Evasion of Innate and Adaptive Immunity by<i>Mycobacterium tuberculosis</i>

Goldberg, Michael F.; Saini, Neeraj Kumar; Porcelli, Steven A.

doi:10.1128/9781555818845.ch36

Cited by 10 publications

(11 citation statements)

References 230 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After Mtb internalization, monocyte-derived macrophages, dendritic cells (DCs), and neutrophils participate in the phagocytic process and express inflammatory mediators, including pro- and anti-inflammatory cytokines, chemokines, and inducible nitric oxide synthase ( 3 , 4 ). However, Mtb has several mechanisms to evade host immune responses, such as phagosome–lysosome fusion interference, inhibition of phagosome acidification, inflammatory immune suppression, and host cell death modulation ( 5 ). Live Mtb induces low levels of cytosolic Ca 2+ release, which is correlated with inhibition of phagosome–lysosome fusion, suggesting that Ca 2+ -induced intracellular signaling pathways contribute to the intracellular pathogen survival and pathogenesis of TB ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine Promotes Phagosome Maturation and Regulates Inflammatory Mediator Production Through the Protein Kinase A–Phosphatidylinositol 3 Kinase–p38 Mitogen-Activated Protein Kinase Signaling Pathway During Mycobacterium tuberculosis Infection in Mouse Macrophages

Lee

Song

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

Tuberculosis is caused by the infectious agent Mycobacterium tuberculosis (Mtb). Mtb has various survival strategies, including blockade of phagosome maturation and inhibition of antigen presentation. Lysophosphatidylcholine (LPC) is a major phospholipid component of oxidized low-density lipoprotein and is involved in various cellular responses, such as activation of second messengers and bactericidal activity in neutrophils. In this study, macrophages were infected with a low infectious dose of Mtb and treated with LPC to investigate the bactericidal activity of LPC against Mtb. In macrophages infected with Mtb strain, H37Ra or H37Rv, LPC suppressed bacterial growth; however, this effect was suppressed in bone marrow-derived macrophages (BMDMs) isolated from G2A (a G protein-coupled receptor involved in some LPC actions) knockout mice. LPC also promoted phagosome maturation via phosphatidylinositol 3 kinase (PI3K)–p38 mitogen-activated protein kinase (MAPK)-mediated reactive oxygen species production and intracellular Ca2+ release during Mtb infection. In addition, LPC induced increased levels of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylated glycogen synthase kinase 3 beta (GSK3β) in Mtb-infected macrophages. Protein kinase A (PKA)-induced phosphorylation of GSK3β suppressed activation of NF-κB in LPC-treated macrophages during Mtb infection, leading to decreased secretion of pro-inflammatory cytokines and increased secretion of anti-inflammatory cytokines. These results suggest that LPC can effectively control Mtb growth by promoting phagosome maturation via cAMP-induced activation of the PKA–PI3K–p38 MAPK pathway. Moreover, LPC can regulate excessive production of pro-inflammatory cytokines associated with bacterial infection of macrophages.

show abstract

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine Promotes Phagosome Maturation and Regulates Inflammatory Mediator Production Through the Protein Kinase A–Phosphatidylinositol 3 Kinase–p38 Mitogen-Activated Protein Kinase Signaling Pathway During Mycobacterium tuberculosis Infection in Mouse Macrophages

Lee

Song

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…During M. tuberculosis infection this strategy is particularly difficult since a major cell target, alveolar macrophages, are also a crucial player in the host immune response. Upon attachment, alveolar macrophages actively phagocytize M. tuberculosis bacilli through multiple mechanisms, and the internalization pathway greatly influences microbiocidal efficiency (58)(59)(60).…”

Section: Macrophage Roles During Infectionmentioning

confidence: 99%

“…The macrophage mannose receptor (MMR) recognizes M. tuberculosis lipoarabinomannan (63,64) and is predicted to signal through a putative cytoplasmic tyrosine domain, which phosphorylates and activates CDC42, RHOB, PAK, or ROCK1, involved in actin reorganization, membrane invagination and phagosome formation (62,(65)(66)(67)(68). Another CLR involved in M. tuberculosis recognition by macrophages is macrophage-inducible C-type lectin which recognizes trehalose-6,6-dimycolate, an abundant mycobacterial cell wall glycolipid (12,59,69). In later stages of infection or in secondary infections, antibody and complement opsonized bacteria are phagocytized through Fc and complement receptors, signaling through a similar mechanism that promotes efficient bacterial killing and controls replication (60,62).…”

Section: Macrophage Roles During Infectionmentioning

confidence: 99%

“…Despite extensive research, it is not yet clear what might be the ideal adaptive immune response leading to efficient control of bacterial replication and clearance with minimal tissue damage (59,81). Mycobacterium tuberculosis bacteria infect professional antigen-presenting cells with a significant impact on antigen presentation and activation of the adaptive immune response.…”

Section: Modulation Of the Host Adaptive Immune Responsementioning

confidence: 99%

See 1 more Smart Citation

Host-Pathogen Interaction as a Novel Target for Host-Directed Therapies in Tuberculosis

2020

View full text Add to dashboard Cite

Tuberculosis (TB) has been a transmittable human disease for many thousands of years, and M. tuberculosis is again the number one cause of death worldwide due to a single infectious agent. The intense 6-to 10-month process of multi-drug treatment, combined with the adverse side effects that can run the spectrum from gastrointestinal disturbances to liver toxicity or peripheral neuropathy are major obstacles to patient compliance and therapy completion. The consequent increase in multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) cases requires that we increase our arsenal of effective drugs, particularly novel therapeutic approaches. Over the millennia, host and pathogen have evolved mechanisms and relationships that greatly influence the outcome of infection. Understanding these evolutionary interactions and their impact on bacterial clearance or host pathology will lead the way toward rational development of new therapeutics that favor enhancing a host protective response. These host-directed therapies have recently demonstrated promising results against M. tuberculosis, adding to the effectiveness of currently available anti-mycobacterial drugs that directly kill the organism or slow mycobacterial replication. Here we review the host-pathogen interactions during M. tuberculosis infection, describe how M. tuberculosis bacilli modulate and evade the host immune system, and discuss the currently available host-directed therapies that target these bacterial factors. Rather than provide an exhaustive description of M. tuberculosis virulence factors, which falls outside the scope of this review, we will instead focus on the host-pathogen interactions that lead to increased bacterial growth or host immune evasion, and that can be modulated by existing host-directed therapies.

show abstract

“…M . tb modulates pathways like reactive oxygen burst, thereby affecting ROS production [ 3 ], apoptosis [ 4 ] and autophagy [ 5 ] letting it remain undetected within the host. These pathways help in recognising and eliminating the pathogen, thereby clearing off the infection inside the host.…”

Section: Introductionmentioning

confidence: 99%

Suppression of Protective Responses upon Activation of L-Type Voltage Gated Calcium Channel in Macrophages during Mycobacterium bovis BCG Infection

et al. 2016

View full text Add to dashboard Cite

The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated Calcium Channel (VGCCs) upon M. tb infection has recently assumed importance in this area. We previously showed a suppressor role of VGCC during M. tb infections and recently reported the mechanisms of its regulation by M. tb. Here in this report, we further characterize the role of VGCC in mediating defence responses of macrophages during mycobacterial infection. We report that activation of VGCC during infection synergistically downmodulates the generation of oxidative burst (ROS) by macrophages. This attenuation of ROS is regulated in a manner which is dependent on Toll like Receptor (TLR) and also on the route of calcium influx, Protein Kinase C (PKC) and by Mitogen Activation Protein Kinase (MAPK) pathways. VGCC activation during infection increases cell survival and downmodulates autophagy. Concomitantly, pro-inflammatory responses such as IL-12 and IFN-γ secretion and the levels of their receptors on cell surface are inhibited. Finally, the ability of phagosomes to fuse with lysosomes in M. bovis BCG and M. tb H37Rv infected macrophages is also compromised when VGCC activation occurs during infection. The results point towards a well-orchestrated strategy adopted by mycobacteria to supress protective responses mounted by the host. This begins with the increase in the surface levels of VGCCs by mycobacteria and their antigens by well-controlled and regulated mechanisms. Subsequent activation of the upregulated VGCC following tweaking of calcium levels by molecular sensors in turn mediates suppressor responses and prepare the macrophages for long term persistent infection.

show abstract

Evasion of Innate and Adaptive Immunity byMycobacterium tuberculosis

Cited by 10 publications

References 230 publications

Lysophosphatidylcholine Promotes Phagosome Maturation and Regulates Inflammatory Mediator Production Through the Protein Kinase A–Phosphatidylinositol 3 Kinase–p38 Mitogen-Activated Protein Kinase Signaling Pathway During Mycobacterium tuberculosis Infection in Mouse Macrophages

Lysophosphatidylcholine Promotes Phagosome Maturation and Regulates Inflammatory Mediator Production Through the Protein Kinase A–Phosphatidylinositol 3 Kinase–p38 Mitogen-Activated Protein Kinase Signaling Pathway During Mycobacterium tuberculosis Infection in Mouse Macrophages

Host-Pathogen Interaction as a Novel Target for Host-Directed Therapies in Tuberculosis

Suppression of Protective Responses upon Activation of L-Type Voltage Gated Calcium Channel in Macrophages during Mycobacterium bovis BCG Infection

Contact Info

Product

Resources

About