Chapter 36 : Immune Evasion by Parasites

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Immune Evasion by Parasites, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816872/9781555815141_Chap36-1.gif /docserver/preview/fulltext/10.1128/9781555816872/9781555815141_Chap36-2.gif


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

Key Concept Ranking

Infection and Immunity
Adaptive Immune System
Immune Systems
Innate Immune System
Major Histocompatibility Complex
Trypanosoma brucei rhodesiense
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Abu-Dayyeh,, I.,, M. T. Shio,, S. Sato,, S. Akira,, B. Cousineau, and, M. Olivier. 2008. Leishmarda- induced IRAK-1 inactivation is mediated by shp-1 interacting with an evolutionarily conserved ktim motif. PLoS Negl. Trop. Dis. 2:e305.
2. Bachmann, M. F., and, R. M. Zinkernagel. 1996. The influence of virus structure on antibody responses and virus serotype formation. Immunol. Today 17:553558.
3. Baltz, T.,, C. Giroud,, D. Baltz,, C. Roth,, A. Raibaud, and, H. Eisen. 1986. Stable expression of two variable surface glycoproteins by cloned Trypanosoma equiperdum. Nature 319:602604.
4. Barkhuizen, M.,, S. Magez,, R. A. Atkinson, and, F. Brombacher. 2007. Interleukin-12p70-dependent interferon-gamma production is crucial for resistance in African trypanosomiasis. J. Infect. Dis. 196:12531260.
5. Barkhuizen, M.,, S. Magez,, B. Ryffel, and, F. Brombacher. 2008. Interleukin-12p70 deficiency increases survival and diminishes pathology in Trypanosoma congolense infection. J. Infect. Dis. 198:12841291.
6. Barry, D., and, R. McCulloch. 2009. Molecular microbiology: a key event in survival. Nature 459:172173.
7. Beschin, A.,, L. Brys,, S. Magez,, M. Radwanska, and, P. De Baetselier. 1998. Trypanosoma brucei infection elicits nitric oxide-dependent and nitric oxide-independent suppressive mechanisms. J. Leukoc. Biol. 63:429439.
8. Blanchette, J.,, N. Racette,, R. Faure,, K. A. Siminovitch, and, M. Olivier. 1999. Leishmarda- induced increases in activation of macrophage shp-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation. Eur. J. Immunol. 29:37373744.
9. Bliska, J. B.,, J. E. Galan, and, S. Falkow. 1993. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell 73:903920.
10. Blum,, J. L.,, J. A. Down,, A. M. Gurnett,, M. Carrington,, M. J. Turner, and, D. C. Wiley. 1993. A structural motif in the variant surface glycoproteins of Trypanosoma brucei. Nature 362:603609.
11. Borst, P. 2002. Antigenic variation and allelic exclusion. Cell 109:58.
12. Borst, P., and, G. A. Cross. 1982. Molecular basis for trypanosome antigenic variation. Cell 29:291303.
13. Borst, P., and, G. Rudenko. 1994. Antigenic variation in African trypanosomes. Science 264:18721873.
14. Borst, P.,, G. Rudenko,, M. C. Taylor,, P. A. Blundell,, F. Vanleeuwen,, W. Bitter,, M. Cross, and, R. McCulloch. 1996. Antigenic variation in trypanosomes. Arch. Med. Res. 27:379388.
15. Borst, P., and, S. Ulbert. 2001. Control of vsg gene expression sites. Mol. Biochem. Parasitol. 114(1):1727.
16. Campbell, G. H.,, K. M. Esser, and, S. M. Phillips. 1978. Trypanosoma rhodesiense infection in congenitally athymic (nude) mice. Infect. Immun. 20:714720.
17. Carrington, M.,, N. Carnall,, M. S. Crow,, A. Gaud,, M. B. Redpath,, C. L. Wasunna, and, H. Webb. 1998. The properties and function of the glycosylphosphatidylinositol-phospholipase c in Trypanosoma brucei. Mol. Biochem. Parasitol. 91:153164.
18. Carrington, M.,, N. Miller,, M. Blum,, I. Roditi,, D. Wiley, and, M. Turner. 1991. Variant specific glycoprotein of Trypanosoma brucei consists of two domains each having an independently conserved pattern of cysteine residues. J. Mol. Biol. 221:823835.
19. Chattopadhyay,, A.,, N. G. Jones,, D. Nietlispach,, P. R. Nielsen,, H. P. Voorheis,, H. R. Mott, and, M. Carrington. 2005. Structure of the c-terminal domain from Trypanosoma brucei variant surface glycoprotein mitat1.2. J. Biol. Chem. 280:72287235.
20. Chaussepied, M.,, D. Lallemand,, M. F. Moreau,, R. Adamson,, R. Hall, and, G. Langsley. 1998. Upregulation of jun and fos family members and permanent jnk activity lead to constitutive ap-1 activation in theileria-transformed leukocytes. Mol. Biochem. Parasitol. 94:215226.
21. Coller, S. P.,, J. M. Mansfield, and, D. M. Paulnock. 2003. Glycosylinositolphosphate soluble variant surface glycoprotein inhibits IFN-gamma-induced nitric oxide production via reduction in STAT1 phosphorylation in African trypanosomiasis. J. Immunol. 171:14661472.
22. Cross, G. A. 1975. Identification, purification and properties of clone-specific glycoprotein antigens constituting the surface coat of Trypanosoma brucei. Parasitol. 71:393417.
23. Cross, G. A. 1990. Cellular and genetic aspects of antigenic variation in trypanosomes. Annu. Rev. Immunol. 8:83110.
24. Cross, G. A. 1996. Antigenic variation in trypanosomes: secrets surface slowly. Bioessays 18:283291.
25. Cross, G. A.,, L. E. Wirtz, and, M. Navarro. 1998. Regulation of vsg expression site transcription and switching in Trypanosoma brucei. Mol. Biochem. Parasitol. 91:7791.
26. Cully, D. F,, H. S. Ip, and, G. A. Cross. 1985. Coordinate transcription of variant surface glycoprotein genes and an expression site associated gene family in Trypanosoma brucei. Cell 42:173182.
27. Dagenais,, T. R.,, K. P. Demick,, J. D. Bangs,, K. T. Forest,, D. M. Paulnock, and, J. M. Mansfield. 2009a. T-cell responses to the trypanosome variant surface glycoprotein are not limited to hypervariable subregions. Infect. Immun. 77:141151.
28. Dagenais,, T. R.,, B. E. Freeman,, K. P. Demick,, D. M. Paulnock, and, J. M. Mansfield. 2009b. Processing and presentation of variant surface glycoprotein molecules to T cells in African trypanosomiasis. J. Immunol. 183:33443355.
29. Daulouede, S.,, B. Bouteille,, D. Moynet,, P. De Baetselier,, P. Courtois,, J. L. Lemesre,, A. Buguet,, R. Cespuglio, and, P. Vincendeau. 2001. Human macrophage tumor necrosis factor (TNF)-alpha production induced by Trypanosoma brucei gambiense and the role of tnf-alpha in parasite control. J. Infect. Dis. 183:988991.
30. De Gee, A. L.,, R. F. Levine, and, J. M. Mansfield. 1988. Genetics of resistance to the African trypanosomes. VI. Heredity of resistance and variable surface glycoproteinspecific immune responses. J. Immunol. 140:283288.
31. De Gee, A. L., and, J. M. Mansfield. 1984. Genetics of resistance to the African trypanosomes. Iv. Resistance of radiation chimeras to Trypanosoma rhodesiense infection. Cell Immunol. 87:8591.
32. De Gee, A. L.,, G. Sonnenfeld, and, J. M. Mansfield. 1985. Genetics of resistance to the African trypanosomes. V. Qualitative and quantitative differences in interferon production among susceptible and resistant mouse strains. J. Immunol. 134:27232726.
33. Demick, K. P.,, M. Suresh,, D. M. Paulnock and, J. M. Mansfield. 2010. A re-examination of the role of T lymphocyte triggering factor (TLTF)/trypanin in trypanosomiasis. (Manuscript in preparation).
34. Dempsey, W. L., and, J. M. Mansfield. 1983. Lymphocyte function in experimental African trypanosomiasis. VI. Parasitespecific immunosuppression. J. Immunol. 130:28962898.
35. Donelson, J. E. 2003. Antigenic variation and the African trypanosome genome. Acta Trop. 85:391404.
36. Drennan,, M. B.,, B. Stijlemans,, J. Van den Abbeele,, V. J. Quesniaux,, M. Barkhuizen,, F. Brombacher,, P. De Baetselier,, B. Ryffel, and, S. Magez. 2005. The induction of a type 1 immune response following a Trypanosoma brucei infection is myd88 dependent. J. Immunol. 175:25012509.
37. Dubois, M. E.,, K. P. Demick, and, J. M. Mansfield. 2005. Trypanosomes expressing a mosaic variant surface glycoprotein coat escape early detection by the immune system. Infect, Immun. 73:26902697.
38. Engstler, M.,, T. Pfohl,, S. Herminghaus,, M. Boshart,, G. Wiegertjes,, N. Heddergott, and, P. Overath. 2007. Hydrodynamic flow-mediated protein sorting on the cell surface of trypanosomes. Cell 131:505515.
39. Esser, K. M., and, M. J. Schoenbechler. 1985. Expression of two variant surface glycoproteins on individual African trypanosomes during antigen switching. Science 229:190193.
40. Fehr, T.,, D. Skrastina,, P. Pumpens, and, R. M. Zinkernagel. 1998. T cell-independent type I antibody response against B cell epitopes expressed repetitively on recombinant virus particles. Proc. Nat. Acad. Sci. USA 95:94779481.
41. Field, M. C., and, J. C. Boothroyd. 1996. Sequence divergence in a family of variant surface glycoprotein genes from trypanosomes: coding region hypervariability and downstream recombinogenic repeats. J. Mol. Evol. 42:500511.
42. Field, M. C.,, A. K. Menon, and, G. Cross. 1991. A glycosylphosphatidylinositol protein anchor from procyclic stage Trypanosoma brucei: lipid structure and biosynthesis. EMBO J. 10:27312739.
43. Forget, G.,, D. J. Gregory, and, M. Olivier. 2005a. Proteasomemediated degradation of stat1 alpha following infection of macrophages with Leishmania donovani. J. Biol. Chem. 280:3054230549.
44. Forget, G.,, D. J. Gregory,, L. A. Whitcombe, and, M. Olivier. 2006. Role of host protein tyrosine phosphatase shp-1 in Leishmania donovani-induced inhibition of nitric oxide production. Infect. Immun. 74:62726279.
45. Forget, G.,, C. Matte,, K. A. Siminovitch,, S. Rivest,, P. Pouliot, and, M. Olivier. 2005b. Regulation of the Leishmania-induced innate inflammatory response by the protein tyrosine phosphatase shp-1. Eur. J. Immunol. 35:19061917.
46. Forget,, G.,, K. A. Siminovitch,, S. Brochu,, S. Rivest,, D. Radzioch, and, M. Olivier. 2001. Role of host phosphotyrosine phosphatase shp-1 in the development of murine leishmaniasis. Eur. J. Immunol. 31:31853196.
47. Freeman, B. E.,, J. M. Mansfield, and, D. M. Paulnock. 2010. Altered antigen processing and presentation by dendritic cells in trypanosomiasis. Ph. D. dissertation. University of Wisconsin, Madison, Madison, WI.
48. Freymann, D.,, J. Down,, M. Carrington,, I. Roditi,, M. Turner, and, D. Wiley. 1990. 2•9 å resolution structure of the n-terminal domain of a variant surface glycoprotein from Trypanosoma brucei. J. Mol. Biol. 216:141160.
49. Gomez,, M. A.,, I. Contreras,, M. Halle,, M. L. Tremblay,, R. W. McMaster, and, M. Olivier. 2009. Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Sci. Signal 2:ra58.
50. Gregory,, D. J.,, M. Godbout,, I. Contreras,, G. Forget, and, M. Olivier. 2008. A novel form of NF-kappaB is induced by Leishmania infection: involvement in macrophage gene expression. Eur. J. Immunol. 38:10711081.
51. Guy, R. A., and, M. Belosevic. 1993. Comparison of receptors required for entry of Leishmania major amastigotes into macrophages. Infect. Immun. 61:15531558.
52. Hanrahan, O.,, H. Webb,, R. O’Byrne,, E. Brabazon,, A. Treumann,, J. D. Sunter,, M. Carrington, and, H. P. Voorheis. 2009. The glycosylphosphatidylinositol-plc in Trypanosoma brucei forms a linear array on the exterior of the flagellar membrane before and after activation. PLoS Pathog. 5:e1000468.
53. Haque, S.,, H. Dumon,, A. Haque, and, L. H. Kasper. 1998. Alteration of intracellular calcium flux and impairment of nuclear factor-at translocation in T cells during acute Toxoplasmagondii infection in mice. J. Immunol. 161:68126818.
54. Harnett, W.,, M. R. Deehan,, K. M. Houston, and, M. M. Harnett. 1999. Immunomodulatory properties of a phosphorylcholine-containing secreted filarial glycoprotein. Parasite Immunol. 21:601608.
55. Harris,, T. H.,, N. M. Cooney,, J. M. Mansfield, and, D. M. Paulnock. (2006). Signal transduction, gene transcription, and cytokine production triggered in macrophages by exposure to trypanosome DNA. Infect. Immun. 74:45304537.
56. Harris, T. H.,, J. M. Mansfield, and, D. M. Paulnock. 2007. Cpg oligodeoxynucleotide treatment enhances innate resistance and acquired immunity to African trypanosomes. Infect. Immun. 75:23662373.
57. Haspel, R. L.,, M. Salditt-Georgieff, and, J. E. Darnell, Jr. 1996. The rapid inactivation of nuclear tyrosine phosphorylated STAT1 depends upon a protein tyrosine phosphatase. EMBO J. 15:62626268.
58. Hertz, C. J.,, H. Filutowicz, and, J. M. Mansfield. 1998. Resistance to the African trypanosomes is IFN-gamma dependent. J. Immunol. 161:67756783.
59. Hertz, C. J., and, J. M. Mansfield. 1999. Ifn-gamma-dependent nitric oxide production is not linked to resistance in experimental African trypanosomiasis. Cell Immunol. 192:2432.
60. Hertz-Fowler,, C.,, L. M. Figueiredo,, M. A. Quail,, M. Becker,, A. Jackson,, N. Bason,, K. Brooks,, C. Churcher,, S. Fahkro,, I. Goodhead,, P. Heath,, M. Kartvelishvili,, K. Mungall,, D. Harris,, H. Hauser,, M. Sanders,, D. Saunders,, K. Seeger,, S. Sharp,, J. E. Taylor,, D. Walker,, B. White,, R. Young,, G. A. Cross,, G. Rudenko,, J. D. Barry,, E. J. Louis, and, M. Berriman. 2008. Telomeric expression sites are highly conserved in Trypanosoma brucei. PLoS ONE 3:e3527.
61. Hoeijmakers,, J. H.,, A. C. Frasch,, A. Bernards,, P. Borst, and, G. A. Cross. 1980. Novel expression-linked copies of the genes for variant surface antigens in trypanosomes. Nature 284:7880.
62. Horn, D., and, G. A. M. Cross. 1997. Analysis of Trypanosoma brucei vsg expression site switching in vitro. Mol. Biochem, Parasitol. 84:189201.
63. Hunter, T. 1993. Signal transduction. Cytokine connections. Nature 366:114116.
64. Hunter, T., and, J. A. Cooper. 1985) Protein-tyrosine kinases. Annu. Rev. Biochem. 54:897930.
65. Inverso, J. A.,, A. L. De Gee, and, J. M. Mansfield. 1988. Genetics of resistance to the African trypanosomes. Vii. Trypanosome virulence is not linked to variable surface glycoprotein expression. J. Immunol. 140:289293.
66. Inverso, J. A., and, J. M. Mansfield. 1983. Genetics of resistance to the African trypanosomes. II. Differences in virulence associated with vssa expression among clones of Trypanosoma rhodesiense. J. Immunol. 130:412417.
67. Inverso,, J. A.,, T. S. Uphoff,, S. C. Johnson,, D. M. Paulnock, and, J. M. Mansfield. 2010. Biological variation among African trypanosomes: I. Clonal expression of virulence is not linked to the variant surfact glycoprotein (VSG) or the VSG gene telomeric expression site. DNA Cell Biol. 29:113.
68. Jayawardena, A. N., and, B. H. Waksman. 1977. Suppressor cells in experimental trypanosomiasis. Nature 265:539530.
69. Jayawardena, A. N.,, B. H. Waksman, and, D. D. Eardley. 1978. Activation of distinct helper and suppressor T cells in experimental trypanosomiasis. J. Immunol. 121:622628.
70. Kaushik,, R. S.,, J. E. Uzonna,, Y. Zhang,, J. R. Gordon, and, H. Tabel. 2000. Innate resistance to experimental African trypanosomiasis: differences in cytokine (TNF-alpha, IL-6, IL-10 and IL-12) production by bone marrow-derived macrophages from resistant and susceptible mice. Cytohne 12:10241034.
71. Kima, P. E.,, N. H. Ruddle, and, D. McMahon-Pratt. 1997. Presentation via the class I pathway by Leishmania amazon- ensisinfected macrophages of an endogenous leishmanial antigen to cd8+ T cells. J. Immunol. 159:18281834.
72. Kozlowski, M.,, I. Mlinaric-Rascan,, G. S. Feng,, R. Shen,, T. Pawson, and, K. A. Siminovitch. 1993. Expression and catalytic activity of the tyrosine phosphatase ptp1c is severely impaired in motheaten and viable motheaten mice. J. Exp. Med. 178:21572163.
73. Kukita, M.,, M. Hirata, and, T. Koga. 1986. Requirement of ca2+ for the production and degradation of inositol 1,4,5-trisphosphate in macrophages. Biochim. Biophys. Acta 885:121128.
74. Landeira, D.,, J. M. Bart,, D. Van Tyne, and, M. Navarro. 2009. Cohesin regulates vsg monoallelic expression in trypanosomes. J. Cell Biol. 186:243254.
75. Leonard, W. J., and, J. J. O’Shea. 1998. Jaks and stats: biological implications. Annu. Rev. Immunol. 16:293322.
76. Leppert, B. J.,, J. M. Mansfield, and, D. M. Paulnock. 2007. The soluble variant surface glycoprotein of African trypanosomes is recognized by a macrophage scavenger receptor and induces I kappa B alpha degradation independently of traf6-mediated tlr signaling. J. Immunol. 179:548556.
77. Liu, B.,, J. Liao,, X. Rao,, S. A. Kushner,, C. D. Chung,, D. D. Chang, and, K. Shuai. 1998. Inhibition of statlmediated gene activation by piasl. Proc. Natl. Acad. Sci. USA 95:1062610631.
78. Lopez, R.,, K. P. Demick,, J. M. Mansfield, and, D. M. Paulnock. 2008. Type I IFNs play a role in early resistance, but subsequent susceptibility, to the African trypanosomes. J. Immunol. 181:49084917.
79. Lucas, R.,, S. Magez,, R. De Leys,, L. Fransen,, J. P. Scheerlinck,, M. Rampelberg,, E. Sablon, and, P. De Baetselier. 1994. Mapping the lectin-like activity of tumor necrosis factor. Science 263:814817.
80. Lucas, R.,, S. Magez,, B. Songa,, A. Darji,, R. Hamers, and, P. de Baetselier. 1993. A role for TNF during African trypanosomiasis: involvement in parasite control, immunosuppression and pathology. Res. Immunol. 144:370376.
81. Lythgoe,, K. A.,, L. J. Morrison,, A. F. Read, and, J. D. Barry. 2007. Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation. Proc. Natl. Acad. Sci. USA 104:80958100.
82. Mackenzie, A. R.,, P. R. Sibley, and, B. P. White. 1979. Differential suppression of experimental allergic diseases in rats infected with trypanosomes. Parasite Immunol. 1:4959.
83. Magez, S.,, M. Geuskens,, A. Beschin,, H. del Favero,, H. Verschueren,, R. Lucas,, E. Pays, and, P. de Baetselier. (1997). Specific uptake of tumor necrosis factor-alpha is involved in growth control of Trypanosoma brucei. J. Cell Biol. 137:715727.
84. Magez, S.,, M. Radwanska,, A. Beschin,, K. Sekikawa, and, P. De Baetselier. (1999). Tumor necrosis factor alpha is a key mediator in the regulation of experimental Trypanosoma brucei infections. Infect. Immun. 67:31283132.
85. Magez, S.,, M. Radwanska,, M. Drennan,, L. Fick,, T. N. Baral,, F. Brombacher, and, P. De Baetselier. 2006. Interferon-gamma and nitric oxide in combination with antibodies are key protective host immune factors during trypanosoma congolense tc13 infections. J. Infect. Dis. 193:15751583.
86. Magez, S.,, B. Stijlemans,, T. Baral, and, P. De Baetselier. 2002. Vsg-gpi anchors of African trypanosomes: their role in macrophage activation and induction of infection-associated immunopathology. Microbes Infect. 4:9991006.
87. Magez, S.,, B. Stijlemans,, M. Radwanska,, E. Pays,, M. A. Ferguson, and, P. De Baetselier. 1998. The glycosyl-inositol-phosphate and dimyristoylglycerol moieties of the glycosylphosphatidylinositol anchor of the trypanosome variant-specific surface glycoprotein are distinct macrophage-activating factors. J. Immunol. 160:19491956.
88. Mansfield, J. 2006. The trypanosome virulence rheostat and loss of host resistance. Parasite Immunol. 28:262263.
89. Mansfield, J. M. 1994. T-cell responses to the trypanosome variant surface glycoprotein: a new paradigm? Parasitol. Today 10:267270.
90. Mansfield, J. M. 1995. Immunobiology of trypanosomiasis: a revisionist view, p. 477-496. In J. Boothroyd (ed.), Molecular Approaches to Parasitology. Wiley-Liss, Inc., New York, NY.
91. Mansfield, J. M., and, O. Bagasra. 1978. Lymphocyte function in experimental African trypanosomiasis. I. B cell responses to helper T cell-independent and -dependent antigens. J. Immunol. 120:759765.
92. Mansfield, J. M.,, T. H. Davis, and, M. E. Dubois. 2002. Immunobiology of African trypanosomiasis: new paradigms, newer questions, p. 79-86. In S. J. Black and J. R. Seed (ed.), The African trypanosomes. Kluwer Academic Press, Boston, MA.
93. Mansfield, J. M., and, J. P. Kreier. 1972. Autoimmunity in experimental Trypanosoma congolense infections of rabbits. Infect. Immun. 5:648656.
94. Mansfield,, J. M.,, R. F. Levine,, W. L. Dempsey,, S. R. Wellhausen, and, C. T. Hansen. 1981. Lymphocyte function in experimental African trypanosomiasis. IV. Immunosuppression and suppressor cells in the athymic nu/nu mouse. Cell Immunol. 63:210215.
95. Mansfield, J. M., and, D. M. Paulnock. 2005. Regulation of innate and acquired immunity in African trypanosomiasis. Parasite Immunol. 27:361371.
96. Mansfield, J. M., and, D. M. Paulnock. 2008. Genetic manipulation of African trypanosomes as a tool to dissect the immunobiology of infection. Parasite Immunol. 30:245253.
97. Mansfield, J. M., and, D. M. Paulnock. 2010. Biological variation among the African trypanosomes. II. Differential expression of genes and proteins associated with clonal changes in parasite virulence. (Manuscript submitted for publication).
98. Mansfield, J. M., and, J. H. Wallace. 1974. Suppression of cell-mediated immunity in experimental African trypanosomiasis. Infect. Immun. 10:335339.
99. Marth, T.,, W. Strober,, R. A. Seder, and, B. L. Kelsall. 1997. Regulation of transforming growth factor-beta production by interleukin-12. Eur. J. Immunol. 27:12131220.
100. Matte,, C.,, J. F. Marquis,, J. Blanchette,, P. Gros,, R. Faure,, B. I. Posner, and, M. Olivier. 2000. Peroxovanadium-mediated protection against murine leishmaniasis: role of the modulation of nitric oxide. Eur. J. Immunol. 30:25552564.
101. Mensa Wilmot, K.,, D. Hereld, and, P. T. Englund. 1990. Genomic organization, chromosomal localization, and developmentally regulated expression of the glycosylphosphatidylinositol-specific phospholipase c of Trypanosoma brucei. Mol. Cell Biol. 10:720726.
102. Metcalf, P.,, M. Blum,, D. Freymann,, M. Turner, and, D. C. Wiley. 1987. Two variant surface glycoproteins of Trypanosoma brucei of different sequence classes have similar 6 a resolution x-ray structures. Nature 325:8486.
103. Millar,, A. E.,, J. Sternberg,, C. McSharry,, X. Q. Wei,, F. Y. Liew, and, C. M. Turner. 1999. T-cell responses during Trypanosoma brucei infections in mice deficient in inducible nitric oxide synthase. Infect. Immun. 67:33343338.
104. Mnaimneh, S.,, M. Geffard,, B. Veyret, and, P. Vincendeau. 1997. Albumin nitrosylated by activated macrophages possesses antiparasitic effects neutralized by antino-acetylatedcysteine antibodies. J. Immunol. 158:308314.
105. Mond, J. J.,, A. Lees, and, C. M. Snapper. 1995. T cell-independent antigens type 2. Annu. Rev. Immunol. 13:655692.
106. Mosser,, D. M., and, P. J. Edelson. 1984. Activation of the alternative complement pathway by Leishmania promastigotes: parasite lysis and attachment to macrophages. J. Immunol.. 132:15011505.
107. Munoz-Jordan, J. L.,, K. P. Davies, and, G. A. Cross. 1996. Stable expression of mosaic coats of variant surface glycoproteins in Trypanosoma brucei. Science 272:17951797.
108. Murray, M., and, W. I. Morrison. 1979. Non-specific induction of increased resistance in mice to Trypanosoma congolense and Trypanosoma brucei by immunostimulants. Parasitohgy 79:349366.
109. Namangala, B.,, L. Brys,, S. Magez,, P. De Baetselier, and, A. Beschin. 2000. Trypanosoma brucei brucei infection impairs mhc class II antigen presentation capacity of macrophages. Parasite Immunol. 22:361370.
110. Navarro, M., and, G. A. Cross. 1998. In situ analysis of a variant surface glycoprotein expression-site promoter region in Trypanosoma brucei. Mol. Biochem. Parasitol. 94:5366.
111. Navarro, M., and, G. A. M. Cross. 1996. Dna rearrangements associated with multiple consecutive directed antigenic switches in Trypanosoma brucei. Mol. Cell. Biol. 16:36153625.
112. Navarro, M., and, K. Gull. 2001. A pol I transcriptional body associated with vsg mono-allelic expression in Trypanosoma brucei. Nature 414:759763.
113. Olivier, M.,, K. G. Baimbridge, and, N. E. Reiner. 1992. Stimulus-response coupling in monocytes infected with Leishmania. Attenuation of calcium transients is related to defective agonist-induced accumulation of inositol phosphates. J. Immunol. 148:11881196.
114. Olivier, M.,, R. W. Brownsey, and, N. E. Reiner. 1992. Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase c. Proc. Natl. Acad. Sci. USA 89:74817485.
115. Olivier, M.,, D. J. Gregory, and, G. Forget. 2005. Subversion mechanisms by which leishmania parasites can escape the host immune response: a signaling point of view. Clin. Microbiol. Rev. 18:293305.
116. Olivier,, M.,, B. J. Romero-Gallo,, C. Matte,, J. Blanchette,, B. I. Posner,, M. J. Tremblay, and, R. Faure. 1998. Modulation of interferon-gamma-induced macrophage activation by phosphotyrosine phosphatases inhibition. Effect on murine leishmaniasis progression. J. Biol. Chem. 273:1394413949.
117. Paulnock, D. M., and, S. P. Coller. 2001. Analysis of macrophage activation in African trypanosomiasis. J. Leukoc. Biol. 69:685690.
118. Paulnock,, D. M.,, C. Smith, and, J. M. Mansfield. 1989. Antigen presenting cell function in African trypanosomiasis, p. 135–144. In L. B. Schook and, J. Tews (ed.), Antigen presenting cells: diversity, differentiation, and regulation. Alan R. Liss, Inc., New York.
119. Posner, B. I.,, R. Faure,, J. W. Burgess,, A. P. Bevan,, D. Lachance,, G. Zhang-Sun,, I. G. Fantus,, J. B. Ng,, D. A. Hall,, B. S. Lum, et al. 1994. Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J. Biol. Chem. 269:45964604.
120. Radwanska, M.,, P. Guirnalda,, C. De Trez,, B. Ryffel,, S. Black, and, S. Magez. 2008. Trypanosomiasis-induced b cell apoptosis results in loss of protective antiparasite antibody responses and abolishment of vaccine-induced memory responses. PLoS Pathog. 4:e1000078.
121. Ray, M.,, A. A. Gam,, R. A. Boykins, and, R. T. Kenney. 2000. Inhibition of interferon-gamma signaling by Leishmania donovani. J. Infect. Dis. 181:11211128.
122. Reiner,, N. E.,, W. Ng,, C. B. Wilson,, W. R. McMaster, and, S. K. Burchett. 1990. Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1. J. Clin. Investig. 85:19141924.
123. Reinitz, D. M.,, B. D. Aizenstein, and, J. M. Mansfield. 1992. Variable and conserved structural elements of trypanosome variant surface glycoproteins. Mol. Biochem. Parasitol. 51:119132.
124. Reinitz, D. M., and, J. M. Mansfield. 1988. Independent regulation of B cell responses to surface and subsurface epitopes of African trypanosome variable surface glycoproteins. J. Immunol. 141:620626.
125. Reinitz, D. M., and, J. M. Mansfield. 1990. T-cell-independent and T-cell-dependent B-cell responses to exposed variant surface glycoprotein epitopes in trypanosome-infected mice. Infect. Immun. 58:23372342.
126. Russell, D. G., and, P. Talamas-Rohana. (1989). Leishmania and the macrophage: a marriage of inconvenience. Immunol. Today 10:328333.
127. Schleifer, K. W.,, H. Filutowicz,, L. R. Schopf, and, J. M. Mansfield. 1993. Characterization of T helper cell responses to the trypanosome variant surface glycoprotein. J. Immunol. 150:29102919.
128. Schleifer, K. W., and, J. M. Mansfield. 1993. Suppressor macrophages in African trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins. J. Immunol. 151:54925503.
129. Schopf, L. R.,, H. Filutowicz,, X. J. Bi, and, J. M. Mansfield. 1998. Interleukin-4-dependent immunoglobulin g1 isotype switch in the presence of a polarized antigen-specific th1-cell response to the trypanosome variant surface glycoprotein. Infect. Immun. 66:451461.
130. Schwarzer, E.,, M. Alessio,, D. Ulliers, and, P. Arese. 1998. Phagocytosis of the malarial pigment, hemozoin, impairs expression of major histocompatibility complex class II antigen, cd54, and cd11c in human monocytes. Infect. Immun. 66:16011606.
131. Schwarzer, E., and, P. Arese. 1996. Phagocytosis of malarial pigment hemozoin inhibits nadph-oxidase activity in human monocyte-derived macrophages. Biochim. Biophs. Acta 1316:169175.
132. Seed, J. R., and, A. A. Gam. 1967. The presence of antibody to a normal rabbit liver antigen in rabbits infected with Trypanosoma gambiense. J. Parasitol. 53:946950.
133. Seed, J. R., and, J. B. Sechelski. 1989. African trypanosomes: inheritance of factors involved in resistance. Exp. Parasitol. 69:18.
134. Shen, S. H.,, L. Bastien,, B. I. Posner, and, P. Chretien. 1991. A protein-tyrosine phosphatase with sequence similarity to the sh2 domain of the protein-tyrosine kinases. Nature 352:736739.
135. Shi, M.,, G. Wei,, W. Pan, and, H. Tabel. 2006. Experimental African trypanosomiasis: a subset of pathogenic, IFN-gamma-producing, MHC class II-restricted cd4+ T cells mediates early mortality in highly susceptible mice. J. Immunol. 176:17241732.
136. Snapper, C. M., and, J. J. Mond. 1996. A model for induction of T cell-independent humoral immunity in response to polysaccharide antigens. J. Immunol. 157:22292233.
137. Snapper, C. M.,, H. Yamaguchi,, M. A. Moorman, and, J. J. Mond. 1994. An in vitro model for T cell-independent induction of humoral immunity. A requirement for NK cells. J. Immunol. 152:48844892.
138. Sternberg, J., and, F. McGuigan. 1992. Nitric oxide mediates suppression of T cell responses in murine Trypanosoma brucei infection. Eur. J. Immunol. 22:27412744.
139. Sternberg, J. M., and, N. A. Mabbott. 1996. Nitric oxidemediated suppression of T cell responses during Trypanosoma brucei infection—soluble trypanosome products and interferon-gamma are synergistic inducers of nitric oxide synthase. Eur. J. Immunol. 26:539543.
140. Sutterwala,, F. S.,, G. J. Noel,, R. Clynes, and, D. M. Mosser. 1997. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J. Exp. Med. 185:19771985.
141. Tachado,, S. D.,, P. Gerold,, R. Schwarz,, S. Novakovic,, M. Mc-Conville, and, L. Schofield. 1997. Signal transduction in macrophages by glycosylphosphatidylinositols of Plasmodium, Trypanosoma, and Leishmania: activation of protein tyrosine kinases and protein kinase c by inositolglycan and diacylglycerol moieties. Proc. Natl. Acad. Sci. USA 94:40224027.
142. Tachado, S. D.,, R. Mazhari-Tabrizi, and, L. Schofield. 1999. Specificity in signal transduction among glycosylphosphatidylinositols of Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Parasite Immunol. 21:609617.
143. Turco, S. J. 1999. Adversarial relationship between the Leishmania lipophosphoglycan and protein kinase c of host macrophages. Parasite Immunol. 21:597600.
144. Turner, C. M., and, J. D. Barry. 1989. High frequency of antigenic variation in Trypanosoma brucei rhodesiense infections. Parasitology 99:6775.
145. Turner, C. M. R. 1997. The rate of antigenic variation in flytransmitted and syringe-passaged infections of Trypanosoma brucei. FEMS Microbiol. Lett. 153:227231.
146. Van der Ploeg, L. H.,, K. Gottesdiener, and, M. G. Lee. 1992. Antigenic variation in African trypanosomes. Trends Genet. 8:452457.
147. Vanhamme, L.,, E. Pays,, R. McCulloch, and, J. D. Barry. 2001. An update on antigenic variation in African trypanosomes. Trends Parasitol. 17:338343.
148. Verstrepen, K. J., and, G. R. Fink. 2009. Genetic and epigenetic mechanisms underlying cell-surface variability in protozoa and fungi. Annu. Rev. Genet. 43:124.
149. Vickerman, K., and, A. G. Luckins. 1968. Cyclical transformation in trypanosomes. J. Gen. Microbiol. 50:13.
150. Vickerman, K., and, A. G. Luckins. 1969. Localization of variable antigens in the surface coat of Trypanosoma brucei using ferritin conjugated antibody. Nature 224:11251126.
151. Vincendeau, P.,, S. Daulouede, and, B. Veyret. 1989. Role of hypochlorous acid in Trypanosoma musculi killing by phagocytes. Parasitology 2:253257.
152. Vincendeau, P.,, S. Daulouede,, B. Veyret,, M. L. Darde,, B. Bouteille, and, J. L. Lemesre. 1992. Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei. Exp. Parasitol. 75:353360.
153. Vos, Q.,, A. Lees,, Z. Q. Wu,, C. M. Snapper, and, J. J. Mond. 2000. B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunol. Rev. 176:154170.
154. Wellhausen, S. R., and, J. M. Mansfield. 1979. Lymphocyte function in experimental African trypanosomiasis. Ii. Splenic suppressor cell activity. J. Immunol. 122:818824.
155. Wellhausen, S. R., and, J. M. Mansfield. 1980a. Characteristics of the splenic suppressor cell—target cell interaction in experimental African trypanosomiasis. Cell Immunol. 54:414424.
156. Wellhausen, S. R., and, J. M. Mansfield. 1980b. Lymphocyte function in experimental African trypanosomiasis. III. Loss of lymph node cell responsiveness. J. Immunol. 124:11831186.
157. Yeung,, Y. G.,, K. L. Berg,, F. J. Pixley,, R. H. Angeletti, and, E. R. Stanley. 1992. Protein tyrosine phosphatase-1c is rapidly phosphorylated in tyrosine in macrophages in response to colony stimulating factor-1. J. Biol. Chem. 267:2344723450.
158. Yi,, T. L.,, J. L. Cleveland,, and J. N. Ihle. 1992. Protein tyrosine phosphatase containing sh2 domains: characterization, preferential expression in hematopoietic cells, and localization to human chromosome 12pl2-pl3. Mol. Cell Biol. 12:836846.
159. Zinkernagel, R. M. 2000. What is missing in immunology to understand immunity? Nature Immunol. 1:181185.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error