Chapter 36 : Immune Evasion by Parasites

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This chapter examines several mechanisms by which two well-known protozoan pathogens, one extracellular and one intracellular, successfully evade host immunity. It discusses how one protozoan parasite has evolutionarily addressed few problems by displaying a highly ordered molecular surface coat that serves largely to protect therypanosome plasma membrane from immunological assault. Many successful parasites exhibit antigenic variation to avoid immune elimination during infection. The most well-known example of immune evasion by parasites is antigenic variation by the African trypanosome, which for nearly a century has provided the classical paradigm for microbial antigenic variation as a means of escaping host immunity. In addition to an apparent absence of variant surface glycoprotein (VSG) C-terminal peptide processing by antigen-presenting cell (APCs) following primary exposure, there is evidence that the processing of parasite antigens may be more broadly regulated during progressive infection. parasites infect host macrophage cells during their life cycle. Development of effective cell-mediated immune responses to these organisms requires that infected macrophages induce significant Th1 cell activation against leishmanial antigens. Parasitic protozoa regulate almost every aspect of host innate and adaptive immunity, and have evolved multiple mechanisms that permit passive and active evasion of host resistance. These mechanisms include not only the expression of variant antigens and specialized surface coats (African ), but also the modulation of antigen expression and signaling pathways of the cells that they infect or interact with (and spp.), effectively subverting or suppressing cellular mechanisms that can affect parasite survival.

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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Image of FIGURE 1

VSG-Ab complexes on the trypanosome surface coat serve as “molecular sails” that, when exposed to the hydrodynamic forces in the bloodstream and trypanosome directional motility, move towards the flagellar pocket and are internalized. Adapted from .

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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Image of FIGURE 2

Sequence comparisons among VSGs related by type and class showing composite and overlapping T-cell reactive sites identified using VSG-specific T cells. The data reveal that T cells preferentially recognize epitopes within the N-terminus of the molecule but not the more conserved C-terminal subregion. Adapted from .

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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Image of FIGURE 3

GIP-sVSG binds to the macrophage membrane, is internalized, and triggers activation of the NF-κB and MAPK signaling pathways with subsequent activation of proinflammatory genes. This response is TRAF6-dependent, augmented in the presence of IFN-γ and down regulated by a TLR-9-dependent pathway. Adapted from . Note, GPI-mediated membrane binding and cell activation are dependent on scavenger receptor interaction(s).

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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Image of FIGURE 4

Virulent trypanosomes overcome genetically based differences in adaptive immune resistance as well as common elements of innate resistance. LouTat 1 is a low virulence parasite while LouTat 1A is a genetically related high virulence organism that arose from LouTat 1. Adapted from Mansfield & Paulnock, manuscript in preparation.

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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Image of FIGURE 5

induced macrophage signaling alteration. Binding of to host cell receptors is potentially responsible for the induction of deactivating events involving proteasome and SHP-1 activation. SHP-1 negatively affects JAK2 kinase and Erk1/Erk2 MAPK conducting to the inhibition of IFN-γ-inducible macrophage functions. Proteolysis of signaling molecules such as STAT-1 contributes to this inactivation process. Other phosphatases (e.g., IP3 phosphatase and calcineurin) and surface parasite molecules (i.e., GP63 and LPG) are recognized for their role in the alteration of various second messengers, acting directly (e.g., LPG-mediated PKC inactivation) or indirectly (e.g., GP63-mediated SHP-1 activation and concurring to kinase inactivation), signaling alteration that ultimately are reflected by abolition of agonist-induced macrophage functions.

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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Image of FIGURE 6

Rapid inactivation of IRAK-1 kinase by PTP upon infection concur to tame down macrophage innate immune response. IRAK-1 is a critical kinase-regulating majority of TLR family members at the exception of TLR-3. The mechanisms whereby the parasite can avoid the induction of the macrophage innate immune response involve the activation of PTPs by the metalloprotease GP63 and the rapid inactivation of IRAK-1 by SHP-1 recognizing a KTIM motif found in the kinase domain of this pivotal second messenger. This inactivation concurs to avoid activation of TLR signaling as also reflected by the complete inhibition of LPS-mediated functions.

Citation: Mansfield J, Olivier M. 2011. Immune Evasion by Parasites, p 453-469. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch36
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