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Low-dose intradermal infection with trypanosoma congolense leads to expansion of regulatory T cells and enhanced susceptibility to reinfection.

ABSTRACT: BALB/c mice are highly susceptible to experimental intraperitoneal Trypanosoma congolense infection. However, a recent report showed that these mice are relatively resistant to primary intradermal low-dose infection. Paradoxically, repeated low-dose intradermal infections predispose mice to enhanced susceptibility to an otherwise noninfectious dose challenge. Here, we explored the mechanisms responsible for this low-dose-induced susceptibility to subsequent low-dose challenge infection. We found that akin to intraperitoneal infection, low-dose intradermal infection led to production of interleukin-10 (IL-10), IL-6, IL-12, tumor necrosis factor alpha (TNF-α), transforming growth factor β (TGF-β), and gamma interferon (IFN-γ) by spleen and draining lymph node cells. Interestingly, despite the absence of parasitemia, low-dose intradermal infection led to expansion of CD4+ CD25+ Foxp3+ cells (T regulatory cells [Tregs]) in both the spleens and lymph nodes draining the infection site. Depletion of Tregs by anti-CD25 monoclonal antibody (MAb) treatment during primary infection or before challenge infection following repeated low-dose infection completely abolished the low-dose-induced enhanced susceptibility. In addition, Treg depletion was associated with dramatic reduction in serum levels of TGF-β and IL-10. Collectively, these findings show that low-dose intradermal infection leads to rapid expansion of Tregs, and these cells mediate enhanced susceptibility to subsequent infection.

SUBMITTER: Onyilagha C

PROVIDER: S-EPMC3957988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Regulatory T cells enhance susceptibility to experimental Trypanosoma congolense infection independent of mouse genetic background.

Project description:BACKGROUND: BALB/c mice are highly susceptible while C57BL/6 are relatively resistant to experimental Trypanosoma congolense infection. Although regulatory T cells (Tregs) have been shown to regulate the pathogenesis of experimental T. congolense infection, their exact role remains controversial. We wished to determine whether Tregs contribute to distinct phenotypic outcomes in BALB/c and C57BL/6 mice and if so how they operate with respect to control of parasitemia and production of disease-exacerbating proinflammatory cytokines. METHODOLOGY/FINDINGS: BALB/c and C57BL/6 mice were infected intraperitoneally (i.p) with 10(3)T. congolense clone TC13 and both the kinetics of Tregs expansion and intracellular cytokine profiles in the spleens and livers were monitored directly ex vivo by flow cytometry. In some experiments, mice were injected with anti-CD25 mAb prior or post T. congolense infection or adoptively (by intravenous route) given highly enriched naïve CD25(+) T lymphocytes prior to T. congolense infection and the inflammatory cytokine/chemokine levels and survival were monitored. In contrast to a transient and non significant increase in the percentages and absolute numbers of CD4(+)CD25(+)Foxp3(+) T cells (Tregs) in C57BL/6 mouse spleens and livers, a significant increase in the percentage and absolute numbers of Tregs was observed in spleens of infected BALB/c mice. Ablation or increasing the number of CD25(+) cells in the relatively resistant C57BL/6 mice by anti-CD25 mAb treatment or by adoptive transfer of CD25(+) T cells, respectively, ameliorates or exacerbates parasitemia and production of proinflammatory cytokines. CONCLUSION: Collectively, our results show that regulatory T cells contribute to susceptibility in experimental murine trypanosomiasis in both the highly susceptible BALB/c and relatively resistant C57BL/6 mice.

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Project description:This protozoa is a major livestock pathogen in Africa

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Project description:Transcriptome sequencng of Trypanosoma congolense for future protein-protein interaction studiesThis data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

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Project description:Trypanosoma congolense are extracellular protozoan parasites of the blood stream of artiodactyls and are one of the main constraints on cattle production in Africa. In cattle, anaemia is the key feature of disease and persists after parasitaemia has declined to low or undetectable levels, but treatment to clear the parasites usually resolves the anaemia.The progress of anaemia after Trypanosoma congolense infection was followed in three mouse strains. Anaemia developed rapidly in all three strains until the peak of the first wave of parasitaemia. This was followed by a second phase, characterized by slower progress to severe anaemia in C57BL/6, by slow recovery in surviving A/J and a rapid recovery in BALB/c. There was no association between parasitaemia and severity of anaemia. Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia. Expression of genes involved in erythropoiesis and iron metabolism was followed in spleen, liver and kidney tissues in the three strains of mice using microarrays. There was no evidence for a response to erythropoietin, consistent with anaemia of chronic disease, which is erythropoietin insensitive. However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng.The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect. Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection.

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Dose-Sparing Intradermal DTaP-sIPV Immunization With a Hollow Microneedle Leads to Superior Immune Responses.

Project description:Dose-sparing intradermal (ID) vaccination may induce the same immune responses as intramuscular (IM) vaccination, which can increase vaccine supplies and save costs. In this study, rats were immunized with fractional-dose of Sabin-derived IPV combined with diphtheria-tetanus-acellular pertussis vaccine (DTaP-sIPV) intradermally with hollow microneedle devices called MicronJet600 and the vaccine immunogenicity and efficacy were evaluated and compared with those of full-dose intramuscular immunization. We tested levels of antibodies and the subclass distribution achieved via different immunization routes. Furthermore, gene transcription in the lung and spleen, cytokine levels and protection against Bordetella pertussis (B. pertussis) infection were also examined. The humoral immune effect of DTaP-sIPV delivered with MicronJet600 revealed that this approach had a significant dose-sparing effect and induced more effective protection against B. pertussis infection by causing Th1/Th17 responses. In conclusion, ID immunization of DTaP-sIPV with the MicronJet600 is a better choice than IM immunization, and it has the potential to be a new DTaP-sIPV vaccination strategy.

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Evidence for viable and stable triploid Trypanosoma congolense parasites.

Project description:Recent whole genome sequencing (WGS) analysis identified a viable triploid strain of Trypanosoma congolense. This triploid strain BANANCL2 was a clone of the field isolate BANAN/83/CRTRA/64 that was collected from cattle in Burkina Faso in 1983.We demonstrated the viability and stability of triploidy throughout the complete life-cycle of the parasite by infecting tsetse flies with the triploid clone BANANCL2. Proboscis-positive tsetse flies efficiently transmitted the parasites to mice resulting in systemic infections. WGS of the parasites was performed at all life-cycle stages, and a method based on a block alternative allele frequency spectrum was developed to efficiently detect the ploidy profiles of samples with low read depth. This approach confirmed the triploid profile of parasites throughout their life-cycle in the tsetse fly and the mammalian host, demonstrating that triploidy is present at all stages and is stable over time.The presence of viable field-isolated triploid parasites indicates another possible layer of genetic diversity in natural T. congolense populations. The comparison between triploid and diploid parasites provides a unique model system to study the impact of chromosome copy number variations in African trypanosomes. In addition, the consequences of triploidy can be further investigated using this stable triploid model.

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Characterization of major surface protease homologues of Trypanosoma congolense.

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