Variant Surface Glycoprotein gene repertoires in Trypanosoma brucei have diverged to become strain-specific

Hutchinson, O. Clyde; Picozzi, Kim; Jones, Nicholas Blurton; Mott, Helen R.; Sharma, R. S.; Welburn, Susan C.; Carrington, Mark

doi:10.1186/1471-2164-8-234

Cited by 46 publications

(48 citation statements)

References 37 publications

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“…1A) is present within internal amphipathic ␣-helices of the VSG homodimer; sequence variation in this subregion is predicted to be the result of selective pressure from T-cell responses to peptides generated by antigen processing and presentation (3,19). However, these predictions have not been tested experimentally, and the presence of such HV subregions is somewhat controversial since they do not seem to be conserved among different strains and isolates of Trypanosoma brucei (21,32,33). Sequence comparisons across VSG classes and types essentially revealed the presence of many microvariable sites rather than well-defined HV subregions (21,32).…”

mentioning

confidence: 99%

T-Cell Responses to the Trypanosome Variant Surface Glycoprotein Are Not Limited to Hypervariable Subregions

Dagenais¹,

Demick²,

Bangs

et al. 2009

Infect Immun

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Variable subregions within the variant surface glycoprotein (VSG) coat displayed by African trypanosomes are predicted sites for T-and B-cell recognition. Hypervariable subregion 1 (HV-1) is localized to an internal amphipathic alpha helix in VSG monomers and may have evolved due to selective pressure by host T-cell responses to epitopes within this subregion. The prediction of T-cell receptor-reactive sites and major histocompatibility complex class II binding motifs within the HV-1 subregion, coupled with the conservation of amino acid residues in other regions of the molecule sufficient to maintain secondary and tertiary VSG structure, prompted us to test the hypothesis that Th cells may preferentially recognize HV-1 subregion peptides. Thus, we examined the fine specificity of VSG-specific T-cell lines, T-cell hybridomas, and Th cells activated during infection. Our results demonstrate that T-cell epitopes are distributed throughout the N-terminal domain of VSG but are not clustered exclusively within HV-1 or other hypervariable subregions. In contrast, T-cell-reactive sites were not detected within the relatively conserved C-terminal domain of VSG. Overall, this study is the first to dissect the fine specificity of T-cell responses to the trypanosome VSG and suggests that evolution of a conserved HV-1 region may be unrelated to selective pressures exerted by host T-cell responses. This study also demonstrates that T cells do not recognize the relatively invariant C-terminal region of the VSG molecule during infection, suggesting that it could serve as a potential subunit vaccine to provide variant cross-specific immunity for African trypanosomiasis.The plasma membrane of African trypanosomes is covered by a dense surface coat comprised of variant surface glycoprotein (VSG) homodimers (4,(8)(9)(10)45). VSG molecules are immunodominant antigens that elicit B-and T-cell responses capable of providing temporal protection for the host during infection (15,20,26,40). B-cell responses directed at surfaceexposed determinants of VSG eliminate parasites from the bloodstream, whereas polarized VSG-specific Th1-cell responses contribute to the production of gamma interferon (IFN-␥), a critical component of relative host resistance that controls the parasite burden within extravascular tissues (17,20,31). However, trypanosomes repeatedly evade complete immune elimination by switching their VSG coats through a process of antigenic variation. Replacement of VSG coats with antigenically distinct surface coats permits trypanosomes to escape from existing B-and T-cell responses and requires the host to make new temporally protective responses throughout infection.VSGs are separated into different families based on N-terminal and C-terminal proteolytic domains, sequence homologies, and the number and distribution of cysteine residues (5). Alignment of different Trypanosoma brucei VSGs within class and type subgroups has demonstrated that the primary amino acid sequences of VSG N-terminal domains are extremely diverse. However...

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mentioning

confidence: 99%

T-Cell Responses to the Trypanosome Variant Surface Glycoprotein Are Not Limited to Hypervariable Subregions

Dagenais¹,

Demick²,

Bangs

et al. 2009

Infect Immun

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“…Superinfection has epidemiologic and pathogenic relevance for pathogens ranging from small-genome RNA viruses, such as human immunodeficiency virus and hepatitis C virus, to complex parasites, such as Trypanosoma brucei (1,10,12,20,24,37). The epidemiologic consequences of superinfection depend on the subsequent fitness of the two strains for onward transmission to a new host.…”

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confidence: 99%

Independence ofAnaplasma marginaleStrains with High and Low Transmission Efficiencies in the Tick Vector following Simultaneous Acquisition by Feeding on a Superinfected Mammalian Reservoir Host

et al. 2009

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Strain superinfection occurs when a second pathogen strain infects a host already carrying a primary strain. Anaplasma marginale superinfection occurs when the second strain carries a variant repertoire different from that of the primary strain, and the epidemiologic consequences depend on the relative efficiencies of tick-borne transmission of the two strains. Following strain superinfection in the reservoir host, we tested whether the presence of two A. marginale (sensu lato) strains that differed in transmission efficiency altered the transmission phenotypes in comparison to those for single-strain infections. Dermacentor andersoni ticks were fed on animals superinfected with the Anaplasma marginale subsp. centrale vaccine strain (low transmission efficiency) and the A. marginale St. Maries strain (high transmission efficiency). Within ticks that acquired both strains, the St. Maries strain had a competitive advantage and replicated to significantly higher levels than the vaccine strain. The St. Maries strain was subsequently transmitted to naïve hosts by ticks previously fed either on superinfected animals or on animals singly infected with the St. Maries strain, consistent with the predicted transmission phenotype of this strain and the lack of interference due to the presence of a competing low-efficiency strain. The vaccine strain was not transmitted by either singly infected or coinfected ticks, consistent with the predicted transmission phenotype and the lack of enhancement due to the presence of a high-efficiency strain. These results support the idea that the strain predominance in regions of endemicity is mediated by the intrinsic transmission efficiency of specific strains regardless of occurrence of superinfection.Strain superinfection occurs when a second pathogen strain infects a host already persistently infected with a primary strain. Superinfection has epidemiologic and pathogenic relevance for pathogens ranging from small-genome RNA viruses, such as human immunodeficiency virus and hepatitis C virus, to complex parasites, such as Trypanosoma brucei (1,10,12,20,24,37). The epidemiologic consequences of superinfection depend on the subsequent fitness of the two strains for onward transmission to a new host. We address this question by studying transmission of Anaplasma marginale, a tick-borne bacterial pathogen which establishes persistent infection in mammalian reservoir hosts (domestic and wild ruminants) (21) and for which the basis for strain superinfection has recently been reported (8).A. marginale strain superinfection occurs when the second strain carries a repertoire of the antigenically variable outer membrane protein (designated major surface protein-2 [Msp2]) different from that of the primary strain, allowing the second strain to escape the immune response generated against the primary strain (8, 25). Once superinfection is established, both strains are maintained in the host, which serves as the reservoir for subsequent tick acquisition and transmission (18). Whether and how patho...

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“…This trend of parasitaemia pattern in the donkeys, suggests trypanosomes ability to reside intermittently in intra-or extravascular fluids of the donkeys as reported by Sudarto et al thereby lowering parasitaemia in peripheral blood which made microscopic detection in later stage of infection difficult [35][36][37]. Trypanosomes also switch their surface glycoprotein to evade host immune responses resulting in relapses of parasitaemia and remittent clinical signs as reported by Hutchinson et al [38]. The latent parasitaemia status detected chronically in the Infected-untreated group using mice inoculation test (MIT), and the death (due to high parasitaemia) of all mice used suggest that infected-untreated donkeys, assume chronic clinical or subclinical carriers status with low level but virulent and pathogenic T. evansi [21].…”

Section: Discussionmentioning

confidence: 57%

“…It can be said that isometamidium chloride did not completely remove T. evansi infection from the treated donkeys but the remaining parasites were rendered non-pathogenic and avirulent. This finding might be due to resistance of T. evansi via switching of its surface glycoprotein coat despite the reported ability of isometamidium to cleavage trypanosomes kinetoplast Deoxyribonucleic acid-topoisomerase (kDNA-topoisomerase) complexes [38,40] and causing disintegration of minicircle network within the T. evansi kinetoplast via mechanisms that are independent of kDNA to cause parasite death [41].…”

Section: Discussionmentioning

confidence: 98%

Gross and Histopathological Alterations in Experimental Trypanosoma Evansi Infection in Donkeys and the Effect of Isometamidium Chloride Treatment

Um¹,

Akb²,

Ai³

et al. 2017

Journal of Veterinary Science and Animal Husbandry

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Variant Surface Glycoprotein gene repertoires in Trypanosoma brucei have diverged to become strain-specific

Cited by 46 publications

References 37 publications

T-Cell Responses to the Trypanosome Variant Surface Glycoprotein Are Not Limited to Hypervariable Subregions

T-Cell Responses to the Trypanosome Variant Surface Glycoprotein Are Not Limited to Hypervariable Subregions

Independence ofAnaplasma marginaleStrains with High and Low Transmission Efficiencies in the Tick Vector following Simultaneous Acquisition by Feeding on a Superinfected Mammalian Reservoir Host

Gross and Histopathological Alterations in Experimental Trypanosoma Evansi Infection in Donkeys and the Effect of Isometamidium Chloride Treatment

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