Chapter 36 : Evasion of Innate and Adaptive Immunity by

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is an extremely successful pathogen that appears to have coevolved with humans as its specific host species for thousands of years ( ). This persistent relationship has uniquely shaped the mycobacterial genome to encode mechanisms that enable the bacilli to resist attack and elimination by the human immune system. Although both innate and adaptive immunity clearly modify the course of infection, this organism can persist and cause disease even in fully immunocompetent hosts. In addition, the currently available vaccine for prevention of tuberculosis, the attenuated strain known as bacille Calmette-Guérin (BCG), has proven largely ineffective despite widespread use. This resistance to host immunity most likely reflects a highly evolved and multifactorial ability of pathogenic mycobacteria to prevent or evade effective host responses. A more complete understanding of how this occurs will likely be crucial to the design and production of better vaccines for prevention of tuberculosis. In this review we summarize current knowledge and recent advances in the study of immune evasion by .

Citation: Goldberg M, Saini N, Porcelli S. 2014. Evasion of Innate and Adaptive Immunity by , p 747-772. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0005-2013
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Figure 1

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.

Citation: Goldberg M, Saini N, Porcelli S. 2014. Evasion of Innate and Adaptive Immunity by , p 747-772. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0005-2013
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Figure 2

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.

Citation: Goldberg M, Saini N, Porcelli S. 2014. Evasion of Innate and Adaptive Immunity by , p 747-772. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0005-2013
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Figure 3

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.

Citation: Goldberg M, Saini N, Porcelli S. 2014. Evasion of Innate and Adaptive Immunity by , p 747-772. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0005-2013
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Figure 4

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).

Citation: Goldberg M, Saini N, Porcelli S. 2014. Evasion of Innate and Adaptive Immunity by , p 747-772. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0005-2013
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