How protozoan parasites evade the immune response

Zambrano-Villa, Sergio; Rosales-Borjas, Disney M.; Carrero, Julio César; Ortiz‐Ortiz, Librado

doi:10.1016/s1471-4922(02)02289-4

Cited by 144 publications

(99 citation statements)

References 52 publications

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“…A ntigenic variation enables pathogens to evade immune responses by continual switching of surface proteins (1,2). The African trypanosomes (Trypanosoma spp.)…”

mentioning

confidence: 99%

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Jackson

Berry

Aslett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

145

206

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Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis ("sleeping sickness") across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly coopted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections.

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“…A ntigenic variation enables pathogens to evade immune responses by continual switching of surface proteins (1,2). The African trypanosomes (Trypanosoma spp.)…”

mentioning

confidence: 99%

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Jackson

Berry

Aslett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

145

206

View full text Add to dashboard Cite

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“…We previously identified AgC10, a T. cruzi surface mucin abundantly expressed at the cell surface of epimastigotes, metacyclic trypomastigotes and amastigotes that can be released during T. cruzi infection [21], as a molecule capable of inhibiting the function of human macrophages by altering TNF and IL-12 production in response to LPS [8]. Those cytokines play a very important role in resistance to T. cruzi infection [6,22]. The important role of this mucin in T. cruzi-mediated macrophage deactivation was reflected by the fact that adding neutralizing antibodies to AgC10 before infecting human macrophages substantially decreased the inhibition of parasite infection on cytokine production [8].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, at the early steps of T. cruzi infection, there is a clear indication that the cytokines produced by macrophages dictate the subsequent type of immune response [3]. To develop a protective immune response, macrophages must secrete cytokines, such as TNF, that are involved in protection against the parasite [6,22]. By altering the ability of macrophages to secrete proinflammatory cytokines through the abundant surface molecule AgC10, T. cruzi modifies the protective immune response to its own benefit, enabling its persistence in the infected host.…”

Section: Discussionmentioning

confidence: 99%

“…TNF and IFN-+ are the most important cytokines involved in the killing of intracellular T. cruzi through an NO-mediated, l-argininedependent killing mechanism [4,5]. On the other hand, parasites have evolved sophisticated systems to evade the immune system [6], and T. cruzi is probably one of the best examples of adaptation to the host. The entry and replication of T. cruzi inside macrophages is required for its dissemination in the host [7], but T. cruzi has the capacity to evade the protective immune response produced by macrophages by escaping from the phagolysosome to the cytoplasm and by altering the profile of secreted cytokines such as TNF or IL-10 [8,9].…”

Section: Introductionmentioning

confidence: 99%

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AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

Alcaide

Fresno

2004

Eur J Immunol

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Secretion of proinflammatory mediators by activated macrophages plays an important role in the immune response to Trypanosoma cruzi. We have previously reported that AgC10, a glycosylphosphatidylinositol-anchored mucin from T. cruzi, inhibits TNF secretion by activated macrophages (de Diego, J., Punzon, C., Duarte, M. and Fresno, M., Alteration of macrophage function by a Trypanosoma cruzi membrane mucin. J. Immunol. 1997. 159: 4983-4989). In this report we have further investigated the molecular mechanisms underlying this inhibition. AgC10 inhibited TNF, IL-10 and cyclooxygenase-2 (COX-2) synthesis by macrophages activated with LPS or LPS plus IFN-+ in a dose-dependent manner. AgC10 did not affect other aspects of macrophage activation induced by LPS, such as inducible nitric oxide synthase (iNOS) expression. AgC10 also had no effect on TNF or COX-2 transcription or the induction of their promoters but inhibited the stability of TNF and COX-2 mRNA, which are regulated post-transcriptionally by the mitogen-activated protein kinase (MAPK) p38 pathway. AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited. This led to TNF and COX-2 mRNA destabilization. In contrast, AgC10 did not affect p38 activation induced by TNF. Furthermore, AgC10 inhibition must lie upstream in the MAPK activation pathway by LPS, since this mucin also inhibited extracellularly regulated kinase (ERK) and Jun kinase (JNK) activation.

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“…Parasites may engage various responses to the host immune system (Zambrano-Villa et al 2002). Some parasites synthesize proteases that specifically target components of the host immune machinery for destruction.…”

Section: Invasion and Evasionmentioning

confidence: 99%

Intriguing parasites and intramembrane proteases: Figure 1.

Rawson

2008

Genes Dev.

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Rhomboid intramembrane proteases occur throughout the kingdoms of life. In this issue of Genes & Development, Baxt and colleagues (pp. 1636-1646) report that the single proteolytic rhomboid (EhROM1) from Entamoeba histolytica cleaves cell surface galactose-binding or N-acetylgalactosamine-binding (Gal/Gal-NAc) lectins. EhROM1 and lectins colocalize during phagocytosis and receptor capping. EhROM1 is found at the base of the cap rather than in the cap proper, suggesting a role in receptor shedding and implying that EhROM1 is crucial for amoebal infection.Parasitic protists are fascinating organisms in their own right, with their typically complex life cycles, distinctive physiologies, and uncertain relationships. They are of immense practical interest as well; parasitic infections account for an enormous proportion of the disease burden on the human population worldwide. The debilitating and often lethal parasitic diseases remain among the most intractable infections and result in between 1.5 and 3 million deaths annually. The enormous costs resulting from lost productivity and caring for the millions who suffer from parasitic disease represent significant hurdles to economic development throughout the world, and these burdens tend to be the highest where the resources to bear them are the least. Advances in our understanding of parasites, such as how they initiate and maintain infections, therefore, have significant potential to improve human health and well-being worldwide.Among parasitic diseases, amoebiasis ranks second only to malaria in global morbidity, affecting vast numbers of people worldwide and killing some 100,000 annually (World Health Organization 1997). The causative agent of human amoebiasis, Entamoeba histolytica, faces many of the same challenges faced by other parasites when establishing infection. Baxt et al. (2008) detail the role of the single rhomboid intramembrane protease from E. histolytica in crucial parasite processes: phagocytosis and immune evasion. The parasitic lifestyleParasitism poses common challenges to the diverse organisms that practice it. Parasites must first locate and enter a host. Next, in many cases, host tissues or cells must be invaded, requiring some means of attachment and introgression. The successful parasite usually establishes a long-term infection, and this potentially affords the host ample time to mount a vigorous immune response to the invader. In order to survive and reproduce while "dining at another's table," the parasite must somehow manage to evade host immune defenses that may act at several stages of the infection cycle. Broadly, extracellular parasites are subject to the humoral response, while intracellular stages are the target of cellular immunity. Invasion and evasionStrategies for evading the host immune response are as complex and varied as the parasites that use them, and most parasites use several different strategies in the course of infection. Parasites may engage various responses to the host immune system (Zambrano-Villa et al. 2002). So...

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How protozoan parasites evade the immune response

Cited by 144 publications

References 52 publications

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

Intriguing parasites and intramembrane proteases: Figure 1.

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