggests that heterogeneity of both host and mycobacterial physiologies in the different lung compartments during the different stages of the infection can influence the emergence of persisters and ultimately, increased drug resistance ( Warner and Mizrahi, 2006 ; Ben-Kahla and Al-Hajoj, 2016 ; Boldrin et al, 2020 ). Novel antimycobacterial drugs that target persisters populations are critical in order to shorten TB treatment and decrease the emergence and transmission of MDR- M.tb strains ( Zhang et al, 2012 ; Mandal et al, 2019 ).…”

Section: Origin and Evolution Of Drug Resistancementioning

confidence: 99%

Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment

2021

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In the last two decades, multi (MDR), extensively (XDR), extremely (XXDR) and total (TDR) drug-resistant Mycobacterium tuberculosis (M.tb) strains have emerged as a threat to public health worldwide, stressing the need to develop new tuberculosis (TB) prevention and treatment strategies. It is estimated that in the next 35 years, drug-resistant TB will kill around 75 million people and cost the global economy $16.7 trillion. Indeed, the COVID-19 pandemic alone may contribute with the development of 6.3 million new TB cases due to lack of resources and enforced confinement in TB endemic areas. Evolution of drug-resistant M.tb depends on numerous factors, such as bacterial fitness, strain’s genetic background and its capacity to adapt to the surrounding environment, as well as host-specific and environmental factors. Whole-genome transcriptomics and genome-wide association studies in recent years have shed some insights into the complexity of M.tb drug resistance and have provided a better understanding of its underlying molecular mechanisms. In this review, we will discuss M.tb phenotypic and genotypic changes driving resistance, including changes in cell envelope components, as well as recently described intrinsic and extrinsic factors promoting resistance emergence and transmission. We will further explore how drug-resistant M.tb adapts differently than drug-susceptible strains to the lung environment at the cellular level, modulating M.tb–host interactions and disease outcome, and novel next generation sequencing (NGS) strategies to study drug-resistant TB.

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“…Increases in SigE expression level are associated with exposure to heat shock, Sodium Dodecyl Sulfate (SDS, a detergent used to mimic surface stress) and antibiotics (such as isoniazid and vancomycin), [ 8 ]. In addition, SigE has been shown to have a major role in determining the amount of bacterial cells surviving prolonged drug treatment [ 9 ] and has been proposed as a switch for dormancy [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Mathematical modelling of SigE regulatory network reveals new insights into bistability of mycobacterial stress response

et al. 2021

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Background The ability to rapidly adapt to adverse environmental conditions represents the key of success of many pathogens and, in particular, of Mycobacterium tuberculosis. Upon exposition to heat shock, antibiotics or other sources of stress, appropriate responses in terms of genes transcription and proteins activity are activated leading part of a genetically identical bacterial population to express a different phenotype, namely to develop persistence. When the stress response network is mathematically described by an ordinary differential equations model, development of persistence in the bacterial population is associated with bistability of the model, since different emerging phenotypes are represented by different stable steady states. Results In this work, we develop a mathematical model of SigE stress response network that incorporates interactions not considered in mathematical models currently available in the literature. We provide, through involved analytical computations, accurate approximations of the system’s nullclines, and exploit the obtained expressions to determine, in a reliable though computationally efficient way, the number of equilibrium points of the system. Conclusions Theoretical analysis and perturbation experiments point out the crucial role played by the degradation pathway involving RseA, the anti-sigma factor of SigE, for coexistence of two stable equilibria and the emergence of bistability. Our results also indicate that a fine control on RseA concentration is a necessary requirement in order for the system to exhibit bistability.

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Tolerance and Persistence to Drugs: A Main Challenge in the Fight Against Mycobacterium tuberculosis

Cited by 42 publications

References 88 publications

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment

Mathematical modelling of SigE regulatory network reveals new insights into bistability of mycobacterial stress response

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