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Evasion of Innate and Adaptive Immunity by

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  • Authors: Michael F. Goldberg1, Neeraj K. Saini2, Steven A. Porcelli3
  • Editors: Graham F. Hatfull5, William R. Jacobs Jr.6
    Affiliations: 1: Department of Microbiology and Immunology; 2: Department of Microbiology and Immunology; 3: Department of Microbiology and Immunology; 4: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; 5: University of Pittsburgh, Pittsburgh, PA; 6: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
  • Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0005-2013
  • Received 11 April 2013 Accepted 05 August 2013 Published 26 September 2014
  • S. A. Porcelli, [email protected]
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  • Abstract:

    Through thousands of years of reciprocal coevolution, has become one of humanity's most successful pathogens, acquiring the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of to avoid immune-mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity. These include the manipulation of their phagosomal environment within host macrophages, the selective avoidance or engagement of pattern recognition receptors, modulation of host cytokine production, and the manipulation of antigen presentation to prevent or alter the quality of T-cell responses. In this article we review an extensive array of published studies that have begun to unravel the sophisticated program of specific mechanisms that enable and other pathogenic mycobacteria to persist and replicate in the face of considerable immunological pressure from their hosts. Unraveling the mechanisms by which evades or modulates host immune function is likely to be of major importance for the development of more effective new vaccines and targeted immunotherapy against tuberculosis.

  • Citation: Goldberg M, Saini N, Porcelli S. 2014. Evasion of Innate and Adaptive Immunity by . Microbiol Spectrum 2(5):MGM2-0005-2013. doi:10.1128/microbiolspec.MGM2-0005-2013.


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Through thousands of years of reciprocal coevolution, has become one of humanity's most successful pathogens, acquiring the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of to avoid immune-mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity. These include the manipulation of their phagosomal environment within host macrophages, the selective avoidance or engagement of pattern recognition receptors, modulation of host cytokine production, and the manipulation of antigen presentation to prevent or alter the quality of T-cell responses. In this article we review an extensive array of published studies that have begun to unravel the sophisticated program of specific mechanisms that enable and other pathogenic mycobacteria to persist and replicate in the face of considerable immunological pressure from their hosts. Unraveling the mechanisms by which evades or modulates host immune function is likely to be of major importance for the development of more effective new vaccines and targeted immunotherapy against tuberculosis.

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Dominant pattern recognition receptor pathways for sensing . Cell wall lipids and lipoproteins, which are associated with the external surface of the bacteria, are probably the initial stimuli for pattern recognition receptors of innate phagocytic cells. The proximal interaction between the macrophage engulfing an bacillus most likely begins with recognition of trehalose-6,6-dimycolate (TDM) by the C-type lectin mincle , which leads to a signaling cascade that initiates inflammatory cytokine gene transcription. Heterodimers of TLR2 with TLR1 or TLR6 at the plasma membrane recognize di- and tri-acylated lipoproteins, lipomannan, and lipoarabinomannan (LAM) from , resulting in the activation of NFκB and cytokine expression. Fragments of hypomethylated DNA from lead to dimerization of TLR9 within endosomes , which promotes type I IFN production through the activation of IRF7. Permeabilization of the phagosomal membrane, which is driven by the secretion of the ESAT-6 protein by , activates NLRP3 and recruits ASC and pro-caspase-1 to form the inflammasome (D), which activates caspase-1 and generates active forms of IL-1β, IL-18, and IL-33 that are subsequently secreted.

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0005-2013
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CD4 T helper cell development in the context of infection. Dendritic cells displaying antigens through the expression of MHC class II activate –specific naïve CD4 T cells. This can lead to a number of different outcomes, which are largely determined by which cytokines predominate in the T cell–priming environment. Following activation, CD4 T cells can differentiate into FoxP3 regulatory T cells (T) that strongly inhibit many immune responses. A related but distinct pathway of T cell differentiation upregulates the transcription factor RORγt, leading to T17 cells that produce IL-17A, IL-17F, and IL-22, which promote neutrophil chemotaxis. Another possible outcome is the development into TH1 cells that express the transcription factor Tbet. These may be either self-renewing Tbet T1 cells that are PD-1 and produce low amounts of IFN-γ and TNF-α, or terminal effector T1 cells that are KLRG1 and produce high levels of IFN-γ and TNF-α that stimulate macrophage effector function during infection.

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0005-2013
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Disruption of MHC class II presentation by . The various steps in the MHC class II processing and presentation pathway that are known or postulated to be influenced by infection are illustrated. New synthesis of MHC class II molecules is blocked by TLR2 signaling due to mycobacterial products such as the 19-kDa lipoprotein. Intracellular trafficking of MHC class II is disrupted by the suppression of cathepsin S, which is due to induction of IL-10 by mycobacterial infection. Generation of peptide antigens for loading onto MHC class II in relevant endocytic compartments (MIIC) is also inhibited by several effects of mycobacterial infection, including inhibition of phagosome-lysosome fusion, by neutralization of phagosomal pH by bacterial urease, and by blockade of recruitment of the vacuolar proton ATPase. Proposed inhibition of autophagy and autophagic vacuole formation also eliminates a potential source of antigenic peptides that can load MHC class II molecules. The reduction of peptide antigen availability and incomplete cleavage of MHC class II associated invariant chain (Ii) resulting from cathepsin S suppression result in a reduced transport of stable peptide-loaded MHC class II molecules to the APC surface.

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0005-2013
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MHC class I presentation pathways in infection. The large cell on the left of the figure represents a macrophage infected with . Newly synthesized MHC class I molecules in the endoplasmic reticulum (ER) are loaded with peptides that are produced by the cytosolic proteosome complex and transported into the ER lumen by TAP (transporter associated with antigen presentation). Additional trimming of the cytosol-derived peptides can occur as a result of aminopeptidase activity in the ER lumen. Escape of mycobacterial proteins from the phagosome into the cytosol can lead to peptide presentation by this classical MHC class I pathway . Mechanisms for loading of peptides onto MHC class I molecules in the lumen of the phagosome are also likely to exist. This vacuolar pathway for cross presentation may involve transfer of ER membrane components (e.g., newly synthesized MHC class I complexes and TAP) to the phagosome membrane, enabling the loading of peptides generated in the cytosol. Alternatively, peptides may be generated by proteases in the phagosome lumen, and these may be loaded by a process of peptide exchange onto MHC class I molecules recycling from the plasma membrane. The so-called detour pathway is a third way that peptides from a vacuolar intracellular pathogen such as can be cross-presented by MHC class I. In this case, an infected cell must first die by apoptosis, and the released apoptotic vesicles carry the mycobacterial antigens into uninfected dendritic cells. Current evidence suggests that all of these pathways are likely to be actively inhibited or effectively bypassed during infection (see text for details).

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0005-2013
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