Although tuberculosis (TB) kills about two million people each year, no new drug for its treatment has been introduced in the past 30 years. Knowledge of the mechanisms by which mycobacteria are able to circumvent host defence responses is essential to the quest for the development of new drug candidates for the treatment of TB.
Pathogenic mycobacteria use several mechanisms that allow them to survive in the hostile environment of the host cell. These include preventing phagosomal maturation, modifying the host apoptotic response and blocking host-signalling pathways that would otherwise trigger an antibacterial response.
Mycobacteria block phagosomal maturation through lipid molecules, such as Man-LAM, that inhibit signalling through Ca2+/calmodulin and phosphatidylinositol-3-kinase pathways. However, the details of the mechanisms that mycobacteria use to suppress these pathways are not well understood.
The suppression of host-cell apoptosis by pathogenic bacteria early in infection facilitates their proliferation and survival. This inhibition of apoptosis takes place through several mechanisms, including preventing increases in the Ca2+ concentration that trigger cytochrome c release from mitochondria, blocking the function of the pro-apoptotic protein Bad and inhibiting TNF-α production.
Pathogenic mycobacteria suppress the MAPK and JAK/STAT signalling pathways that are crucial for many innate and adaptive immune responses to infection. They suppress the sustained activation of the MAPKs p38 and ERK1/2 and are able to inhibit JAK/STAT signalling by inhibiting phosphorylation of JAKs and translocation of STAT to the nucleus, and by inducing the expression of the SOCS protein, which binds and inactivates JAKs.
The prevention of dendritic cell maturation and the activation of T cells by pathogenic bacteria is another method by which they minimize the host immune response. Binding of Man-LAM to DC-SIGN receptors on dendritic cells prevents their maturation and leads to the secretion of IL-10, an immunosuppressive chemokine.
The release of the complete genome sequence of Mycobacterium tuberculosis has identified eukaryotic-like protein kinases and phosphatases. In several bacterial species, protein kinases and phosphatases are important virulence mediators that disrupt host-signalling networks. Some of the mycobacterial kinases and phosphatases might modulate the eukaryotic signalling machinery for intracellular survival.
Mycobacterial kinases and phosphatases show potential as targets for TB therapeutics; kinase inhibitors suppress mycobacterial infection in vitro; inhibitors of both kinases and phosphatases have been developed for the treatment of other diseases. As our understanding of the mechanisms involved in mycobacterial survival increases, the range of other potential targets for anti-TB drugs will expand.
Pathogenesis by mycobacteria requires the exploitation of host-cell signalling pathways to enhance the intracellular survival and persistence of the pathogen. The disruption of these pathways by mycobacteria causes impaired maturation of phagosomes into phagolysosomes, modulates host-cell apoptotic pathways and suppresses the host immune response. This review highlights the strategies employed by mycobacteria to subvert host-cell signalling and identifies key molecules involved in these processes that might serve as potential targets for new antimycobacterial therapies.
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We are grateful to K. Drilica (Public Health Research Institute, New York, USA) and to G. Bacher, H. Daub and G. Müller (Axxima AG) for critical reading of the manuscript, and to Y. Av-Gay (University of British Columbia, Vancouver, Canada) and J. Pieters (University of Basel, Switzerland) for helpful conversations. Our thanks go to I. Bhattacharya (MPI-Martinsried, Germany) for help with the references and to our colleagues at Axxima for useful insights into mycobacterial drug development.
The authors declare no competing financial interests.
Cells that belong to the mononuclear phagocyte system and are responsible for phagocytosis of foreign material.
A vesicle that is formed by invagination of the plasma membrane during endocytosis and fuses with primary lysosomes to degrade engulfed material.
Membrane-limited cellular organelles with a low internal pH that contain acid hydrolases for the degradation of polymers such as proteins, RNA, DNA, polysaccharides and lipids.
A cytokine that activates the innate immune response, thereby preventing replication of pathogens.
(PI3K). PI3Ks are a conserved family of lipid kinases that phosphorylate the 3′-OH group of the inositol ring of membrane-bound phosphatidylinositides.
- G-PROTEIN COUPLED RECEPTORS
(GPCRs). These cell surface receptors, which are characterized by seven transmembrane domains, are coupled to small G-proteins. Activation of GPCRs induces binding of GTP to the G-proteins, which leads to stimulation, or repression, of downstream signalling events.
Polynuclear leucocytes belonging to the myeloid lineage that migrate to sites of infection or wounds and mediate the inflammatory response.
Low-molecular-weight proteins that are important for immunity, inflammation and development, and which contribute to the pathophysiology of acute and chronic infections.
- INNATE IMMUNE RESPONSE
A cellular defence reaction to counteract invading pathogens such as bacteria and viruses. It uses interferon-dependent signalling and leads to the activation of genes that are responsible for bactericidal or antiviral responses.
Having identical genotypes.
A member of one form of a polymorphic species.
cAMP response element (CRE)-binding protein. It stimulates the basal transcription of CRE-containing genes and mediates induction of transcription following phosphorylation by protein kinases.
- ADAPTIVE IMMUNE RESPONSE
This involves specificity and immunological memory. It is mediated by T and B cells through activation of cytotoxic CD8+ T cells for pathogen killing, or by interaction with CD4+ T cells for antibody production.
- GLYOXYLATE SHUNT
A biochemical pathway that is used by plants and microorganisms to metabolize acetate or long-chain fatty acids as a source of energy.
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Koul, A., Herget, T., Klebl, B. et al. Interplay between mycobacteria and host signalling pathways. Nat Rev Microbiol 2, 189–202 (2004). https://doi.org/10.1038/nrmicro840
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The coordinated outcome of STIM1-Orai1 and superoxide signalling is crucial for headkidney macrophage apoptosis and clearance of Mycobacterium fortuitum
Developmental & Comparative Immunology (2021)
Distinct functional properties of secretory l-asparaginase Rv1538c involved in phagosomal survival of Mycobacterium tuberculosis