Journal articles: 'Immune response/trypanosomes'

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Dubois, Melissa E., Karen P. Demick, and John M. Mansfield. "Trypanosomes Expressing a Mosaic Variant Surface Glycoprotein Coat Escape Early Detection by the Immune System." Infection and Immunity 73, no. 5 (May 2005): 2690–97. http://dx.doi.org/10.1128/iai.73.5.2690-2697.2005.

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ABSTRACT Host resistance to African trypanosomiasis is partially dependent on an early and strong T-independent B-cell response against the variant surface glycoprotein (VSG) coat expressed by trypanosomes. The repetitive array of surface epitopes displayed by a monotypic surface coat, in which identical VSG molecules are closely packed together in a uniform architectural display, cross-links cognate B-cell receptors and initiates T-independent B-cell activation events. However, this repetitive array of identical VSG epitopes is altered during the process of antigenic variation, when former and nascent VSG proteins are transiently expressed together in a mosaic surface coat. Thus, T-independent B-cell recognition of the trypanosome surface coat may be disrupted by the introduction of heterologous VSG molecules into the coat structure. To address this hypothesis, we transformed Trypanosoma brucei rhodesiense LouTat 1 with the 117 VSG gene from Trypanosoma brucei brucei MiTat 1.4 in order to produce VSG double expressers; coexpression of the exogenous 117 gene along with the endogenous LouTat 1 VSG gene resulted in the display of a mosaic VSG coat. Results presented here demonstrate that the host's ability to produce VSG-specific antibodies and activate B cells during early infection with VSG double expressers is compromised relative to that during infection with the parental strain, which displays a monotypic coat. These findings suggest a previously unrecognized mechanism of immune response evasion in which coat-switching trypanosomes fail to directly activate B cells until coat VSG homogeneity is achieved. This process affords an immunological advantage to trypanosomes during the process of antigenic variation.

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CNOPS, JENNIFER, STEFAN MAGEZ, and CARL De TREZ. "Escape mechanisms of African trypanosomes: why trypanosomosis is keeping us awake." Parasitology 142, no. 3 (December 5, 2014): 417–27. http://dx.doi.org/10.1017/s0031182014001838.

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SUMMARYAfrican trypanosomes have been around for more than 100 million years, and have adapted to survival in a very wide host range. While various indigenous African mammalian host species display a tolerant phenotype towards this parasitic infection, and hence serve as perpetual reservoirs, many commercially important livestock species are highly disease susceptible. When considering humans, they too display a highly sensitive disease progression phenotype for infections withTrypanosoma brucei rhodesienseorTrypanosoma brucei gambiense, while being intrinsically resistant to infections with other trypanosome species. As extracellular trypanosomes proliferate and live freely in the bloodstream and lymphatics, they are constantly exposed to the immune system. Due to co-evolution, this environment however no longer poses a hostile threat, but has become the niche environment where trypanosomes thrive and obligatory await transmission through the bites of tsetse flies or other haematophagic vectors, ideally without causing severe side infection-associated pathology to their host. Hence, African trypanosomes have acquired various mechanisms to manipulate and control the host immune response, evading effective elimination. Despite the extensive research into trypanosomosis over the past 40 years, many aspects of the anti-parasite immune response remain to be solved and no vaccine is currently available. Here we review the recent work on the different escape mechanisms employed by African Trypanosomes to ensure infection chronicity and transmission potential.

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Radwanska, Magdalena, Hang Thi Thu Nguyen, and Stefan Magez. "African Trypanosomosis Obliterates DTPa Vaccine-Induced Functional Memory So That Post-Treatment Bordetella pertussis Challenge Fails to Trigger a Protective Recall Response." Vaccines 9, no. 6 (June 4, 2021): 603. http://dx.doi.org/10.3390/vaccines9060603.

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Salivarian trypanosomes are extracellular parasites causing anthroponotic and zoonotic infections. Anti-parasite vaccination is considered the only sustainable method for global trypanosomosis control. Unfortunately, no single field applicable vaccine solution has been successful so far. The active destruction of the host’s adaptive immune system by trypanosomes is believed to contribute to this problem. Here, we show that Trypanosome brucei brucei infection results in the lasting obliteration of immunological memory, including vaccine-induced memory against non-related pathogens. Using the well-established DTPa vaccine model in combination with a T. b. brucei infection and a diminazene diaceturate anti-parasite treatment scheme, our results demonstrate that while the latter ensured full recovery from the T. b. brucei infection, it failed to restore an efficacious anti-B. pertussis vaccine recall response. The DTPa vaccine failure coincided with a shift in the IgG1/IgG2a anti-B. pertussis antibody ratio in favor of IgG2a, and a striking impact on all of the spleen immune cell populations. Interestingly, an increased plasma IFNγ level in DTPa-vaccinated trypanosome-infected mice coincided with a temporary antibody-independent improvement in early-stage trypanosomosis control. In conclusion, our results are the first to show that trypanosome-inflicted immune damage is not restored by successful anti-parasite treatment.

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PAULNOCK, DONNA M., BAILEY E. FREEMAN, and JOHN M. MANSFIELD. "Modulation of innate immunity by African Trypanosomes." Parasitology 137, no. 14 (November 18, 2010): 2051–63. http://dx.doi.org/10.1017/s0031182010001460.

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SUMMARYThe experimental studies ofBruceigroup trypanosomes presented here demonstrate that the balance of host and parasite factors, especially IFN-γGPI-sVSG respectively, and the timing of cellular exposure to them, dictate the predominant MP and DC activation profiles present at any given time during infection and within specific tissues. The timing of changes in innate immune cell functions following infection consistently support the conclusion that the key events controlling host resistance occur within a short time following initial exposure to the parasite GPI substituents. Once the changes in MP and DC activities are initiated, there appears little that the host can do to reverse these changes and alter the final outcome of these regulatory events. Instead, despite the availability of multiple innate and adaptive immune mechanisms that can control parasites, there is an inability to control trypanosome numbers sufficiently to prevent the emergence and establishment of virulent trypanosomes that eventually kill the host. Overall it appears that trypanosomes have carefully orchestrated the host innate and adaptive immune response so that parasite survival and transmission, and alterations of host immunity, are to its ultimate benefit.

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Taylor, Katherine A., and Bea Mertens. "Immune Response of Cattle Infected with African Trypanosomes." Memórias do Instituto Oswaldo Cruz 94, no. 2 (March 1999): 239–44. http://dx.doi.org/10.1590/s0074-02761999000200022.

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Magez, Stefan, Zeng Li, Hang Thi Thu Nguyen, Joar Esteban Pinto Torres, Pieter Van Wielendaele, Magdalena Radwanska, Jakub Began, Sebastian Zoll, and Yann G. J. Sterckx. "The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples." Pathogens 10, no. 8 (August 19, 2021): 1050. http://dx.doi.org/10.3390/pathogens10081050.

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Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

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Vincendeau, Philippe, and Bernard Bouteille. "Immunology and immunopathology of African trypanosomiasis." Anais da Academia Brasileira de Ciências 78, no. 4 (December 2006): 645–65. http://dx.doi.org/10.1590/s0001-37652006000400004.

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Major modifications of immune system have been observed in African trypanosomiasis. These immune reactions do not lead to protection and are also involved in immunopathology disorders. The major surface component (variable surface glycoprotein,VSG) is associated with escape to immune reactions, cytokine network dysfunctions and autoantibody production. Most of our knowledge result from experimental trypanosomiasis. Innate resistance elements have been characterised. In infected mice, VSG preferentially stimulates a Th 1-cell subset. A response of <FONT FACE=Symbol>gd</FONT> and CD8 T cells to trypanosome antigens was observed in trypanotolerant cattle. An increase in CD5 B cells, responsible for most serum IgM and production of autoantibodies has been noted in infected cattle. Macrophages play important roles in trypanosomiasis, in synergy with antibodies (phagocytosis) and by secreting various molecules (radicals, cytokines, prostaglandins,...). Trypanosomes are highly sensitive to TNF-alpha, reactive oxygen and nitrogen intermediates. TNF-alpha is also involved in cachexia. IFN-gamma acts as a parasite growth factor. These various elements contribute to immunosuppression. Trypanosomes have learnt to use immune mechanisms to its own profit. Recent data show the importance of alternative macrophage activation, including arginase induction. L-ornithine produced by host arginase is essential to parasite growth. All these data reflect the deep insight into the immune system realised by trypanosomes and might suggest interference therapeutic approaches.

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Sima, Núria, Emilia Jane McLaughlin, Sebastian Hutchinson, and Lucy Glover. "Escaping the immune system by DNA repair and recombination in African trypanosomes." Open Biology 9, no. 11 (November 2019): 190182. http://dx.doi.org/10.1098/rsob.190182.

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African trypanosomes escape the mammalian immune response by antigenic variation—the periodic exchange of one surface coat protein, in Trypanosoma brucei the variant surface glycoprotein (VSG), for an immunologically distinct one. VSG transcription is monoallelic, with only one VSG being expressed at a time from a specialized locus, known as an expression site. VSG switching is a predominantly recombination-driven process that allows VSG sequences to be recombined into the active expression site either replacing the currently active VSG or generating a ‘new’ VSG by segmental gene conversion. In this review, we describe what is known about the factors that influence this process, focusing specifically on DNA repair and recombination.

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Harris, Tajie H., John M. Mansfield, and Donna M. Paulnock. "CpG Oligodeoxynucleotide Treatment Enhances Innate Resistance and Acquired Immunity to African Trypanosomes." Infection and Immunity 75, no. 5 (March 5, 2007): 2366–73. http://dx.doi.org/10.1128/iai.01649-06.

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ABSTRACTRelative resistance to African trypanosomiasis is based on the development of a type I cytokine response, which is partially dependent on innate immune responses generated through MyD88 and Toll-like receptor 9 (TLR9). Therefore, we asked whether enhancement of the immune response by artificial stimulation with CpG oligodeoxynucleotide (ODN), a TLR9 agonist, would result in enhanced protection against trypanosomes. In susceptible BALB/c mice, relative resistance to infection was significantly enhanced by CpG ODN treatment and was associated with decreased parasite burden, increased cytokine production, and elevated parasite-specific B- and T-cell responses. In relatively resistant C57BL/6 mice, survival was not enhanced but early parasitemia levels were reduced 100-fold and the majority of the parasites were nondividing, short stumpy (SS) forms. CpG ODN treatment of lymphocyte-deficient C57BL/6-scidand BALB/cByJ-scidmice also enhanced survival and reduced parasitemia, indicating that innate resistance to trypanosome infection can be enhanced. In C57BL/6-scidand BALB/cByJ-scidmice, the parasites were also predominantly SS forms during the outgrowth of parasitemia. However, the effect of CpG ODN treatment on parasite morphology was not as marked in gamma interferon (IFN-γ)-knockout mice, suggesting that downstream effects of IFN-γ production may play a discrete role in parasite cell differentiation. Overall, these studies provide the first evidence that enhancement of resistance to African trypanosomes can be induced in susceptible animals in a TLR9-dependent manner and that CpG ODN treatment may influence the developmental life cycle of the parasites.

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Vaidya, Tushar, Moiz Bakhiet, Kent L. Hill, Tomas Olsson, Krister Kristensson, and John E. Donelson. "The Gene for a T Lymphocyte Triggering Factor from African Trypanosomes." Journal of Experimental Medicine 186, no. 3 (August 4, 1997): 433–38. http://dx.doi.org/10.1084/jem.186.3.433.

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An early and essential event in the protective immune response against most viruses and protozoa is the production of interferon-γ (IFN-γ). In contrast, during infection with African trypanosomes, protozoan parasites that cause human sleeping sickness, the increased levels of IFN-γ do not correlate with a protective response. We showed previously that African trypanosomes express a protein called T lymphocyte triggering factor (TLTF), which triggers CD8+ T lymphocytes to proliferate and to secrete IFN-γ. Here, we isolate the gene for TLTF and demonstrate that the recombinant version of TLTF specifically induces CD8+, but not CD4+, T cells to secrete IFN-γ. Studies with TLTF fused to the green fluorescent protein show that TLTF is localized to small vesicles that are found primarily at or near the flagellar pocket, the site of secretion in trypanosomes. TLTF is likely to be only the first example of a class of proteins that we designate as trypanokines, i.e., factors secreted by trypanosomes that modulate the cytokine network of the host immune system for the benefit of the parasite.

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Vickerman, K. "Trypanosome sociology and antigenic variation." Parasitology 99, S1 (January 1989): S37—S47. http://dx.doi.org/10.1017/s0031182000083402.

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SUMMARYSurvival of the trypanosome (Trypanosoma brucei) population in the mammalian body depends upon paced stimulation of the host's humoral immune response by different antigenic variants and serial sacrifice of the dominant variant (homotype) so that minority variants (heterotypes) can continue the infection and each become a homotype in its turn. New variants are generated by a spontaneous switch in gene expression so that the trypanosome puts on a surface coat of a glycoprotein differing in antigenic specificity from its predecessor. Homotypes appear in a characteristic order for a given trypanosome clone but what determines this order and the pacing of homotype generation so that the trypanosome does not quickly exhaust its repertoire of variable antigens, is not clear. The tendency of some genes to be expressed more frequently than others may reflect the location within the genome and mode of expression of the genes concerned and may influence homotype succession. Differences in the doubling time of different variants or in the rate at which trypanosomes belonging to a particular variant differentiate into non-dividing (vector infective) stumpy forms have also been invoked to explain how a heterotype's growth characteristics may determine when it becomes a homotype. Recent estimations of the frequency of variable antigen switching in trypanosome populations after transmission through the tsetse fly vector, however, suggest a much higher figure (0·97–2·2 × 10−3switches per cell per generation) than that obtained for syringe-passed infections (10−5–10−7switches per cell per generation) and it seems probable that most of the variable antigen genes are expressed as minority variable antigen types very early in the infection. Instability of expression is a feature of trypanosome clones derived from infective tsetse salivary gland (metacyclic) trypanosomes and it is suggested that high switching rates in tsetse-transmitted infections may delay the growth of certain variants to homotype status until later in the infection.

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Flores-Villegas, A. L., P. M. Salazar-Schettino, A. Córdoba-Aguilar, A. E. Gutiérrez-Cabrera, G. E. Rojas-Wastavino, M. I. Bucio-Torres, and M. Cabrera-Bravo. "Immune defence mechanisms of triatomines against bacteria, viruses, fungi and parasites." Bulletin of Entomological Research 105, no. 5 (June 17, 2015): 523–32. http://dx.doi.org/10.1017/s0007485315000504.

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AbstractTriatomines are vectors that transmit the protozoan haemoflagellate Trypanosoma cruzi, the causative agent of Chagas disease. The aim of the current review is to provide a synthesis of the immune mechanisms of triatomines against bacteria, viruses, fungi and parasites to provide clues for areas of further research including biological control. Regarding bacteria, the triatomine immune response includes antimicrobial peptides (AMPs) such as defensins, lysozymes, attacins and cecropins, whose sites of synthesis are principally the fat body and haemocytes. These peptides are used against pathogenic bacteria (especially during ecdysis and feeding), and also attack symbiotic bacteria. In relation to viruses, Triatoma virus is the only one known to attack and kill triatomines. Although the immune response to this virus is unknown, we hypothesize that haemocytes, phenoloxidase (PO) and nitric oxide (NO) could be activated. Different fungal species have been described in a few triatomines and some immune components against these pathogens are PO and proPO. In relation to parasites, triatomines respond with AMPs, including PO, NO and lectin. In the case of T. cruzi this may be effective, but Trypanosoma rangeli seems to evade and suppress PO response. Although it is clear that three parasite-killing processes are used by triatomines – phagocytosis, nodule formation and encapsulation – the precise immune mechanisms of triatomines against invading agents, including trypanosomes, are as yet unknown. The signalling processes used in triatomine immune response are IMD, Toll and Jak-STAT. Based on the information compiled, we propose some lines of research that include strategic approaches of biological control.

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MacLean, Lorna, John E. Chisi, Martin Odiit, Wendy C. Gibson, Vanessa Ferris, Kim Picozzi, and Jeremy M. Sternberg. "Severity of Human African Trypanosomiasis in East Africa Is Associated with Geographic Location, Parasite Genotype, and Host Inflammatory Cytokine Response Profile." Infection and Immunity 72, no. 12 (December 2004): 7040–44. http://dx.doi.org/10.1128/iai.72.12.7040-7044.2004.

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ABSTRACT The mechanisms underlying virulence in human African trypanosomiasis are poorly understood, although studies with experimental mice suggest that unregulated host inflammatory responses are associated with disease severity. We identified two trypanosomiasis foci with dramatically different disease virulence profiles. In Uganda, infections followed an acute profile with rapid progression to the late stage (meningoencephalitic infection) in the majority of patients (86.8%). In contrast, infections in Malawi were of a chronic nature, in which few patients progressed to the late stage (7.1%), despite infections of several months' duration. All infections were confirmed to be Trypanosoma brucei rhodesiense by testing for the presence of the serum resistance-associated (SRA) gene, but trypanosomes isolated from patients in Uganda or Malawi were distinguished by an SRA gene polymorphism. The two disease profiles were associated with markedly different levels of tumor necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β) in plasma. In Uganda but not Malawi early-stage TNF-α was elevated, while in Malawi but not Uganda early-stage TGF-β was elevated. Thus, rapid disease progression in Uganda is associated with TNF-α-mediated inflammatory pathology, whereas in the milder disease observed in Malawi this may be ameliorated by counterinflammatory cytokines. These differing host responses may result either from differing virulence phenotypes of northern and southern trypanosomes or from immune response polymorphisms in the different host populations.

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Turner, C. M. "Antigenic variation in Trypanosoma brucei infections: an holistic view." Journal of Cell Science 112, no. 19 (October 1, 1999): 3187–92. http://dx.doi.org/10.1242/jcs.112.19.3187.

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Trypanosoma brucei parasites undergo clonal phenotypic (antigenic) variation to promote their transmission between mammals and tsetse-fly vectors. This process is classically considered to be a mechanism for evading humoral immune responses, but such an explanation cannot account for the high rate of switching between variable antigens or for their hierarchical (i.e. non-random) expression. I suggest that these anomalies can be explained by a new model: that antigenic variation has evolved as a bifunctional, rather than as a unifunctional, strategy that not only evades humoral immune responses but also enables competition between parasite strains in concomitantly infected hosts. This competition causes a depression of cellular responses. My proposal gives rise to a number of testable predictions. First, low numbers of trypanosomes should express some variable antigen types (VATs) in infections several weeks before these VATs are detectable. Second, as an infection progresses, the number of VATs expressed simultaneously in the population should decrease. Third, immunisation to generate a T helper 1 response against those VATs that are expressed most frequently should lower parasitaemias and reduce virulence.

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Graham, Sheila V., Ben Wymer, and J. David Barry. "Activity of a Trypanosome Metacyclic Variant Surface Glycoprotein Gene Promoter Is Dependent upon Life Cycle Stage and Chromosomal Context." Molecular and Cellular Biology 18, no. 3 (March 1, 1998): 1137–46. http://dx.doi.org/10.1128/mcb.18.3.1137.

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ABSTRACT African trypanosomes evade the mammalian host immune response by antigenic variation, the continual switching of their variant surface glycoprotein (VSG) coat. VSG is first expressed at the metacyclic stage in the tsetse fly as a preadaptation to life in the mammalian bloodstream. In the metacyclic stage, a specific subset (<28; 1 to 2%) of VSG genes, located at the telomeres of the largest trypanosome chromosomes, are activated by a system very different from that used for bloodstream VSG genes. Previously we showed that a metacyclic VSG (M-VSG) gene promoter was subject to life cycle stage-specific control of transcription initiation, a situation unique in Kinetoplastida, where all other genes are regulated, at least partly, posttranscriptionally (S. V. Graham and J. D. Barry, Mol. Cell. Biol. 15:5945–5956, 1985). However, while nuclear run-on analysis had shown that the ILTat 1.22 M-VSG gene promoter was transcriptionally silent in bloodstream trypanosomes, it was highly active when tested in bloodstream-form transient transfection. Reasoning that chromosomal context may contribute to repression of M-VSG gene expression, here we have integrated the 1.22 promoter, linked to a chloramphenicol acetyltransferase (CAT) reporter gene, back into its endogenous telomere or into a chromosomal internal position, the nontranscribed spacer region of ribosomal DNA, in both bloodstream and procyclic trypanosomes. Northern blot analysis and CAT activity assays show that in the bloodstream, the promoter is transcriptionally inactive at the telomere but highly active at the chromosome-internal position. In contrast, it is inactive in both locations in procyclic trypanosomes. Both promoter sequence and chromosomal location are implicated in life cycle stage-specific transcriptional regulation of M-VSG gene expression.

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LISCHKE, Antje, Christian KLEIN, York-Dieter STIERHOF, Michaela HEMPEL, Angela MEHLERT, Igor C. ALMEIDA, Michael A. J. FERGUSON, and Peter OVERATH. "Isolation and characterization of glycosylphosphatidylinositol-anchored, mucin-like surface glycoproteins from bloodstream forms of the freshwater-fish parasite Trypanosoma carassii." Biochemical Journal 345, no. 3 (January 25, 2000): 693–700. http://dx.doi.org/10.1042/bj3450693.

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Wild and farmed freshwater fishes are widely and heavily parasitized by the haemoflagellate Trypanosoma carassii. In contrast, common carp, a natural host, can effectively control experimental infections by the production of specific anti-parasite antibodies. In this study we have identified and partially characterized mucin-like glycoproteins which are expressed in high abundance [(6.0±1.7)×106 molecules·cell-1] at the surface of the bloodstream trypomastigote stage of the parasite. The polypeptide backbone of these glycoproteins is dominated by threonine, glycine, serine, alanine, valine and proline residues, and is modified at its C-terminus by a glycosylphosphatidylinositol membrane anchor. On average, each polypeptide carries carbohydrate chains composed of about 200 monosaccharide units (galactose, N-acetylglucosamine, xylose, sialic acid, fucose, mannose and arabinose), which are most probably O-linked to hydroxy amino acids. The mucin-like molecules are the target of the fish's humoral immune response, but do not undergo antigenic variation akin to that observed for the variant surface glycoprotein in salivarian trypanosomes. The results are discussed with reference to the differences between natural and experimental infections, and in relation to the recently delineated molecular phylogeny of trypanosomes.

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Aresta-Branco, Francisco, Margarida Sanches-Vaz, Fabio Bento, João A. Rodrigues, and Luisa M. Figueiredo. "African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system." Proceedings of the National Academy of Sciences 116, no. 41 (September 25, 2019): 20725–35. http://dx.doi.org/10.1073/pnas.1905120116.

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Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression, and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed prolonged survival in which nearly 90% of the mice survived a 30-d period of infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reducing disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental to the parasite, even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.

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Graham, S. V., and J. D. Barry. "Transcriptional regulation of metacyclic variant surface glycoprotein gene expression during the life cycle of Trypanosoma brucei." Molecular and Cellular Biology 15, no. 11 (November 1995): 5945–56. http://dx.doi.org/10.1128/mcb.15.11.5945.

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In antigenic variation in African trypanosomes, switching of the variant surface glycoprotein (VSG) allows evasion of the mammalian host immune response. Trypanosomes first express the VSG in the tsetse fly vector, at the metacyclic stage, in preparation for transfer into the mammal. In this life cycle stage, a small, specific subset (1 to 2%) of VSGs are activated, and we have shown previously that the system of activation and expression of metacyclic VSG (M-VSG) genes is very different from that used for bloodstream VSG genes (S.V. Graham, K.R. Matthews, P.G. Shiels, and J.D. Barry, Parasitology 101:361-367, 1990). Now we show that unlike other trypanosome genes including bloodstream VSG genes, M-VSG genes are expressed from promoters subject to exclusively transcriptional regulation in a life cycle stage-dependent manner. We have located an M-VSG gene promoter, and we demonstrate that it is specifically up-regulated at the metacyclic stage. This is the first demonstration of gene expression being regulated entirely at the level of transcription among the Kinetoplastida; all other protein-coding genes examined in these organisms are, at least partly, under posttranscriptional control. The distinctive mode of expression of M-VSG genes may be due to a stochastic mechanism for metacyclic VSG activation.

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Vos, G. J., and P. R. Gardiner. "Parasite-specific antibody reponses of responses of ruminants infected withTrypanosoma vivax." Parasitology 100, no. 1 (February 1990): 93–100. http://dx.doi.org/10.1017/s0031182000060157.

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SummarySera from goats and cattle that were infected with twoTrypanosoma vivaxclones (ILDat 1.2 and ILDat 2.1) derived from different stocks were analysed for antibody activity against the variable surface glycoproteins (VSGs) of the infecting clones by enzyme-linked immune assays (ELISA) and immune lysis. To obtain purified VSG, lysed trypanosomes were separated on dodecyl sulphate-polyacrylamide gels. The gels were copper stained and the VSG protein band was excised from the gel. After destaining, the proteins were electroeluted from the gel slices and used as antigens in ELISA. High titres of IgM and IgG1antibodies and lytic antibodies against the VSG of the infecting clone were detected. The IgG1response appeared about 4 days later than the IgM response. IgG2antibodies were only detected in goats and cattle that were infected with ILDat 1.2. Two goats and two calves that were infected with ILDat 1.2 showed recurrent peaks in lytic activity and of IgM and IgG1antibody activity to the VSG of the infecting variable antigenic type (VAT). Two goats that were infected with ILDat 2.1 showed a similar pattern, but in two other goats there was a recurrent peak only in the IgM class. Recurrent peaks of antibody activity to the VSG of ILDat 1.2 and ILDat 2.1 were not detected in the sera of goats that had been inoculated with irradiated trypanosomes or that had been infected with an unrelatedT. vivaxclone. The recurrence of antibody peaks against the VSG of infecting VATs suggests that trypanosomes with completely or partially identical surface determinants reappear duringT. vivaxinfection of ruminants.

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Berger, B. J., and A. H. Fairlamb. "Interactions between immunity and chemotherapy in the treatment of the trypanosomiases and leishmaniases." Parasitology 105, S1 (January 1992): S71—S78. http://dx.doi.org/10.1017/s0031182000075375.

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SUMMARYThe immune status of a host infected withTrypanosomaspp. orLeishmaniaspp. can play an important role in successful chemotherapy. In animal models, treatment of African trypanosomiasis with difluoromethylornithine or melarsoprol requires an appropriate antibody-mediated immune response. An intact immune system is also necessary for rapid clearance of trypanosomes from the bloodstream following treatment with suramin or quinapyramine. Similarly, an efficient cell-mediated immune response is required for maximal efficacy of pentavalent antimonials in the treatment of leishmaniasis. However, the potential relationship between parasite-induced or acquired immunosuppression and effective chemotherapy has been poorly studied. Macrophages which have been activated by bacterial cell wall components or gamma-interferon are known to display increased activity againstLeishmania donovaniorTrypanosoma cruzi. In experimental and clinical visceral leishmaniasis, use of macrophage activators together with pentavalent antimonials has lowered the dose of antimony required to cure the infection.

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Landeira, David, Jean-Mathieu Bart, Daria Van Tyne, and Miguel Navarro. "Cohesin regulates VSG monoallelic expression in trypanosomes." Journal of Cell Biology 186, no. 2 (July 27, 2009): 243–54. http://dx.doi.org/10.1083/jcb.200902119.

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Antigenic variation allows Trypanosoma brucei to evade the host immune response by switching the expression of 1 out of ∼15 telomeric variant surface glycoprotein (VSG) expression sites (ESs). VSG ES transcription is mediated by RNA polymerase I in a discrete nuclear site named the ES body (ESB). However, nothing is known about how the monoallelic VSG ES transcriptional state is maintained over generations. In this study, we show that during S and G2 phases and early mitosis, the active VSG ES locus remains associated with the single ESB and exhibits a delay in the separation of sister chromatids relative to control loci. This delay is dependent on the cohesin complex, as partial knockdown of cohesin subunits resulted in premature separation of sister chromatids of the active VSG ES. Cohesin depletion also prompted transcriptional switching from the active to previously inactive VSG ESs. Thus, in addition to maintaining sister chromatid cohesion during mitosis, the cohesin complex plays an essential role in the correct epigenetic inheritance of the active transcriptional VSG ES state.

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Lorger, Mihaela, Markus Engstler, Matthias Homann, and H. Ulrich Göringer. "Targeting the Variable Surface of African Trypanosomes with Variant Surface Glycoprotein-Specific, Serum-Stable RNA Aptamers." Eukaryotic Cell 2, no. 1 (February 2003): 84–94. http://dx.doi.org/10.1128/ec.2.1.84-94.2003.

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ABSTRACT African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.

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OVERATH, P., J. HAAG, M. G. MAMEZA, and A. LISCHKE. "Freshwater fish trypanosomes: definition of two types, host control by antibodies and lack of antigenic variation." Parasitology 119, no. 6 (December 1999): 591–601. http://dx.doi.org/10.1017/s0031182099005089.

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Haemoflagellates of the genus Trypanosoma are prevalent in freshwater fishes and are transmitted by leeches as vectors. As demonstrated by sequence comparisons of nuclear small subunit rRNA genes, trypanosomes isolated from several fish species at different localities can be divided into at least 2 closely related types, designated Type A and Type B. A clone derived from a Type A isolate from carp (Cyprinus carpio) was used to study the anti-parasite immune response in specified pathogen-free outbred carp. Infection leads to an initial rise in parasitaemia in the blood followed by a sharp decline in all fish (acute phase). Thereafter, in some carp, parasites become undetectable both in the blood and in internal organs while, in others, low numbers can be found in the blood for up to 1 year (chronic phase). Fish that have controlled an acute infection with the clone are not only protected against an homologous challenge infection, but also against the infection with parasite lines derived from carp in the chronic phase of infection. Passive immunization experiments with IgM purified from serum of recovered carp indicate that the infection is controlled by antibodies. The anti-parasite antibody level in recovered carp remains high for many months although the parasitaemia is controlled at very low levels and the half life of IgM, t1/2=22·5 days, is comparatively short. The effective control of trypanosomes in laboratory infections is in contrast to the high prevalence in natural and farmed freshwater fish populations.

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SEED, JOHN RICHARD, and JOHN B. SECHELSKI. "Immune response to minor variant antigen types (VATs) in a mixed VAT infection of the African trypanosomes." Parasite Immunology 10, no. 5 (September 1988): 569–79. http://dx.doi.org/10.1111/j.1365-3024.1988.tb00244.x.

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CLAES, F., E. C. AGBO, M. RADWANSKA, M. F. W. TE PAS, T. BALTZ, D. T. DE WAAL, B. M. GODDEERIS, E. CLAASSEN, and P. BÜSCHER. "How does Trypanosoma equiperdum fit into the Trypanozoon group? A cluster analysis by RAPD and Multiplex-endonuclease genotyping approach." Parasitology 126, no. 5 (May 2003): 425–31. http://dx.doi.org/10.1017/s0031182003002968.

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The pathogenic trypanosomes Trypanosoma equiperdum, T. evansi as well as T. brucei are morphologically identical. In horses, these parasites are considered to cause respectively dourine, surra and nagana. Previous molecular attempts to differentiate these species were not successful for T. evansi and T. equiperdum; only T. b. brucei could be differentiated to a certain extent. In this study we analysed 10 T. equiperdum, 8 T. evansi and 4 T. b. brucei using Random Amplified Polymorphic DNA (RAPD) and multiplex-endonuclease fingerprinting, a modified AFLP technique. The results obtained confirm the homogeneity of the T. evansi group tested. The T. b. brucei clustered out in a heterogenous group. For T. equiperdum the situation is more complex: 8 out of 10 T. equiperdum clustered together with the T. evansi group, while 2 T. equiperdum strains were more related to T. b. brucei. Hence, 2 hypotheses can be formulated: (1) only 2 T. equiperdum strains are genuine T. equiperdum causing dourine; all other T. equiperdum strains actually are T. evansi causing surra or (2) T. equiperdum does not exist at all. In that case, the different clinical outcome of horse infections with T. evansi or T. b. brucei is primarily related to the host immune response.

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Radwanska, Magdalena, Stefan Magez, Alain Michel, Benoît Stijlemans, Maurice Geuskens, and Etienne Pays. "Comparative Analysis of Antibody Responses against HSP60, Invariant Surface Glycoprotein 70, and Variant Surface Glycoprotein Reveals a Complex Antigen-Specific Pattern of Immunoglobulin Isotype Switching during Infection byTrypanosoma brucei." Infection and Immunity 68, no. 2 (February 1, 2000): 848–60. http://dx.doi.org/10.1128/iai.68.2.848-860.2000.

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ABSTRACT During Trypanosoma brucei infections, the response against the variant surface glycoprotein (VSG) of the parasite represents a major interaction between the mammalian host immune system and the parasite surface. Since immune recognition of other parasite derived factors also occurs, we examined the humoral host response against trypanosome heat shock protein 60 (HSP60), a conserved antigen with an autoimmune character. During experimental T. bruceiinfection in BALB/c mice, the anti-HSP60 response was induced when parasites differentiated into stumpy forms. This response was characterized by a stage-specific immunoglobulin isotype switching as well as by the induction of an autoimmune response. Specific recognition of trypanosome HSP60 was found to occur during the entire course of infection. Immunoglobulin G2a (IgG2a) and IgG2b antibodies, induced mainly in a T-cell-independent manner, were observed during the first peak of parasitemia, whereas IgG1 and IgG3 antibodies were found at the end of the infection, due to a specific T-cell-mediated response. Comparative analysis of the kinetics of anti-HSP60, anti-invariant surface glycoprotein 70 (ISG70), and anti-VSG antibody responses indicated that the three trypanosome antigens give rise to specific and independent patterns of immunoglobulin isotype switching.

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BLACK, S. J., P. GUIRNALDA, D. FRENKEL, C. HAYNES, and V. BOCKSTAL. "Induction and regulation ofTrypanosoma bruceiVSG-specific antibody responses." Parasitology 137, no. 14 (December 22, 2009): 2041–49. http://dx.doi.org/10.1017/s003118200999165x.

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SUMMARYThe review addresses how infection withTrypanosoma bruceiaffects the development, survival and functions of B lymphocytes in mice. It discusses (1) the contributions of antibodies to trypanosome clearance from the bloodstream, (2) how B lymphocytes, the precursors of antibody producing plasma cells, interact with membrane form variable surface glycoprotein (VSG), i.e. with monovalent antigen that is free to diffuse within the lipid bilayer of the trypanosome plasma membrane and consequently can cross-link B cell antigen specific receptors by indirect processes only and (3) the extent and underlying causes of dysregulation of humoral immune responses in infected mice, focusing on the impact of wild type and GPI-PLC−/−trypanosomes on bone marrow and extramedullary B lymphopoiesis, B cell maturation and survival.

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Naguleswaran, Arunasalam, Paula Fernandes, Shubha Bevkal, Ruth Rehmann, Pamela Nicholson, and Isabel Roditi. "Developmental changes and metabolic reprogramming during establishment of infection and progression of Trypanosoma brucei brucei through its insect host." PLOS Neglected Tropical Diseases 15, no. 9 (September 20, 2021): e0009504. http://dx.doi.org/10.1371/journal.pntd.0009504.

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Trypanosoma brucei ssp., unicellular parasites causing human and animal trypanosomiasis, are transmitted between mammals by tsetse flies. Periodic changes in variant surface glycoproteins (VSG), which form the parasite coat in the mammal, allow them to evade the host immune response. Different isolates of T. brucei show heterogeneity in their repertoires of VSG genes and have single nucleotide polymorphisms and indels that can impact on genome editing. T. brucei brucei EATRO1125 (AnTaR1 serodeme) is an isolate that is used increasingly often because it is pleomorphic in mammals and fly transmissible, two characteristics that have been lost by the most commonly used laboratory stocks. We present a genome assembly of EATRO1125, including contigs for the intermediate chromosomes and minichromosomes that serve as repositories of VSG genes. In addition, de novo transcriptome assemblies were performed using Illumina sequences from tsetse-derived trypanosomes. Reads of 150 bases enabled closely related members of multigene families to be discriminated. This revealed that the transcriptome of midgut-derived parasites is dynamic, starting with the expression of high affinity hexose transporters and glycolytic enzymes and then switching to proline uptake and catabolism. These changes resemble the transition from early to late procyclic forms in culture. Further metabolic reprogramming, including upregulation of tricarboxylic acid cycle enzymes, occurs in the proventriculus. Many transcripts upregulated in the salivary glands encode surface proteins, among them 7 metacyclic VSGs, multiple BARPs and GCS1/HAP2, a marker for gametes. A novel family of transmembrane proteins, containing polythreonine stretches that are predicted to be O-glycosylation sites, was also identified. Finally, RNA-Seq data were used to create an optimised annotation file with 5’ and 3’ untranslated regions accurately mapped for 9302 genes. We anticipate that this will be of use in identifying transcripts obtained by single cell sequencing technologies.

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Kalantar, Kurosh, Raúl Manzano-Román, Esmaeel Ghani, Reza Mansouri, Gholamreza Hatam, Paul Nguewa, and Sajad Rashidi. "Leishmanial apolipoprotein A-I expression: a possible strategy used by the parasite to evade the host’s immune response." Future Microbiology 16, no. 8 (May 2021): 607–13. http://dx.doi.org/10.2217/fmb-2020-0303.

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Apolipoprotein A-I (apo A-I) represents the main component of the Trypanosome lytic factor (TLF) which contributes to the host innate immunity against Trypanosoma and Leishmania. These parasites use complex and multiple strategies such as molecular mimicry to evade or subvert the host immune system. Previous studies have highlighted the adaptation mechanisms of TLF-resistant Trypanosoma species. These data might support the hypothesis that Leishmania parasites (amastigote forms in macrophages) might express apo A-I to bypass and escape from TLF action as a component of the host innate immune responses. The anti-inflammatory property of apo A-I is another mechanism that supports our idea that apo A-I may play a role in Leishmania parasites allowing them to bypass the host innate immune system.

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Harris, Tajie H., Nicole M. Cooney, John M. Mansfield, and Donna M. Paulnock. "Signal Transduction, Gene Transcription, and Cytokine Production Triggered in Macrophages by Exposure to Trypanosome DNA." Infection and Immunity 74, no. 8 (August 2006): 4530–37. http://dx.doi.org/10.1128/iai.01938-05.

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ABSTRACT Activation of a type I cytokine response is important for early resistance to infection with Trypanosoma brucei rhodesiense, the extracellular protozoan parasite that causes African sleeping sickness. The work presented here demonstrates that trypanosome DNA activates macrophages to produce factors that may contribute to this response. Initial results demonstrated that T. brucei rhodesiense DNA was present in the plasma of C57BL/6 and C57BL/6-scid mice following infection. Subsequently, the effect of trypanosome DNA on macrophages was investigated; parasite DNA was found to be less stimulatory than Escherichia coli DNA but more stimulatory than murine DNA, as predicted by the CG dinucleotide content. Trypanosome DNA stimulated the induction of a signal transduction cascade associated with Toll-like receptor signaling in RAW 264.7 macrophage cells. The signaling cascade led to expression of mRNAs, including interleukin-12 (IL-12) p40, IL-6, IL-10, cyclooxygenase-2, and beta interferon. The treatment of RAW 264.7 cells and bone marrow-derived macrophages with trypanosome DNA induced the production of NO, prostaglandin E2, and the cytokines IL-6, IL-10, IL-12, and tumor necrosis factor alpha. In all cases, DNase I treatment of T. brucei rhodesisense DNA abolished the activation. These results suggest that T. brucei rhodesiense DNA serves as a ligand for innate immune cells and may play an important contributory role in early stimulation of the host immune response during trypanosomiasis.

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Murray, M., H. Hirumi, and S. K. Moloo. "Suppression of Trypanosoma congolense, T. vivax and T. brucei infection rates in tsetse flies maintained on goats immunized with uncoated forms of trypanosomes grown in vitro." Parasitology 91, no. 1 (August 1985): 53–66. http://dx.doi.org/10.1017/s0031182000056511.

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Significant suppression in the incidence of cyclical development of Trypanosonia congolense, T. vivax and T. brucei occurred in Glossina morsitans centralis maintained on goats immunized with in vitro-propagated uncoated forms of T. congolense, T. vivax and T. brucei, respectively. This was observed when tsetse given a T. congolense-infected feed were subsequently maintained on uninfected immunized goats and also when uninfected tsetse were fed on immunized goats infected with T. congolense, T. vivax and T. brucei. Suppression of infection rates in tsetse was trypanosome species specific, but was independent of the trypanosome stock used for immunization of goats. These findings were reflected in antibody responses to uncoated trypanosomes, as measured by immunofluorescence and the solid-phase immuno radiometric binding assay. Thus, antibody from goats immunized with uncoated trypano somes of one species exhibited minimal reactivity with uncoated forms of other species of trypanosomes, but showed high levels of activity with uncoated forms of the same or unrelated stocks of the same species. However, in view of the range of hosts upon which tsetse feed, it is open to question whether the use of a vaccine which suppresses trypanosome infection rates in tsetse would have any significant effect in the field.

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Frasch, A. C. C. "Trans-sialidase, SAPA amino acid repeats and the relationship betweenTrypanosoma cruziand the mammalian host." Parasitology 108, S1 (March 1994): S37—S44. http://dx.doi.org/10.1017/s0031182000075703.

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SUMMARYDuring invasion of multicellular organisms, protozoan parasites expose functional molecules that become targets for the host immune response. Recent research onTrypanosoma cruzi, the agent of Chagas' disease, suggests a new model of how the parasite might deal with this problem. Several antigens ofT. cruzihave tandemly repeated amino acid motifs in molecules with as yet unknown functions. In two cases, these repeats are in molecules with a defined structure or function. Both proteins are implicated in the invasion of host-cells by the parasite. One of these is the core protein of a putative mucin-like glycoprotein that has Thr/Pro–rich repeats which, by themselves, might define the structure of a highlyO-glycosylated molecule. The other protein is SAPA/trans-sialidase/neuraminidase, a molecule able to transfer sialic acid, that has so far only been described in trypanosomes. The amino acid repeats present in SAPA/trans-sialidase/neuraminidase are unrelated to the enzymic activity and constitute an immunodominant C–terminal domain. The N–terminal domain of SAPA/trans-sialidase/neuraminidase controls the enzymic activity since a recombinant molecule lacking the repeats conserves trans-sialidase activity. That both domains are functionally independent is also indicated by experiments that show that antibodies directed against the amino acid repeats are unable to inhibit trans-sialidase activity. A large number of proteins having trans-sialidase related sequences but lacking enzymic activity are also present in the surface membrane of the parasite. The immunodominant SAPA/trans-sialidase/neuraminidase repeats, together with the complex network of cross-reacting epitopes present in related but enzymically inactive proteins might contribute to the delay in mounting an effective antibody response. However, antibodies neutralizing trans-sialidase activity are generated later during the infection. These antibody specificities are directed to the enzymic domain of the molecule and might contribute to the control of parasite dissemination after the early period of the infection.

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Namangala, Boniface, Chihiro Sugimoto, and Noboru Inoue. "Effects of Exogenous Transforming Growth Factor β on Trypanosoma congolense Infection in Mice." Infection and Immunity 75, no. 4 (January 29, 2007): 1878–85. http://dx.doi.org/10.1128/iai.01452-06.

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ABSTRACT The socioeconomic implications of trypanosomosis in sub-Saharan Africa and the limitations of its current control regimes have stimulated research into alternative control methods. Considering the pro- and anti-inflammatory properties of transforming growth factor β1 (TGF-β1) and its potential to enhance immunity against protozoan parasites, we examined the effects of intraperitoneally delivered TGF-β1 in C57BL/6 mice infected with Trypanosoma congolense, the hemoprotozoan parasite causing nagana in cattle. A triple dose of 10 ng TGF-β1 significantly reduced the first parasitemic peak and delayed mortality of infected mice. Furthermore, exogenous TGF-β1 significantly decreased the development of trypanosome-induced anemia and splenomegaly. The apparent TGF-β1-induced antitrypanosome protection, occurring mainly during the early stage of infection, correlated with an enhanced parasite antigen-specific Th1 cell response characterized by a skewed type I cytokine response and a concomitant stronger antitrypanosome immunoglobulin G2a antibody response. Infected TGF-β1-pretreated mice exhibited a significant reduction in the trypanosome-induced hyperexpansion of B cells. Furthermore, evidence is provided herein that exogenous TGF-β1 activates macrophages that may contribute to parasite control. Collectively, these data indicate that exogenous TGF-β1 is immunostimulative, inducing partial protection against T. congolense infection, possibly through mechanisms involving innate immune responses.

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YANG, HYUN MO. "A MATHEMATICAL MODEL TO ASSESS THE IMMUNE RESPONSE AGAINSTTRYPANOSOMA CRUZIINFECTION." Journal of Biological Systems 23, no. 01 (March 2015): 131–63. http://dx.doi.org/10.1142/s0218339015500084.

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A mathematical model is developed to assess humoral and cellular immune responses against Trypanosoma cruzi infection. Analysis of the model shows a unique non-trivial equilibrium, which is locally asymptotically stable, except in the case of a strong cellular response. When the proliferation of the activated CD8 T cells is increased, this equilibrium becomes unstable and a limit cycle appears. However, this behavior can be avoided by increasing the action of the humoral response. Therefore, unbalanced humoral and cellular responses can be responsible for long asymptomatic period, and the control of Trypanosoma cruzi infection is a consequence of well coordinated action of both humoral and cellular responses.

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Morrison, Liam J., Sarah McLellan, Lindsay Sweeney, Chi N. Chan, Annette MacLeod, Andy Tait, and C. Michael R. Turner. "Role for Parasite Genetic Diversity in Differential Host Responses to Trypanosoma brucei Infection." Infection and Immunity 78, no. 3 (January 19, 2010): 1096–108. http://dx.doi.org/10.1128/iai.00943-09.

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ABSTRACT The postgenomic era has revolutionized approaches to defining host-pathogen interactions and the investigation of the influence of genetic variation in either protagonist upon infection outcome. We analyzed pathology induced by infection with two genetically distinct Trypanosoma brucei strains and found that pathogenesis is partly strain specific, involving distinct host mechanisms. Infections of BALB/c mice with one strain (927) resulted in more severe anemia and greater erythropoietin production compared to infections with the second strain (247), which, contrastingly, produced greater splenomegaly and reticulocytosis. Plasma interleukin-10 (IL-10) and gamma interferon levels were significantly higher in strain 927-infected mice, whereas IL-12 was higher in strain 247-infected mice. To define mechanisms underlying these differences, expression microarray analysis of host genes in the spleen at day 10 postinfection was undertaken. Rank product analysis (RPA) showed that 40% of the significantly differentially expressed genes were specific to infection with one or the other trypanosome strain. RPA and pathway analysis identified LXR/RXR signaling, IL-10 signaling, and alternative macrophage activation as the most significantly differentially activated host processes. These data suggest that innate immune response modulation is a key determinant in trypanosome infections, the pattern of which can vary, dependent upon the trypanosome strain. This strongly suggests that a parasite genetic component is responsible for causing disease in the host. Our understanding of trypanosome infections is largely based on studies involving single parasite strains, and our results suggest that an integrated host-parasite approach is required for future studies on trypanosome pathogenesis. Furthermore, it is necessary to incorporate parasite variation into both experimental systems and models of pathogenesis.

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Madison, M. Nia, Yuliya Y. Kleshchenko, Pius N. Nde, Kaneatra J. Simmons, Maria F. Lima, and Fernando Villalta. "Human Defensin α-1 Causes Trypanosoma cruzi Membrane Pore Formation and Induces DNA Fragmentation, Which Leads to Trypanosome Destruction." Infection and Immunity 75, no. 10 (July 16, 2007): 4780–91. http://dx.doi.org/10.1128/iai.00557-07.

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ABSTRACT Human defensins play a fundamental role in the initiation of innate immune responses to some microbial pathogens. Here we show that human defensin α-1 displays a trypanocidal role against Trypanosoma cruzi, the causative agent of Chagas' disease. The toxicity of human defensin α-1 against T. cruzi is mediated by membrane pore formation and the induction of nuclear and mitochondrial DNA fragmentation, leading to trypanosome destruction. Exposure of trypomastigote and amastigote forms of T. cruzi to defensin α-1 significantly reduced parasite viability in a peptide concentration-dependent and saturable manner. The toxicity of defensin α-1 against T. cruzi is blocked by anti-defensin α-1 immunoglobulin G. Electron microscopic analysis of trypomastigotes exposed to defensin α-1 revealed pore formation in the cellular and flagellar membranes, membrane disorganization, and blebbing as well as cytoplasmic vacuolization. Furthermore, human defensin α-1 enters the trypanosome when membrane pores are present and is associated with later intracellular damage. Trypanosome membrane depolarization abolished the toxicity of defensin α-1 against the parasite. Preincubation of trypomastigotes with defensin α-1 followed by exposure to human epithelial cells significantly reduced T. cruzi infection in these cells. Thus, human defensin α-1 is an innate immune molecule that causes severe toxicity to T. cruzi and plays an important role in reducing cellular infection. This is the first report showing that human defensin α-1 causes membrane pore formation in a human parasite, leading to trypanosome destruction.

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Johnson, Candice A., Girish Rachakonda, Yuliya Y. Kleshchenko, Pius N. Nde, M. Nia Madison, Siddharth Pratap, Tatiana C. Cardenas, Chase Taylor, Maria F. Lima, and Fernando Villalta. "Cellular Response to Trypanosoma cruzi Infection Induces Secretion of Defensin α-1, Which Damages the Flagellum, Neutralizes Trypanosome Motility, and Inhibits Infection." Infection and Immunity 81, no. 11 (August 26, 2013): 4139–48. http://dx.doi.org/10.1128/iai.01459-12.

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ABSTRACTHuman defensins play a fundamental role in the initiation of innate immune responses to some microbial pathogens. Here we show that colonic epithelial model HCT116 cells respond toTrypanosoma cruziinfection by secreting defensin α-1, which reduces infection. We also report the early effects of defensin α-1 on invasive trypomastigotes that involve damage of the flagellar structure to inhibit parasite motility and reduce cellular infection. Short exposure of defensin α-1 to trypomastigotes shows that defensin α-1 binds to the flagellum, resulting in flagellar membrane and axoneme alterations, followed by breaking of the flagellar membrane connected to the trypanosome body, leading to detachment and release of the parasite flagellum. In addition, defensin α-1 induces a significant reduction in parasite motility in a peptide concentration-dependent manner, which is abrogated by anti-defensin α-1 IgG. Preincubation of trypomastigotes with a concentration of defensin α-1 that inhibits 50% trypanosome motility significantly reduced cellular infection by 80%. Thus, human defensin α-1 is an innate immune molecule that is secreted by HCT116 cells in response toT. cruziinfection, inhibitsT. cruzimotility, and plays an important role in reducing cellular infection. This is the first report showing a novel cellular innate immune response to a human parasite by secretion of defensin α-1, which neutralizes the motility of a human parasite to reduce cellular infection. The mode of activity of human defensin α-1 againstT. cruziand its function may provide insights for the development of new antiparasitic strategies.

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Alvarenga, Nelson J., Elisabeth Bronfen, Alessandra L. A. Botelho, Lilian M. G. Bahia-Oliveira, Juliana A. S. Gomes, Rodrigo Correa-Oliveira, and Maria José F. Morato. "Human immune response to triatomine embryo extract." Revista da Sociedade Brasileira de Medicina Tropical 30, no. 1 (February 1997): 73–74. http://dx.doi.org/10.1590/s0037-86821997000100015.

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Dipetalogaster maximus embryo extracts were used to stimulate peripheral blood mononuclear cells (PBMC) and in ELISA with sera either from Trypanosoma cruzi infected or non-infected individuals. The results showed that there was significant proliferative response and high antibody titers in sera of chagasic patients.

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Arsic-Arsenijevic, Valentina, Aleksandar Dzamic, Sanja Mitrovic, Ivana Radonjic, and Ivana Kranjcic-Zec. "Characteristics of immune response to protozoan infections." Medical review 56, no. 11-12 (2003): 557–63. http://dx.doi.org/10.2298/mpns0312557a.

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Introduction When protozoa enter the blood stream or tissues they can often survive and replicate because they adapt to the resisting natural host defenses. The interaction of immune system with infectious organisms is a dynamic interplay of host mechanisms aimed at eliminating infections and microbial strategies designed to permit survival in the face of powerful effectors mechanisms. Protozoa cause chronic and persistent infections, because natural immunity against them is weak and because protozoa have evolved multiple mechanisms for evading and resisting specific immunity. Natural and specific immune response to protozoa Different protozoa vary greatly in their structural and biochemical properties and stimulate distinct patterns of immune responses and have evolved unique mechanisms for evading specific immunity. Protozoa activate quite distinct specific immune responses, which are different from the responses to fungi, bacteria and viruses. Protozoa may be phagocytozed by macrophages, but many are resistant to phagocytic killing and may even replicate within macrophages. T. brucei gambiense is the best example of protozoa which can induce humoral immune response because of its extra-cellular location. In Leishmania sp. infections, cellular defense mechanisms depend upon CD4+ T-lymphocytes and activate macrophages as effectors cells that are regulated by cytokines of Th1 subset. Plasmodium sp. is a protozoa which show the diversity of defence mechanisms which can be cellular or humoral, depending on Ag and protozoa's location. Immune evasion mechanisms of protozoa Different protozoa have developed remarkably effective ways of resisting specific immunity: a) anatomic sequestration is commonly observed with protozoa Plasmodium and T. gondii; b) some protozoa can become resistant to immune effectors mechanisms: Trypanosoma, Leishmania and T. gondii; c) some protozoa have developed effective mechanisms for varying their surface antigens: Plasmodium and Trypanosoma; d) some protozoa shed their antigen coats, either spontaneously or after binding with specific antibodies: E. histolytica; e) some protozoa alter host immune response by nonspecific and generalized immunosuppression (abnormalities in cytokine production, deficient T cell activation): Trypanosoma, Leishmania, Toxoplasma, Entamoeba. Conclusion Protozoa activate numerous, different immune mechanisms in human body. Evolution, progression and outcome of diseases depend upon these mechanisms. Resent progresses in research have defined and selected Ag as candidates for new vaccines. Better definitions regarding the role of cytokines in protozoaninfections will facilitate rational development of cytokines and cytokine antagonists and their use as immunotherapeutic agents.

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Basso, Beatriz, Elsa Vottero-Cima, and Edgardo R. A. Moretti. "Immune Response and Trypanosoma Cruzi Infection in Trypanosoma Rangeli-Immunized Mice." American Journal of Tropical Medicine and Hygiene 44, no. 4 (April 1, 1991): 413–19. http://dx.doi.org/10.4269/ajtmh.1991.44.413.

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Dias-Guerreiro, Tatiana, Joana Palma-Marques, Patrícia Mourata-Gonçalves, Graça Alexandre-Pires, Ana Valério-Bolas, Áurea Gabriel, Telmo Nunes, et al. "African Trypanosomiasis: Extracellular Vesicles Shed by Trypanosoma brucei brucei Manipulate Host Mononuclear Cells." Biomedicines 9, no. 8 (August 20, 2021): 1056. http://dx.doi.org/10.3390/biomedicines9081056.

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African trypanosomiasis or sleeping sickness is a zoonotic disease caused by Trypanosoma brucei, a protozoan parasite transmitted by Glossina spp. (tsetse fly). Parasite introduction into mammal hosts triggers a succession of events, involving both innate and adaptive immunity. Macrophages (MΦ) have a key role in innate defence since they are antigen-presenting cells and have a microbicidal function essential for trypanosome clearance. Adaptive immune defence is carried out by lymphocytes, especially by T cells that promote an integrated immune response. Like mammal cells, T. b. brucei parasites release extracellular vesicles (TbEVs), which carry macromolecules that can be transferred to host cells, transmitting biological information able to manipulate cell immune response. However, the exact role of TbEVs in host immune response remains poorly understood. Thus, the current study examined the effect elicited by TbEVs on MΦ and T lymphocytes. A combined approach of microscopy, nanoparticle tracking analysis, multiparametric flow cytometry, colourimetric assays and detailed statistical analyses were used to evaluate the influence of TbEVs in mouse mononuclear cells. It was shown that TbEVs can establish direct communication with cells of innate and adaptative immunity. TbEVs induce the differentiation of both M1- and M2-MΦ and elicit the expansion of MHCI+, MHCII+ and MHCI+MHCII+ MΦ subpopulations. In T lymphocytes, TbEVs drive the overexpression of cell-surface CD3 and the nuclear factor FoxP3, which lead to the differentiation of regulatory CD4+ and CD8+ T cells. Moreover, this study indicates that T. b. brucei and TbEVs seem to display opposite but complementary effects in the host, establishing a balance between parasite growth and controlled immune response, at least during the early phase of infection.

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Kayama, Hisako, and Kiyoshi Takeda. "The innate immune response to Trypanosoma cruzi infection." Microbes and Infection 12, no. 7 (July 2010): 511–17. http://dx.doi.org/10.1016/j.micinf.2010.03.005.

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Ongele, E., M. Ashraf, R. Nesbitt, P. Humphrey, and C. Lee. "Effects of selenium deficiency in the development of trypanosomes and humoral immune responses in mice infected with Trypanosoma musculi." Parasitology Research 88, no. 6 (March 16, 2002): 540–45. http://dx.doi.org/10.1007/s00436-002-0617-4.

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Acuña, Stephanie Maia, Lucile Maria Floeter-Winter, and Sandra Marcia Muxel. "MicroRNAs: Biological Regulators in Pathogen–Host Interactions." Cells 9, no. 1 (January 2, 2020): 113. http://dx.doi.org/10.3390/cells9010113.

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An inflammatory response is essential for combating invading pathogens. Several effector components, as well as immune cell populations, are involved in mounting an immune response, thereby destroying pathogenic organisms such as bacteria, fungi, viruses, and parasites. In the past decade, microRNAs (miRNAs), a group of noncoding small RNAs, have emerged as functionally significant regulatory molecules with the significant capability of fine-tuning biological processes. The important role of miRNAs in inflammation and immune responses is highlighted by studies in which the regulation of miRNAs in the host was shown to be related to infectious diseases and associated with the eradication or susceptibility of the infection. Here, we review the biological aspects of microRNAs, focusing on their roles as regulators of gene expression during pathogen–host interactions and their implications in the immune response against Leishmania, Trypanosoma, Toxoplasma, and Plasmodium infectious diseases.

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Taylor, K. "Immune responses of cattle to African trypanosomes: protective or pathogenic?" International Journal for Parasitology 28, no. 2 (February 1998): 219–40. http://dx.doi.org/10.1016/s0020-7519(97)00154-9.

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Frare, Eduardo Osório, Fabricia Helena Santello, Leony Cristina Caetano, Jerri C. Caldeira, Míriam Paula Alonso Toldo, and José Clóvis do Prado. "Growth hormones therapy in immune response against Trypanosoma cruzi." Research in Veterinary Science 88, no. 2 (April 2010): 273–78. http://dx.doi.org/10.1016/j.rvsc.2009.10.001.

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Pereira, Valéria Rêgo Alves, Virginia Maria Barros de Lorena, Mineo Nakazawa, Ana Paula Galvão da Silva, Ulisses Montarroyos, Rodrigo Correa-Oliveira, and Yara de Miranda Gomes. "Evaluation of the immune response to CRA and FRA recombinant antigens of Trypanosoma cruzi in C57BL/6 mice." Revista da Sociedade Brasileira de Medicina Tropical 36, no. 4 (July 2003): 435–40. http://dx.doi.org/10.1590/s0037-86822003000400001.

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Humoral and cellular immune responses were evaluated in 44 C57BL/6 mice immunized with the Trypanosoma cruzi recombinant antigens CRA and FRA. Both antigens induced cutaneous immediate-type hypersensitivity response. The levels of IgG1, IgG2a, IgG2b and IgG3 were high in CRA immunized mice. IgG3 was the predominant isotype. Although no difference in antibody levels was observed in FRA-immunized mice when compared to control mice, both antigens were able to induce lymphoproliferation in immunized mice. Significant differences were observed between incorporation of [³H]- thymidine by spleen cell stimulated in vitro with CRA or FRA and the control group. These results suggest that CRA and FRA could be involved in mechanisms of resistance to Trypanosoma cruzi infection.

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Duthie, Malcolm S., Maria Kahn, Arsen Zakayan, Maria White, and Stuart J. Kahn. "Parasite-Induced Chronic Inflammation Is Not Exacerbated by Immunotherapy before or during Trypanosoma cruzi Infection." Clinical and Vaccine Immunology 14, no. 8 (May 30, 2007): 1005–12. http://dx.doi.org/10.1128/cvi.00087-07.

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ABSTRACT Trypanosoma cruzi infection causes Chagas' disease, a chronic inflammatory disease. The specific inflammatory responses that cause Chagas' disease remain unclear, but data argue that parasites that persist in the host stimulate chronic self-damaging immune responses. Because T. cruzi appears to stimulate self-damaging responses, the enthusiasm to develop vaccines that boost antiparasite responses that might increase self-damaging responses has been limited. We previously demonstrated that immunization with a T. cruzi trans-sialidase protein or adoptive transfer of trans-sialidase-specific T-cell clones decreased parasitemia, morbidity, and mortality. Here we report that immunization or adoptive transfer with the protein or clones, before or during T. cruzi infection, boosts the anti-T. cruzi immune response without exacerbating acute or chronic tissue inflammation. These results argue that prophylactic and therapeutic immunotherapy for Chagas' disease can be developed safely.

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Lana, M., L. M. Vieira, G. L. L. Machado-Coelho, E. Chiari, V. M. Veloso, and W. L. Tafuri. "Humoral immune response in dogs experimentally infected with Trypanosoma cruzi." Memórias do Instituto Oswaldo Cruz 86, no. 4 (December 1991): 471–73. http://dx.doi.org/10.1590/s0074-02761991000400019.

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Kemmerling, Ulrike, Christian Castillo, Ana Liempi, Lisvaneth Medina, Ileana Carrillo, Daniel Droguett, Juan D. Maya, and Norbel Galanti. "The immune response against Trypanosoma cruzi in the human placenta." Emerging Topics in Life Sciences 1, no. 6 (December 22, 2017): 573–77. http://dx.doi.org/10.1042/etls20170115.

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Congenital Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is partially responsible for the increasing globalization of Chagas disease despite its low transmission. During congenital transmission, the parasite reaches the fetus by crossing the placental barrier. However, the success or impairment of congenital transmission of the parasite is the product of a complex interaction between the parasite, the maternal and fetus/newborn immune responses and placental factors. There is other evidence apart from the low congenital transmission rates, which suggests the presence of defense mechanisms against T. cruzi. Thus, the typical amastigote nests (intracellular parasites) cannot be observed in placentas from mothers with chronic Chagas disease nor in human placental chorionic villi explants infected in vitro with the parasite. In the latter, only a few parasite antigens and DNA are identified. Accordingly, other infections of the placenta are not commonly observed. All these evidences suggest that the placenta can mount defense mechanisms against T. cruzi.

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Journal articles on the topic 'Immune response/trypanosomes'

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