transforming-growth-factor-beta and Toxoplasmosis

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients' morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with

Topics: Animals; Apoptosis; Humans; Kidney; Leishmaniasis; Malaria; Oxidative Stress; Parasitic Diseases; Protozoan Infections; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan causing several forms of toxoplasmosis in humans. The main mechanisms that allow the development of the prolonged forms of the disease and its subsequent pathology are yet to be clarified. However, many researchers have hypothesized that immunological and genetic parameters may play crucial roles in the etiology of the disease. Transforming growth factor beta (TGF-β) is a cytokine with a dual role in the regulation of immune responses including those against parasites. However, the relationship between TGF-β and immune responses against T .gondii are not fully understood. The important roles played by TGF-β in the development of Th17 and T regulatory lymphocytes, mucosal immunity and regulation of immune responses have been documented and this provides insights into TGF-β function during parasitic infections such as toxoplasmosis. Therefore, the aim of this review is to collate the current information regarding the status and association of TGF-β with T. gondii infection.

Topics: Adaptive Immunity; Animals; Cytokines; Humans; Immunity, Innate; Interferon-gamma; Mice; T-Lymphocytes, Regulatory; Th17 Cells; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Animal; Transforming Growth Factor beta

Toxoplasma gondii infection is usually benign in Europe due to the strong predominance of type II strains. Few studies have been conducted to examine the immunological course of infection in humans and have yielded conflicting results, maybe influenced by heterogeneous parasite strains.. We measured 23 immune mediators in 39, 40, and 29 sera of French noninfected, acutely infected, and chronically infected immunocompetent pregnant women, respectively.. Four different cytokine patterns were identified regarding their dynamics through infection phases. For 11 of the cytokines (IFN-β, IFN-γ, IL-4, IL5, IL-6, IL-10, IL-12, IL-15, CXCL9, CCL2, and CSF2) the serum levels were significantly elevated during acute infection. The inflammatory mediators IL-1β, IL-17A, IL-18, TNF-α, and CSF3 remained unchanged during acute infection, while they were significantly lower in chronically infected compared to noninfected patients. As for the anti-inflammatory cytokines TGF-β and CCL5, their levels remained significantly elevated during chronic infection. We also observed a significant negative correlation of several cytokine concentrations with IgG levels, indicating a rapid decline of serum concentrations during the acute phase.. These results indicate an anti-inflammatory pattern in chronically infected patients in a type II dominated setting and demonstrate the highly dynamic immune situation during acute infection.

Topics: Cytokines; Female; France; Humans; Interleukin-12; Pregnancy; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Toxoplasma gondii is able to manipulate the host immune system to establish a persistent and efficient infection, contributing to the development of brain abnormalities with behavioral repercussions. In this context, this work aimed to evaluate the effects of T. gondii infection on the systemic inflammatory response and structure of the primary somatosensory cortex (PSC). C57BL/6 and BALB/c mice were infected with T. gondii ME49 strain tissue cysts and accompanied for 30 days. After this period, levels of cytokines IFN-γ, IL-12, TNF-α and TGF-β were measured. After blood collection, mice were perfused and the brains were submitted to immunohistochemistry for perineuronal net (PNN) evaluation and cyst quantification. The results showed that C57BL/6 mice presented higher levels of TNF-α and IL-12, while the levels of TGF-β were similar between the two mouse lineages, associated with the elevated number of tissue cysts, with a higher occurrence of cysts in the posterior area of the PSC when compared to BALB/c mice, which presented a more homogeneous cyst distribution. Immunohistochemistry analysis revealed a greater loss of PNN labeling in C57BL/6 animals compared to BALB/c. These data raised a discussion about the ability of T. gondii to stimulate a systemic inflammatory response capable of indirectly interfering in the brain structure and function.

Topics: Animals; Interleukin-12; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Somatosensory Cortex; Systemic Inflammatory Response Syndrome; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Toxoplasmosis is a parasitic zoonosis distributed worldwide, caused by the ingestion of contaminated water/food with the parasite

Topics: Adolescent; Adult; Cytokines; Female; Humans; Immunoglobulin G; Infectious Disease Transmission, Vertical; Lymphocyte Activation; Pregnancy; Toxoplasmosis; Transforming Growth Factor beta; Young Adult

Toxoplasmosis is mostly associated with other intestinal parasitic infections especially Giardia due to shared mode of peroral infection. Toxoplasma and Giardia induce a strong T-helper 1- immune response. Our aim was to induce a protective immune response that results in significant impact on intestinal and extra-intestinal phases of Toxoplasma infection. This study was conducted in experimental animals and assessment of Giardia cyst extract effect on Toxoplasma infection was investigated by histopathological examination of small intestine and brain, Toxoplasma cyst count and iNOS staining of the brain, measurement of IFN-γ and TGF-β in intestinal tissues. Results showed that the brain Toxoplasma cyst number was decreased in mice infected with Toxoplasma then received Giardia cyst extract as compared to mice infected with Toxoplasma only. This effect was produced because Giardia cyst extract augmented the immune response to Toxoplasma infection as evidenced by severe inflammatory reaction in the intestinal and brain tissues, increased levels of IFN-γ and TGF-β in intestinal tissues and strong iNOS staining of the brain. In conclusion, Giardia cyst extract generated a protective response against T. gondii infection. Therefore, Giardia antigen will be a suitable candidate for further researches as an immunomodulatory agent against Toxoplasma infection.

Topics: Animals; Antigens, Protozoan; Brain; Female; Giardia; Giardiasis; Inflammation; Interferon-gamma; Intestine, Small; Mice; Nitric Oxide Synthase Type II; Th1 Cells; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Animal; Transforming Growth Factor beta

This study detected and compared the levels of IFN-γ, TNF-α, TGF-β and nitric oxide (NO) in amniotic fluid (AF) and serum of pregnancies with acute toxoplasmosis, Southern Brazil. It also was compared the levels of the same mediators in the serum of pregnancies in acute and chronic toxoplasmosis with non-infected. Serological investigation, anti-T gondii IgM and IgG, of the 67 pregnancies was determined by Elisa MEIA. Forty two were uninfected, eight in chronic phase and 17 in acute phase. Among the acute phase, seven agreed to amniocentesis. The cytokines, in serum and in AF, were assessed by sandwich ELISA, and NO was estimated from the nitrite measurement with Griess reagent. The IFN-γ and TGF-β levels in the AF and blood were similar, while TNF-α levels was lower in the AF. On the other hand, NO was higher in the AF. Chronically infected pregnant women have showed lower levels of INF-γ than those in acute and uninfected pregnancies. The serological levels of TNF-α were lower in pregnancies with toxoplasmosis, when compared with non-infected. TGF-β levels were higher in pregnancies in acute phase when compared with uninfected or chronically infected. NO in the serum of the infected had lower levels than those non-infected. In summary, higher concentrations of NO and lower levels of TNF-α were observed in the AF than in the serum of acute pregnancies, while TGF-β e INF-γ levels were similar in both biological material. In the serum of infected pregnancies was observed decrease in inflammatory mediators and increase of TGF-β.

Topics: Amniotic Fluid; Brazil; Female; Humans; Interferon-gamma; Nitric Oxide; Pregnancy; Toxoplasmosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1-dependent to a Blimp-1-independent pathway in IL-27-induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.

Topics: Animals; Interleukin-10; Interleukin-12; Interleukins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Positive Regulatory Domain I-Binding Factor 1; Proto-Oncogene Proteins c-maf; Receptors, Notch; Signal Transduction; STAT4 Transcription Factor; Th1 Cells; Toxoplasmosis; Transcription Factors; Transforming Growth Factor beta

Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.

Topics: Animals; Asthma; Bronchoalveolar Lavage; CD4 Antigens; Forkhead Transcription Factors; Hypersensitivity; Inflammation; Interferon-gamma; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Respiratory Hypersensitivity; Th2 Cells; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta

According to hygiene hypothesis, a lower exposure to infection is associated with increased prevalence of allergic diseases. This study aimed to investigate the association between atopy and Toxoplasma gondii (Tg) infection by analyzing the antibody and cytokine responses to house dust mite allergens and T. gondii antigens in Brazilian subjects. A total of 275 individuals were assessed and divided into atopics (n=129) and non-atopics (n=146) based on markers of allergy (positive skin prick test and ELISA-IgE to mite allergens) or Tg-seropositive (n=116) and Tg-seronegative (n=159) groups according to infection markers (positive ELISA-IgG to T. gondii). Tg-seropositive individuals presented lower allergenic sensitization (37%) to mite allergens than Tg-seronegative subjects (54%). A significant association was found between atopy and negative serology to T. gondii (OR: 2.0; 95% CI: 1.23-3.26; P<0.05). Proliferative responses and cytokine production after antigenic stimulation showed predominant synthesis of Th1-cytokines as IFN-gamma in Tg-seropositive patients, whether atopics or non-atopics. Conversely, Th2-cytokines as IL-5 prevailed in atopics compared to non-atopics, regardless the seropositivity to T. gondii. Levels of IL-10, IL-13, IL-17, and TGF-beta were not able to discriminate the groups. Hence, a negative association between atopy and infection by T. gondii was demonstrated for the first time in Brazilian subjects, focusing on the antibody and cytokine responses and indicating that the immunomodulation induced by the parasite may play a protective role in the development of allergic diseases.

Topics: Adult; Antibodies; Antigens; Antigens, Dermatophagoides; Brazil; Cell Proliferation; Cytokines; Female; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-5; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Phytohemagglutinins; Skin Tests; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta; Young Adult

Toxoplasma gondii is a ubiquitous intracellular parasite affecting most mammals including humans. In epidemiological studies, infection with T. gondii and allergy development have been postulated to be inversely related. Using a mouse model of birch pollen allergy we investigated whether infection with T. gondii influences allergic immune responses to birch pollen. BALB/c mice were infected with T. gondii oocysts either before or at the end of sensitisation with the major birch pollen allergen Bet v 1 and thereafter aerosol challenged with birch pollen extract. During the acute phase of infection, clinical signs correlated with increased levels of serum TNF-alpha, IL-6, IFN-gamma and anti-Toxoplasma-IgM. In the chronic phase, Toxoplasma-specific serum IgG, brain tissue cysts and high IFN-gamma production in spleen cell cultures were detected. Mice infected prior to allergic sensitisation produced significantly less allergen-specific IgE and IgG1, while IgG2a levels were markedly increased. IL-5 levels in spleen cell cultures and bronchoalveolar lavage fluid were significantly reduced, and airway inflammation was prevented in these mice. Notably, in mice infected at the end of the allergic sensitisation process, systemic and local immune responses to the allergen were markedly reduced. T.gondii infection was associated with up-regulation of Toll-like receptor 2 (TLR2), 4, 9 and 11, as well as T-bet (a differentiation factor for Th1 cells) mRNA expression in splenocytes; moreover, enhanced TGF-beta, IL-10 and Foxp3 mRNA expression in these cells suggested that regulatory mechanisms were involved in suppression of the allergic immune response. Kinetic studies confirmed the induction of Foxp3(+)CD4(+)CD25(+) regulatory T cells preferentially during the chronic phase of T. gondii infection. Our data demonstrate that T. gondii exhibits strong immunomodulating properties which lead to prevention of allergic immune responses and thereby support the hygiene hypothesis.

Topics: Allergens; Animals; Betula; Brain; Bronchoalveolar Lavage Fluid; Chronic Disease; Cytokines; Disease Models, Animal; Immunoglobulin G; Immunoglobulin M; Interferon-gamma; Interleukin-5; Interleukin-6; Mice; Mice, Inbred BALB C; Pollen; Respiratory Hypersensitivity; RNA, Messenger; Spleen; Toll-Like Receptors; Toxoplasmosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Transforming growth factor beta-1 (TGF-beta1) is a pleiotropic cytokine with both pro- and antiinflammatory properties, depending on its environment and concentration. The present study evaluated the effects of orally-delivered TGF-beta1 on mice parenterally-infected with various protozoan parasites. We report that while orally-administered TGF-beta1 seems to confer partial protection against murine chronic babesiosis and acute trypanosomosis, no beneficial clinical effects were observed against acute babesiosis, malaria or toxoplasmosis. Taken together, these preliminary data suggest that the systemic effects conferred by exogenous TGF-beta1 could be parasite species-specific. The variations in different parasitic infections could be due to (i) intrinsic differences between parasite species and/or strains in their ability to induce production of immunosuppressive molecules and/or (ii) differences in mechanisms governing host protection against different parasitic infections.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Babesia; Babesiosis; Female; Malaria; Mice; Mice, Inbred BALB C; Parasitic Diseases; Plasmodium berghei; Protozoan Infections; Survival Rate; Toxoplasma; Toxoplasmosis; Transforming Growth Factor beta

Intraepithelial lymphocytes (IEL) play a key role in gut homeostasis and are critical effector cells preventing the inflammatory intestinal lesions induced in mice following oral infection with Toxoplasma gondii. In this intestinal inflammatory model, CD4(+) T lymphocytes from the lamina propria (LP) synergize with the infected enterocytes to secrete pro-inflammatory chemokines and cytokines. In this study, we assessed the mechanisms accounting for the ability of IEL to modulate the inflammatory activity of these cells. Adoptive transfer of IEL purified from wild-type mice, or CD154-,CD95L- or IL-10-deficient mice infected with T. gondii completely impairs the development of the lethal ileitis in recipient mice orally infected with T. gondii. Compared with unprimed IEL isolated from naive mice, the CD8 alpha beta TCR alpha beta subset of primed IEL, isolated from T. gondii-infected mice, secretes increased amount of TGF-beta. IEL interact with the LP CD4(+) T lymphocytes, down-regulate their production of inflammatory cytokines such as IFN-gamma and reduce their proliferative activity. These effects are linked to the secretion of TGF-beta and are correlated with a shift in the balance between Smad7/T-bet down-regulation and Smad2/Smad3 up-regulation in LP CD4(+) T lymphocytes.

Topics: Adoptive Transfer; Animals; DNA-Binding Proteins; Female; Ileitis; Immunoblotting; Inflammation; Intestinal Mucosa; Intestines; Mice; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad Proteins; T-Lymphocytes; Toxoplasma; Toxoplasmosis; Trans-Activators; Transforming Growth Factor beta

The loss of homeostasis is a hallmark of inflammatory bowel disease. Oral infection of susceptible mice with Toxoplasma gondii results in an acute lethal ileitis characterized by increased interferon gamma, tumor necrosis factor alpha, and inducible nitric oxide synthase; homeostasis results from transforming growth factor beta production by intraepithelial lymphocytes. The synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a potent anti-inflammatory molecule previously shown in vitro to suppress the de novo synthesis of inducible nitric oxide synthase and to induce the transcription and activation of genes from the transforming growth factor beta signaling pathway.. We evaluated the immune response in the small intestine and by intraepithelial lymphocytes after a single intraperitoneal dose of CDDO at the time of T. gondii oral infection. We abrogated the homeostatic effects of CDDO by blocking transforming growth factor beta in vivo.. CDDO acid prevented ileitis development through the global down-regulation of inflammatory cytokines and chemokines. Total transforming growth factor beta(1) production by the intraepithelial lymphocytes increased, as did Smad2 expression. Blocking transforming growth factor beta reversed CDDO-induced protection and prevented the up-regulation of Smad2 in the small intestine.. CDDO acid is a novel anti-inflammatory molecule capable of preventing ileitis by activating the transforming growth factor beta signaling pathway in a pathogen-driven ileitis model. This could represent a new treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Down-Regulation; Female; Ileitis; Injections, Intraperitoneal; Lymphocytes; Mice; Models, Animal; Oleanolic Acid; Signal Transduction; Toxoplasmosis; Transforming Growth Factor beta

Acute inflammatory ileitis occurs in susceptible (C57BL/6) mice after oral infection with Toxoplasma gondii. Overproduction of interferon (IFN)-gamma and synthesis of nitric oxide mediate the inflammation. We evaluated the role of transforming growth factor (TGF)-beta produced by intraepithelial lymphocytes (IELs) in this process.. We analyzed the histologic and immunologic consequences of adoptive transfer of antigen-primed IELs into susceptible mice treated with anti-TGF-beta before oral challenge with T. gondii cysts. An in vitro coculture of enterocytes and IELs assessed the production of chemokines and cytokines in the presence of anti-TGF-beta.. Antigen-primed IELs prevent acute ileitis in susceptible mice that is reversed with anti-TGF-beta. Resistant mice (CBA/J) develop ileitis after treatment with anti-TGF-beta. Antigen-primed IELs can induce systemic immunosuppression as measured by depressed IFN-gamma production. In vitro, primed IELs reduce the production of inflammatory chemokines by infected enterocytes and IFN-gamma by splenocytes.. Regulation of the ileal inflammatory process resulting from T. gondii is dependent on TGF-beta-producing IELs. The IELs are an essential component in gut homeostasis after oral infection with this parasite.

Topics: Animals; Chemokines; Disease Susceptibility; Down-Regulation; Enterocytes; Female; Ileitis; Inflammation Mediators; Intestinal Mucosa; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Toxoplasma; Toxoplasmosis; Transfection; Transforming Growth Factor beta