Mycobacterium tuberculosis cords within lymphatic endothelial cells to evade host immunity

Lerner, Thomas R.; Queval, Christophe J.; Lai, Rachel; Russell, Mark; Fearns, Antony; Greenwood, Daniel J.H.; Collinson, Lucy; Wilkinson, Robert J.; Gutiérrez, Maximiliano G.

doi:10.1172/jci.insight.136937

Cited by 37 publications

(56 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Biofilm growth accompanied by cording-like growth morphology is also reported for other mycobacteria and Mtb, in which the surface interactions mediated by e.g., mycolic acids modulating the mycomembrane/capsule hydrophobicity (11, 33). The proteomic data presented here suggest that subtype-specific changes in cord-factor TDM-synthesis (mycolyltransferase Ag85), Esx1-secretion, phthiocerol dimycocerosate (PDIM) export (MmpL7), MA cyclopropanation (PcaA/Cma2), and lectin synthesis (33-37) may have affected the mycomembrane composition and thereby contributed to distinct biofilm growth morphologies in Mmr.…”

Section: Discussionmentioning

confidence: 88%

Surface-Shaving Proteomics ofMycobacterium marinumIdentifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance and Persistence

Savijoki

Myllymäki

Luukinen

et al. 2021

Preprint

View full text Add to dashboard Cite

The complex cell wall and biofilm matrix (ECM) act as key barriers to antibiotics in mycobacteria. Here, the ECM-proteins of Mycobacterium marinum ATCC927, a non-tuberculous mycobacterial model, was monitored over three months by label-free proteomics and compared with cell-surface proteins on planktonic cells to uncover pathways leading to virulence, tolerance, and persistence. We show that ATCC927 forms pellicle-type (PBFs) and submerged-type (SBFs) biofilms after two weeks and two days of growth, respectively, and that the increased CelA1 synthesis in this strain prevents biofilm formation and leads to reduced rifampicin tolerance. The proteomic data suggests that specific changes in mycolic acid synthesis (cord factor), Esx1-secretion, and cell-wall adhesins explain the appearance of PBFs as ribbon-like cords and SBFs as lichen-like structures. A subpopulation of cells resisting the 64 × MIC rifampicin (persisters) were detected in both biofilm subtypes, and already in one-week-old SBFs. The key forces boosting their development could include subtype-dependent changes in asymmetric cell division, cell wall biogenesis, tricarboxylic acid/glyoxylate cycle activities, and energy/redox/iron metabolisms. The effect of varying ambient oxygen tensions on each cell type and non-classical protein secretion are likely factors explaining majority of the subtype-specific changes. The proteomic findings also imply that Esx1-type protein secretion is more efficient in PL and PBF cells, while SBF may prefer both the Esx5- and non-classical pathways to control virulence and prolonged viability/persistence. In conclusion, this study reports a first proteomic insight into aging mycobacterial biofilm-ECMs and indicates biofilm subtype-dependent mechanisms conferring increased adaptive potential and virulence on non-tuberculous mycobacteria.IMPORTANCEMycobacteria are naturally resilient and mycobacterial infections are notoriously difficult to treat with antibiotics, with biofilm formation being the main factor complicating the successful treatment of TB. The present study shows that non-tuberculous Mycobacterium marinum ATCC927 forms submerged- and pellicle-type biofilms with lichen- and ribbon-like structures, respectively, as well as persister cells under the same conditions. We show that both biofilm subtypes differ in terms of virulence-, tolerance- and persistence-conferring activities, highlighting the fact that both subtypes should be targeted to maximize the power of antimycobacterial treatment therapies.

show abstract

Section: Discussionmentioning

confidence: 88%

Surface-Shaving Proteomics ofMycobacterium marinumIdentifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance and Persistence

Savijoki

Myllymäki

Luukinen

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Their presence also stimulates Mtb phagocytosis mediated by CR3 (Astarie-Dequeker et al, 2009), contributes to the phagosome maturation inhibition (Astarie-Dequeker et al, 2009;Passemar et al, 2014), modulates autophagic response (Bah et al, 2020), is required for phagosomal escape and cell death induction (Augenstreich et al, 2017;Barczak et al, 2017;Quigley et al, 2017). Studies of infection of human endothelial cells also showed that PDIMs are required for phagosomal escape (Lerner et al, 2018) and intracellular cording (Lerner et al, 2020). Presently, no host cell receptor for PDIM was identified, as the effect PDIM on CR3-mediated phagocytosis did not reveal any binding (Arbues et al, 2016).…”

Section: Pdim Pglmentioning

confidence: 81%

“…TDM binds to the host cell receptor Mincle and leads to macrophage and dendritic cell activation (Ishikawa et al, 2009;Ostrop et al, 2015) and also to the TDM-induced granuloma formation in the lungs of mice injected with TDM (Ishikawa et al, 2009). Inside macrophages, TDM contributes to enhance the survival of Mtb, as they are involved in phagosome maturation inhibition (Indrigo et al, 2003) and intracellular cording was recently associated to an inhibition of cytosolic detection of Mtb in endothelial cells, thus favoring persistence in lymphoid tissues (Lerner et al, 2020). Accordingly, Mtb mutants which have a deficiency of cycloprane modification in the mycolic acid chains of TDM show a defect in cording and a decrease in the granulomatous response in vivo, as well as the persistence in the host (Glickman et al, 2000;Rao et al, 2005).…”

Section: Tdm Dat/pat Sl-1mentioning

confidence: 99%

Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

Augenstreich

Briken

2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Mycobacterium tuberculosis (Mtb) is a very successful pathogen, strictly adapted to humans and the cause of tuberculosis. Its success is associated with its ability to inhibit host cell intrinsic immune responses by using an arsenal of virulence factors of different nature. It has evolved to synthesize a series of complex lipids which form an outer membrane and may also be released to enter host cell membranes. In addition, secreted protein effectors of Mtb are entering the host cell cytosol to interact with host cell proteins. We briefly discuss the current model, involving the ESX-1 type seven secretion system and the Mtb lipid phthiocerol dimycoserosate (PDIM), of how Mtb creates pores in the phagosomal membrane to allow Mtb proteins to access to the host cell cytosol. We provide an exhaustive list of Mtb secreted proteins that have effector functions. They modify (mostly inhibit but sometimes activate) host cell pathways such as: phagosome maturation, cell death, cytokine response, xenophagy, reactive oxygen species (ROS) response via NADPH oxidase 2 (NOX2), nitric oxide (NO) response via NO Synthase 2 (NOS2) and antigen presentation via MHC class I and class II molecules. We discuss the host cell targets for each lipid and protein effector and the importance of the Mtb effector for virulence of the bacterium.

show abstract

“…Reintroducing the extended esx-1 locus in BCG allowed the translocation to the cytosol and increased virulence providing clear evidence for an essential role of this Type VII secretion system in escape (16,(25)(26)(27)(28). In addition, it is shown that virulent Mtb can form cords in the cytosol and not in the phagosome in human lymphatic endothelial cells in vitro (23). This cording is dependent on the ESX-1 secretion system and PDIM glycolipids.…”

Section: Introductionmentioning

confidence: 97%

“…We hypothesized that bacterial translocation from the phagosome to the cytosol might also be regulated by IL-1. In vitro, Mtb can translocate from the phago-lysosome to the cytosol (16)(17)(18)(19)(20)(21)(22)(23) in an ESX-1 dependent manner (16,21,22). This system is responsible for the secretion of a number of proteins, including EsxA (ESAT-6) and…”

Section: Introductionmentioning

confidence: 99%

IL-1R1 dependent signals improve clearance of cytosolic virulent mycobacteriain vivo

Niet

Zon

Punder

et al. 2020

Preprint

View full text Add to dashboard Cite

Mycobacterium tuberculosis infections claim more than a million lives each year and better treatments or vaccines are required. A crucial pathogenicity factor is translocation from the phago-lysosomes to the cytosol upon phagocytosis by macrophages. The translocation from the phago-lysosome into the cytosol is an ESX-1 dependent process as previously shown in vitro. Here we show that in vivo, mycobacteria also translocate to the cytosol but mainly when host immunity is compromised. We observed only low numbers of cytosolic bacilli in mice, armadillo, zebrafish and patient material infected with M. tuberculosis, M. marinum or M. leprae. In contrast, when innate or adaptive immunity was compromised, as in SCID or IL-1R1 deficient mice, a significant number of cytosolic M. tuberculosis bacilli were detected in lungs of infected mice. Taken together, the cytosolic localization of mycobacteria in vivo is controlled by adaptive immune responses as well as IL-1R1-mediated host resistance to M. tuberculosis.

show abstract

Mycobacterium tuberculosis cords within lymphatic endothelial cells to evade host immunity

Cited by 37 publications

References 36 publications

Surface-Shaving Proteomics ofMycobacterium marinumIdentifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance and Persistence

Surface-Shaving Proteomics ofMycobacterium marinumIdentifies Biofilm Subtype-Specific Changes Affecting Virulence, Tolerance and Persistence

Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

IL-1R1 dependent signals improve clearance of cytosolic virulent mycobacteriain vivo

Contact Info

Product

Resources

About