transforming-growth-factor-beta and Trypanosomiasis--African

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.

Topics: Animals; Antibodies, Monoclonal; CD4 Antigens; Cells, Cultured; Disease Susceptibility; Female; Forkhead Transcription Factors; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Interleukins; Lymph Nodes; Mice; Mice, Inbred BALB C; Parasitemia; Spleen; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Trypanosoma congolense; Trypanosomiasis, African; Tumor Necrosis Factor-alpha

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 beta1 (TGF-beta1) and its potential to enhance immunity against protozoan parasites, we examined the effects of intraperitoneally delivered TGF-beta1 in C57BL/6 mice infected with Trypanosoma congolense, the hemoprotozoan parasite causing nagana in cattle. A triple dose of 10 ng TGF-beta1 significantly reduced the first parasitemic peak and delayed mortality of infected mice. Furthermore, exogenous TGF-beta1 significantly decreased the development of trypanosome-induced anemia and splenomegaly. The apparent TGF-beta1-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-beta1-pretreated mice exhibited a significant reduction in the trypanosome-induced hyperexpansion of B cells. Furthermore, evidence is provided herein that exogenous TGF-beta1 activates macrophages that may contribute to parasite control. Collectively, these data indicate that exogenous TGF-beta1 is immunostimulative, inducing partial protection against T. congolense infection, possibly through mechanisms involving innate immune responses.

Topics: Anemia; Animals; Antibodies, Protozoan; B-Lymphocytes; Cytokines; Disease Models, Animal; Female; Immunoglobulin G; Immunologic Factors; Macrophage Activation; Mice; Mice, Inbred C57BL; Parasitemia; Splenomegaly; Th1 Cells; Transforming Growth Factor beta; Trypanosoma congolense; Trypanosomiasis, African

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-alpha) and transforming growth factor beta (TGF-beta) in plasma. In Uganda but not Malawi early-stage TNF-alpha was elevated, while in Malawi but not Uganda early-stage TGF-beta was elevated. Thus, rapid disease progression in Uganda is associated with TNF-alpha-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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Child; Child, Preschool; Cytokines; Disease Progression; Genotype; Humans; Membrane Glycoproteins; Middle Aged; Polymerase Chain Reaction; Protozoan Proteins; Transforming Growth Factor beta; Trypanosoma brucei rhodesiense; Trypanosomiasis, African; Tumor Necrosis Factor-alpha

Microbial infection can impact on the course of autoimmune disease, both in disease-inducing and disease-protecting capacities. Here we investigated if infection with Trypanosoma brucei brucei (Tbb), the protozoan causative agent of African Sleeping Sickness, could ameliorate the course of CIA in the Dark Agouti rat, an experimental model which shares many features with human rheumatoid arthritis. Infection of animals with living, but not inoculation with dead Tbb resulted in complete or significant reduction of clinical arthritic symptoms. Infection prior to collagen immunization was more effective than a later treatment, and this effect was related to the level of parasitaemia. Using reverse transcriptase-polymerase chain reaction we detected an increase in interferon-gamma mRNA in the draining lymph nodes of Tbb-treated animals relative to controls at day 28 after disease induction. Transforming growth factor-beta could be detected in the lymph nodes in four out of six animals that had received Tbb. In the joints, immunohistochemistry revealed reduced production of tumour necrosis factor-alpha in Tbb-treated animals relative to controls. The most striking difference between Tbb-infected and control groups, as measured by ELISA, was the down-regulation of anti-collagen II IgG antibody responses in parasite-infected animals. We conclude that live parasites can exert an immunomodulatory and protective effect in CIA in which several mechanisms may work in parallel, although the almost complete down-regulation of the anti-collagen antibody response may alone explain the protective effect in CIA. The described model may be useful in further attempts to use the mechanisms involved in parasite immune defence to prevent and treat certain autoimmune conditions.

Topics: Animals; Arthritis, Rheumatoid; Collagen; Disease Models, Animal; Hypersensitivity, Delayed; Immunoglobulin G; Interferon-gamma; Interleukin-2; Interleukin-4; Male; Rats; Transforming Growth Factor beta; Trypanosoma brucei brucei; Trypanosomiasis, African; Tumor Necrosis Factor-alpha

African trypanosomes are important pathogens of both humans and livestock. We investigated the association of cytokine responses with disease susceptibility in Trypanosoma congolense-infected cattle. Changes in interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-12 p40, tumor necrosis factor-alpha (TFN-alpha), CD40L, and transforming growth factor-beta (TGF-beta) gene expression were compared in peripheral blood mononuclear cells of infected trypanotolerant N'Dama (Bos taurus) and trypanosusceptible Boran (Bos indicus) cattle. Results revealed that IL-2 transcription was decreased in both breeds of cattle at 21 days after infection. IL-12 p40 mRNA expression was increased in N'Dama cattle at 21 days after infection and at a later time in Boran cattle. The highest IL-4 mRNA expression was observed at 32 days after infection in N'Dama cattle. IL-6 mRNA expression increased in Boran cattle at 11 days after infection and was elevated at 21 and 32 days after infection in both breeds. Transcripts for IL-5 were barely detectable throughout the experimental period in both Boran and N'Dama cattle. Expression of TNF-alpha, IL-1beta, and TGF-beta mRNA did not change notably during the course of infection. In summary, differences in the expression of IL-4 and IL-6 mRNA were identified between the two breeds of cattle during infection with T. congolense, suggesting a possible protective role for IL-4 and a disease-promoting role for IL-6 in bovine trypanosomosis.

Topics: Animals; Cattle; Cattle Diseases; Cytokines; Disease Susceptibility; Gene Expression; Interleukin-4; Interleukin-5; Interleukin-6; Leukocytes, Mononuclear; Monocytes; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Trypanosoma congolense; Trypanosomiasis, African

Cytokines are important signalling proteins, which have been shown to contribute to immunopathogenesis of several inflammatory and infectious diseases such as African trypanosomiasis. The present study was conducted in order to evaluate the early induction of five potential cytokines in the central nervous system (CNS) and spleens from Trypanosoma brucei brucei (T. b. brucei)-inoculated and uninfected control Sprague-Dawley rats. In brain, choroid plexus and spleen, cytokine levels were examined by in situ hybridization and immunohistochemistry, while ELISA was used to measure cytokine levels in cerebrospinal fluid (CSF). Our results showed that interferon (IFN)-gamma and transforming growth factor (TGF)-beta were highly expressed in all compartments, but low interleukin (IL)-4, IL-10 and tumour necrosis factor (TNF)-alpha mRNA levels were registered. The pattern of these cytokines is in context with the severity of the disease because (i) IFN-gamma was previously demonstrated to promote parasite growth (ii) TNF-alpha was previously demonstrated to kill the parasites and (iii) IL-4 was previously demonstrated to promote antibody production necessary for elimination of the infection. These data support the hypothesis that cytokines may have a role in developing the disease either by enhancing the parasite growth or by suppressing the immune response.

Topics: Animals; Central Nervous System; Cytokines; Disease Models, Animal; Interleukin-10; Interleukin-4; Male; Rats; Rats, Sprague-Dawley; Spleen; Transforming Growth Factor beta; Trypanosoma brucei brucei; Trypanosomiasis, African; Tumor Necrosis Factor-alpha