Interactions between Mycobacterium tuberculosis and host cells: are mycobacterial sugars the key?

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

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Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis

Nature Communications ◽

10.1038/s41467-020-20533-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Uday Tak ◽

Terje Dokland ◽

Michael Niederweis

Keyword(s):

Mycobacterium Tuberculosis ◽

Pore Formation ◽

Molecular Switches ◽

Water Soluble ◽

Host Cells ◽

Solvent Exposure ◽

Membrane Channel ◽

Toxin Secretion ◽

Outer Membrane Channel ◽

Membrane Spanning

AbstractMycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles into oligomers and long filaments, binds to membranes, and forms stable membrane-spanning channels. Electron microscopy of EsxEF reveals mainly pentameric structures with a central pore. Mutations of both WXG motifs and of a GXW motif do not affect dimerization, but abolish pore formation, membrane deformation and TNT secretion. The WXG/GXW mutants are locked in conformations with altered thermostability and solvent exposure, indicating that the WXG/GXW motifs are molecular switches controlling membrane interaction and pore formation. EsxF is accessible on the bacterial cell surface, suggesting that EsxEF form an outer membrane channel for toxin export. Thus, our study reveals a protein secretion mechanism in bacteria that relies on pore formation by small WXG proteins.

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Mycobacterium tuberculosis adhesins: potential biomarkers as anti-tuberculosis therapeutic and diagnostic targets

Microbiology ◽

10.1099/mic.0.082206-0 ◽

2014 ◽

Vol 160 (9) ◽

pp. 1821-1831 ◽

Cited By ~ 22

Author(s):

Viveshree S. Govender ◽

Saiyur Ramsugit ◽

Manormoney Pillay

Keyword(s):

Immune Response ◽

Mycobacterium Tuberculosis ◽

Control Strategies ◽

Host Cells ◽

Tuberculosis Control ◽

Surface Molecules ◽

Host Pathogen Interaction ◽

Bacterial Aggregation ◽

Insight Into

Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a process vital to the host’s defence against infection. Adhesins are microbial cell surface molecules or structures that mediate the attachment of the microbe to host cells and thus the host–pathogen interaction. They also play a crucial role in bacterial aggregation and biofilm formation. In this review, we discuss the role of adhesins in the pathogenesis of the aetiological agent of tuberculosis, Mycobacterium tuberculosis. We also provide insight into the structure and characteristics of some of the characterized and putative M. tuberculosis adhesins. Finally, we examine the potential of adhesins as targets for the development of tuberculosis control strategies.

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Neurons Are Host Cells for Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.00474-13 ◽

2014 ◽

Vol 82 (5) ◽

pp. 1880-1890 ◽

Cited By ~ 6

Author(s):

Philippa J. Randall ◽

Nai-Jen Hsu ◽

Dirk Lang ◽

Susan Cooper ◽

Boipelo Sebesho ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mycobacterium Tuberculosis ◽

Host Cells ◽

Productive Infection ◽

Target Cells ◽

Dependent Manner ◽

Content Type ◽

The Central Nervous System

ABSTRACTMycobacterium tuberculosisinfection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions ofM. tuberculosiswith neuronsin vitroandin vivowere investigated. The data obtained demonstrate that neurons can act as host cells forM. tuberculosis.M. tuberculosisbacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization ofM. tuberculosisbacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalizeM. tuberculosis. InternalizedM. tuberculosisbacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h.M. tuberculosisbacillus infection of neurons was confirmedin vivoin the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells forM. tuberculosiswithin the central nervous system.

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Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo

Journal of Experimental Medicine ◽

10.1084/jem.20151248 ◽

2016 ◽

Vol 213 (5) ◽

pp. 809-825 ◽

Cited By ~ 75

Author(s):

Yancheng Liu ◽

Shumin Tan ◽

Lu Huang ◽

Robert B. Abramovitch ◽

Kyle H. Rohde ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Host Cell ◽

Stress Responses ◽

Drug Action ◽

Host Cells ◽

Transcriptional Analysis ◽

Drug Pressure ◽

Cytokine Activation ◽

The Impact

Successful chemotherapy against Mycobacterium tuberculosis (Mtb) must eradicate the bacterium within the context of its host cell. However, our understanding of the impact of this environment on antimycobacterial drug action remains incomplete. Intriguingly, we find that Mtb in myeloid cells isolated from the lungs of experimentally infected mice exhibit tolerance to both isoniazid and rifampin to a degree proportional to the activation status of the host cells. These data are confirmed by in vitro infections of resting versus activated macrophages where cytokine-mediated activation renders Mtb tolerant to four frontline drugs. Transcriptional analysis of intracellular Mtb exposed to drugs identified a set of genes common to all four drugs. The data imply a causal linkage between a loss of fitness caused by drug action and Mtb’s sensitivity to host-derived stresses. Interestingly, the environmental context exerts a more dominant impact on Mtb gene expression than the pressure on the drugs’ primary targets. Mtb’s stress responses to drugs resemble those mobilized after cytokine activation of the host cell. Although host-derived stresses are antimicrobial in nature, they negatively affect drug efficacy. Together, our findings demonstrate that the macrophage environment dominates Mtb’s response to drug pressure and suggest novel routes for future drug discovery programs.

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Gold Nanorods as Drug Delivery Vehicles for Rifampicin Greatly Improve the Efficacy of Combating Mycobacterium tuberculosis with Good Biocompatibility with the Host Cells

Bioconjugate Chemistry ◽

10.1021/acs.bioconjchem.6b00430 ◽

2016 ◽

Vol 27 (10) ◽

pp. 2486-2492 ◽

Cited By ~ 27

Author(s):

Hala R. Ali ◽

Moustafa R. K. Ali ◽

Yue Wu ◽

Salah A. Selim ◽

Hazem F. M. Abdelaal ◽

...

Keyword(s):

Drug Delivery ◽

Mycobacterium Tuberculosis ◽

Gold Nanorods ◽

Host Cells ◽

Drug Delivery Vehicles ◽

Good Biocompatibility ◽

Delivery Vehicles

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Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of Mycobacterium tuberculosis PPE37 Protein

mBio ◽

10.1128/mbio.01712-17 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 16

Author(s):

Javeed Ahmad ◽

Aisha Farhana ◽

Rita Pancsa ◽

Simran Kaur Arora ◽

Alagiri Srinivasan ◽

...

Keyword(s):

Dendritic Cells ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Terminal Segment ◽

Host Protein ◽

Host Cells ◽

Productive Infection ◽

Disordered Proteins ◽

Intrinsically Disordered

ABSTRACT Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS). PPE37, expressed as a function of low iron stress, was cleaved by M. tuberculosis protease into N- and C-terminal segments. A recombinant N-terminal segment (P37N) caused proliferation and differentiation of monocytic THP-1 cells, into CD11c, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin)-positive semimature dendritic cells exhibiting high interleukin-10 (IL-10) but negligible IL-12 and also low tumor necrosis factor alpha (TNF-α) secretion—an environment suitable for maintaining tolerogenic immune cells. The C-terminal segment entered the macrophage nucleus and induced caspase-3-dependent apoptosis of host cells. Mice immunized with recombinant PPE37FL and PPE37N evoked strong anti-inflammatory response, validating the in vitro immunostimulatory effect. Analysis of the IgG response of PPE37FL and PPE37N revealed significant immunoreactivities in different categories of TB patients, viz. pulmonary TB (PTB) and extrapulmonary TB (EPTB), vis-a-vis healthy controls. These results support the role of IDPs in performing contrasting activities to modulate the host processes, possibly through molecular mimicry and cross talk in two spatially distinct host environments which may likely aid M. tuberculosis survival and pathogenesis. IMPORTANCE To hijack the human host cell machinery to enable survival inside macrophages, the pathogen Mycobacterium tuberculosis requires a repertoire of proteins that can mimic host protein function and modulate host cell machinery. Here, we have shown how a single protein can play multiple functions and hijack the host cell for the benefit of the pathogen. Full-length membrane-anchored PPE37 protein is cleaved into N- and C-terminal domains under iron-depleted conditions. The N-terminal domain facilitates the propathogen semimature tolerogenic state of dendritic cells, whereas the C-terminal segment is localized into host cell nucleus and induces apoptosis. The immune implications of these in vitro observations were assessed and validated in mice and also human TB patients. This study presents novel mechanistic insight adopted by M. tuberculosis to survive inside host cells.

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Mycobacterium tuberculosis infection of host cells in space and time

FEMS Microbiology Reviews ◽

10.1093/femsre/fuz006 ◽

2019 ◽

Vol 43 (4) ◽

pp. 341-361 ◽

Cited By ~ 31

Author(s):

Claudio Bussi ◽

Maximiliano G Gutierrez

Keyword(s):

Mycobacterium Tuberculosis ◽

Host Cell ◽

Cell Biology ◽

Current Knowledge ◽

Bacterial Pathogen ◽

Infectious Agent ◽

Host Cells ◽

Cellular Mechanisms ◽

Mycobacterium Tuberculosis Infection ◽

Human Host

ABSTRACTTuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains one of the deadliest infectious diseases with over a billion deaths in the past 200 years (Paulson 2013). TB causes more deaths worldwide than any other single infectious agent, with 10.4 million new cases and close to 1.7 million deaths in 2017. The obstacles that make TB hard to treat and eradicate are intrinsically linked to the intracellular lifestyle of Mtb. Mtb needs to replicate within human cells to disseminate to other individuals and cause disease. However, we still do not completely understand how Mtb manages to survive within eukaryotic cells and why some cells are able to eradicate this lethal pathogen. Here, we summarise the current knowledge of the complex host cell-pathogen interactions in TB and review the cellular mechanisms operating at the interface between Mtb and the human host cell, highlighting the technical and methodological challenges to investigating the cell biology of human host cell-Mtb interactions.

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ScreeningMycobacterium tuberculosisSecreted Proteins Identifies Mpt64 as a Eukaryotic Membrane-Binding Bacterial Effector

mSphere ◽

10.1128/msphere.00354-19 ◽

2019 ◽

Vol 4 (3) ◽

Cited By ~ 2

Author(s):

Chelsea E. Stamm ◽

Breanna L. Pasko ◽

Sujittra Chaisavaneeyakorn ◽

Luis H. Franco ◽

Vidhya R. Nair ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Mycobacterium Tuberculosis ◽

Unfolded Protein Response ◽

Molecular Mechanisms ◽

Membrane Binding ◽

Host Cells ◽

Secreted Proteins ◽

Content Type ◽

Unfolded Protein ◽

Protein Response

ABSTRACTMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis, is one of the most successful human pathogens. One reason for its success is that Mtb can reside within host macrophages, a cell type that normally functions to phagocytose and destroy infectious bacteria. However, Mtb is able to evade macrophage defenses in order to survive for prolonged periods of time. Many intracellular pathogens secrete virulence factors targeting host membranes and organelles to remodel their intracellular environmental niche. We hypothesized that Mtb secreted proteins that target host membranes are vital for Mtb to adapt to and manipulate the host environment for survival. Thus, we characterized 200 secreted proteins from Mtb for their ability to associate with eukaryotic membranes using a unique temperature-sensitive yeast screen and to manipulate host trafficking pathways using a modified inducible secretion screen. We identified five Mtb secreted proteins that both associated with eukaryotic membranes and altered the host secretory pathway. One of these secreted proteins, Mpt64, localized to the endoplasmic reticulum during Mtb infection of murine and human macrophages and impaired the unfolded protein response in macrophages. These data highlight the importance of secreted proteins in Mtb pathogenesis and provide a basis for further investigation into their molecular mechanisms.IMPORTANCEAdvances have been made to identify secreted proteins ofMycobacterium tuberculosisduring animal infections. These data, combined with transposon screens identifying genes important forM. tuberculosisvirulence, have generated a vast resource of potentialM. tuberculosisvirulence proteins. However, the function of many of these proteins inM. tuberculosispathogenesis remains elusive. We have integrated three cell biological screens to characterize nearly 200M. tuberculosissecreted proteins for eukaryotic membrane binding, host subcellular localization, and interactions with host vesicular trafficking. In addition, we observed the localization of one secreted protein, Mpt64, to the endoplasmic reticulum (ER) duringM. tuberculosisinfection of macrophages. Interestingly, although Mpt64 is exported by the Sec pathway, its delivery into host cells was dependent upon the action of the type VII secretion system. Finally, we observed that Mpt64 impairs the ER-mediated unfolded protein response in macrophages.

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Automated glycan assembly of arabinomannan oligosaccharides from Mycobacterium tuberculosis

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.15.288 ◽

2019 ◽

Vol 15 ◽

pp. 2936-2940 ◽

Cited By ~ 1

Author(s):

Alonso Pardo-Vargas ◽

Priya Bharate ◽

Martina Delbianco ◽

Peter H Seeberger

Keyword(s):

Mycobacterium Tuberculosis ◽

Macrophage Activation ◽

Core Structure ◽

Host Cells ◽

Reaction Conditions ◽

The Core ◽

Clinical Biomarkers ◽

Diagnostic Agents

Arabinomannan (AM) polysaccharides are clinical biomarkers for Mycobacterium tuberculosis (MTB) infections due to their roles in the interaction with host cells and interference with macrophage activation. Collections of defined AM oligosaccharides can help to improve the understanding of these polysaccharides and the development of novel therapeutical and diagnostic agents. Automated glycan assembly (AGA) was employed to prepare the core structure of AM from MTB, containing α-(1,6)-Man, α-(1,5)-Ara, and α-(1,2)-Man linkages. The introduction of a capping step after each glycosylation and further optimized reaction conditions allowed for the synthesis of a series of oligosaccharides, ranging from hexa- to branched dodecasaccharides.

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