transforming-growth-factor-beta and Malaria

The main causative agent of malaria in humans is Plasmodium falciparum, which is spread through biting Anopheles mosquitoes. Immunoregulation in the host involving the pleiotropic cytokine transforming growth factor-β (TGF-β) has a vital role in controlling the immune response to P. falciparum infection. Based on a search of the published literature, this study investigated the correlation between malaria and immune cells, specifically the role of TGF-β in the immune response. The studies analyzed showed that, when present in low amounts, TGF-β promotes inflammation, but inhibits inflammation when present in high concentrations; thus, it is an essential regulator of inflammation. It has also been shown that the quantity of TGF-β produced by the host can influence how badly the parasite affects the host. Low levels of TGF-β in the host prevent the host from being able to manage the inflammation that Plasmodium causes, which results in a pathological situation that leaves the host vulnerable to fatal infection. Additionally, the amount of TGF-β fluctuates throughout the host's Plasmodium infection. At the beginning of a Plasmodium infection, TGF-β levels are noticeably increased, and as Plasmodium multiplies quickly, they start to decline, hindering further growth. In addition, it is also involved in the growth, proliferation, and operation of various types of immune cell and correlated with levels of cytokines associated with the immune response to malaria. TGF-β levels were positively connected with the anti-inflammatory cytokine interleukin-10 (IL-10), but negatively correlated with the proinflammatory cytokines interferon-γ (IFN-γ) and IL-6 in individuals with severe malaria. Thus, TGF-β might balance immune-mediated pathological damage and the regulation and clearance of infectious pathogens. Numerous domestic and international studies have demonstrated that TGF-β maintains a dynamic balance between anti-inflammation and pro-inflammation in malaria immunity by acting as an anti-inflammatory factor when inflammation levels are too high and as a pro-inflammatory factor when inflammation levels are deficient. Such information could be of relevance to the design of urgently needed vaccines and medications to meet the emerging risks associated with the increasing spread of malaria and the development of drug resistance.

Topics: Animals; Cytokines; Humans; Immunity; Inflammation; Malaria; Malaria, Falciparum; Transforming Growth Factor beta; Transforming Growth Factors

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

Malarial disease caused by

Topics: Animals; Cytokines; Humans; Immunity, Cellular; Immunity, Humoral; Immunomodulation; Interferon-gamma; Interleukin-10; Malaria; Mice; Th1 Cells; Transforming Growth Factor beta

Malaria has re-emerged as a global health problem, leading to an increased focus on the cellular and molecular biology of the mosquito Anopheles and the parasite Plasmodium with the goal of identifying novel points of intervention in the parasite life cycle. Anti-parasite defenses mounted by both mammalian hosts and Anopheles can suppress the growth of Plasmodium. Nonetheless, the parasite is able to escape complete elimination in vivo, perhaps by thwarting or co-opting these mechanisms for its own survival, as do numerous other pathogens. Among the defense systems used by the mammalian host against Plasmodium is the synthesis of nitric oxide (NO), catalyzed by an inducible NO synthase (iNOS). Nitric oxide produced by the action of an inducible Anopheles stephensi NO synthase (AsNOS) may be central to the anti-parasitic arsenal of this mosquito. In mammals, iNOS can be modulated by members of the transforming growth factor-beta (TGF-beta) cytokine superfamily. Transforming growth factor-beta is produced as an inactive precursor that is activated following dissociation of certain inhibitory proteins, a process that can be promoted by reaction products of NO as well as by hemin. Ingestion by Anopheles of blood containing Plasmodium initiates parasite development, blood digestion which results in the accumulation of hematin (hemin) in the insect midgut, and induction of both AsNOS and TGF-beta-like (As60A) gene expression in the midgut epithelium. Active mammalian TGF-beta1 can be detected in the A. stephensi midgut up to 48h post-ingestion and latent TGF-beta1 can be activated by midgut components in vitro, a process that is potentiated by NO and that may involve hematin. Further, mammalian TGF-beta1 is perceived as a cytokine by A. stephensi cells in vitro and can alter Plasmodium development in vivo. Bloodfeeding by Anopheles, therefore, results in a juxtaposition of evolutionarily conserved mosquito and mammalian TGF-beta superfamily homologs that may influence transmission dynamics of Plasmodium in endemic regions.

Topics: Animals; Anopheles; Cytokines; Heme; Humans; Insect Proteins; Malaria; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrogen Oxides; Plasmodium; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor beta (TGF-beta) is an important regulator of inflammation, being proinflammatory at low concentrations and anti-inflammatory at high concentrations. As such, TGF-beta might be important in maintaining the balance between control and clearance of infectious organisms on the one hand and prevention of immune-mediated pathology on the other. In this article, Fakhereldin Omer, Jørgen Kurtzhals and Eleanor Riley review the immunoregulatory properties of TGF-beta in the context of parasitic infections. Data from murine malaria infections suggest that TGF-beta modifies the severity of the disease, and a number of potential protective mechanisms are discussed. Evidence is accumulating that TGF-beta is important for the regulation of other host-parasite interactions and that parasites might directly influence TGF-beta-dependent pathways via the synthesis of TGF-beta or TGF-beta-receptor homologues.

Topics: Animals; Chagas Disease; Genetic Variation; Host-Parasite Interactions; Humans; Leishmaniasis; Malaria; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmodium falciparum; Schistosoma mansoni; Schistosomiasis mansoni; Transforming Growth Factor beta; Trypanosoma cruzi

This study investigated the role of genetic variant rs8177374 in MAL/TIRAP gene in mediating the cytokine levels of IFN-γ, TNF-α, IL-10, and TGF-β in malaria patients due to Plasmodium falciparum or P. vivax infection. The study included human blood samples collected from patients with malaria (n = 228) and healthy controls (n = 226). P. falciparum and P. vivax groups were established based on the causative species of Plasmodium. Malaria samples were divided into mild and severe malaria groups based on the symptoms that appeared in the patients, according to the WHO criteria. In a previous study, we genotyped rs8177374 via allele specific PCR strategy. In this study, cytokine levels were estimated in the blood plasma of rs8177374 genotype samples via Sandwich Enzyme Linked Immunosorbent Assay kits. Increased IFN-γ and TNF-α levels in presence of CC genotype indicates the role of CC genotype in both severe and mild malaria groups. Enhanced IL-10 levels in the CT genotype and mild malaria groups suggest a role of CT genotype and IL-10 in the mild clinical outcomes of malaria. The rs8177374 polymorphism in MAL/TIRAP plays an important role in malaria pathogenesis.

Topics: Cytokines; Humans; Interferon-gamma; Interleukin-10; Malaria; Malaria, Vivax; Myeloid Differentiation Factor 88; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Cytokines and chemokines are immune response molecules that display diverse functions, such as inflammation and immune regulation. In Plasmodium vivax infections, the uncontrolled production of these molecules is thought to contribute to pathogenesis and has been proposed as a possible predictor for disease complications. The objective of this study was to evaluate the cytokine profile of P. vivax malaria patients with different clinical outcomes to identify possible immune biomarkers for severe P. vivax malaria. The study included patients with non-severe (n = 56), or severe (n = 50) P. vivax malaria and healthy controls (n = 50). Patient plasma concentrations of IL-4, IL-2, CXCL10, IL-1β, TNF-α, CCL2, IL-17A, IL-6, IL-10, IFN-γ, IL-12p70, CXCL8 and active TGF-β1 were determined through flow cytometry. The levels of several cytokines and chemokines, CXCL10, IL-10, IL-6, IL-4, CCL2 and IFN-γ were found to be significantly higher in severe, compared to non-severe P. vivax malaria patients. Severe thrombocytopenia was positively correlated with IL-4, CXCL10, IL-6, IL-10 and IFN-γ levels, renal dysfunction was related to an increase in IL-2, IL-1β, IL-17A and IL-8, and hepatic impairment with CXCL10, MCP-1, IL-6 and IFN-γ. A Lasso regression model suggests that IL-4, IL-10, CCL2 and TGF-β might be developed as biomarkers for severity in P. vivax malaria. Severe P. vivax malaria patients present specific cytokine and chemokine profiles that are different from non-severe patients and that could potentially be developed as biomarkers for disease severity.

Topics: Biomarkers; Chemokine CCL2; Chemokines; Cytokines; Humans; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-8; Malaria; Malaria, Vivax; Plasmodium vivax; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-β1 and TGF-β3 in this process using novel monoclonal antibodies to measure their plasma concentrations in comparison with other cytokines and the expression of FOXP3 mRNA. Plasma cytokine levels were measured in 80 patients with severe anaemic malaria and 186 with a mild presentation using ELISA, and rtPCR was used to measure FOXP3 mRNA expression. While no mature TGF-β isoforms were detected in the plasma, the latent TGF-β1 and TGF-β3 were strongly upregulated in patients with mild malaria and nearly undetected in patients with severe disease. Similar selective upregulation in mild patients was observed for IL-9 and FOXP3 mRNA, while IL-7, IL-10, IL-17, and IL-27, although higher in mild cases, were also detected in severe disease. In contrast, a clearly skewed trend of severe cases towards higher pro-inflammatory (IL-6, IL-13, TNF-α) and Th1 (IFN-γ) responses was observed, which was associated with a higher level of parasitaemia as well as lower IgG and higher IgM responses. Together, these results suggest that the stimulation of regulatory T cells through TGF-β1/TGF-β3 and IL-9 is paramount to an effective and balanced protective immunity in natural human malaria infection.

Topics: Antibodies, Monoclonal; Cytokines; Forkhead Transcription Factors; Humans; Immunoglobulin G; Immunoglobulin M; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-27; Interleukin-6; Interleukin-7; Interleukin-9; Malaria; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta3; Tumor Necrosis Factor-alpha; Up-Regulation

The immune status of women changes during and after pregnancy, differs between blood compartments at delivery and is affected by environmental factors particularly in tropical areas endemic for multiple infections. We quantified the plasma concentration of a set of thirty-one T

Topics: Adult; Brazil; Chemokines; Cohort Studies; Colombia; Cytokines; Female; Guatemala; Hepatocyte Growth Factor; Humans; Immunoglobulin G; India; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Malaria; Papua New Guinea; Placenta; Plasmodium; Pregnancy; Pregnancy Complications, Parasitic; Pregnant Women; Spain; Transforming Growth Factor beta

After a controlled human malaria infection (CHMI), presentation of clinical signs and symptoms and host responses is heterogeneous. Transforming growth factor-beta (TGF-β) is the first serum cytokine that changes in malaria-naïve volunteers after CHMI. We studied a possible relation between TGF-β changes, pro-inflammatory cytokines, activation of haemostasis and endothelial cells and clinical symptoms.. A panel of cytokines including TGF-β, and markers of activation of haemostasis and endothelial cells were measured in blood samples of 15 volunteers at baseline before CHMI and during CHMI at day of treatment. The change of the parameters on the day of treatment was examined for a significant alteration during infection.. Nine of 15 volunteers showed a significant decrease in TGF-β compared to baseline, with concomitant increased concentrations of D-dimer (p = 0.012), Von Willebrand factor (p = 0.017), IL-6 (p = 0.012) and IFN-γ (0.028) and a significantly decreased platelet count (p = 0.011). In contrast, 6 of 15 volunteers showed sustained or increased TGF-β concentrations without change in the aforementioned parameters. The sustained responders presented with less moderate and severe clinical symptoms than the negative responders (p = 0.036) and had a higher baseline lymphocyte count (p = 0.026). TGF-β concentrations did not correlate with the parasitaemia on day of treatment.. Early decreases of serum TGF-β might function a marker for a pro-inflammatory host response and downstream clinical symptoms and pathology during CHMI.

Topics: Adult; Blood Platelets; Correlation of Data; Down-Regulation; Endothelial Cells; Female; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Inflammation; Interferon-gamma; Interferons; Interleukin-6; Lymphocytes; Malaria; Male; Parasitemia; Platelet Count; Transforming Growth Factor beta; Up-Regulation; von Willebrand Factor

Toll-like receptor (TLR) signals play vital roles during the blood-stage of malaria infections. However, the roles of TLR agonists in the regulation of immune responses and the development of protective immunity to malaria remain poorly understood.. BALB/c mice were pre-treated with TLR4, TLR7 and TLR9 agonists, followed by infection with Plasmodium chabaudi. After infection, splenic dendritic cells (DCs), Th1 cells and programmed death-1 (PD-1) expressed on Th1 cells, as well as regulatory T cells (Tregs) were analyzed by flow cytometry. The levels of IFN-γ, TNF-α, TGF-β and IL-10 in splenocytes and IgG1 and IgG2a in serum were measured by ELISA.. Administration of TLR4, TLR7 and TLR9 agonists prior to infection improved disease outcomes. All TLR agonists promoted DC activation, and the proportions of Th1 cells increased. In TLR4, TLR7 and TLR9 agonist treated groups the levels of pro-inflammatory cytokines IFN-γ and TNF-α were elevated, and IgG1 and IgG2a serum levels were also significantly increased. TLR4, TLR7 and TLR9 agonists diminished the activation of Tregs and down-regulated the anti-inflammatory cytokines TGF-β and IL-10. Finally, PD-1 expressed on Th1 cells were decreased in TLR4, TLR7 and TLR9 agonist treated groups compared with control groups.. TLR4, TLR7 and TLR9 agonists activated DC-mediated innate immune responses and adaptive immune response, which against the blood-stage of Plasmodium and might be applied to malaria protection and treatment.

Topics: Adaptive Immunity; Animals; Dendritic Cells; Female; Immunity, Innate; Immunoglobulin G; Interferon-gamma; Interleukin-10; Life Cycle Stages; Malaria; Membrane Glycoproteins; Mice, Inbred BALB C; Parasitemia; Plasmodium chabaudi; Programmed Cell Death 1 Receptor; Spleen; T-Lymphocytes, Regulatory; Th1 Cells; Toll-Like Receptor 4; Toll-Like Receptor 7; Toll-Like Receptor 9; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

A direct role for IgA either for elimination of malaria parasite or for improvement in tissue pathology has not been investigated in case of Malaria infection while IgG, IgE and IgM were all implicated in the adverse pathology. In this communication, we delineate further that Malaria specific IgA appears to be significant among individuals who had multiple episodes of infection. Interestingly, the IgA elicited by immunization of the homologous peptides derived from Plasmodium berghei ANKA have also resulted in protection of host from adverse lung pathology, while the parasite load is unaffected. The PfrVI immunized mice and mice infected with repeated cycles of 'infection and recovery', simulating an endemic like situation, have resulted in development of B cell population that secretes the IgA specific to this region VI. Summarily, our results suggest that the IgA specific to the malarial antigen can confer significant advantage to hosts in protecting the overall tissue pathology.

Topics: Animals; B-Lymphocytes; Erythrocytes; Immunization; Immunoglobulin A; Ligands; Malaria; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmodium berghei; Transforming Growth Factor beta

Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver's response to malarial infection.. Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot.. Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice.. Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

Topics: Actins; Adaptor Proteins, Signal Transducing; Anilides; Animals; Cell Cycle Proteins; Chemokines, C; Collagen Type I; Collagen Type I, alpha 1 Chain; Hedgehog Proteins; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Malaria; Male; Mice; Mice, Inbred C57BL; Phosphoproteins; Plasmodium berghei; Pyridines; Signal Transduction; Thymosin; Transforming Growth Factor beta; Up-Regulation; Vimentin; YAP-Signaling Proteins

Malaria is a major infectious disease in several countries and is caused by protozoa of the genus Plasmodium. In vivax malaria patients, inflammatory processes occur, as well as changes in cytokines and blood flow. The present study analyzed the cytokine modulation of blood viscosity from patients infected with Plasmodium vivax (P. vivax). Blood samples were collected from 42 non-infected individuals (control group) and 37 individuals infected with P. vivax. The IL-2, IL-4, IL-6, IL-10, TNFα, TGF-β and IL-17 cytokine concentrations in the serum were assessed, and the blood rheological properties were determined. The analysis of blood viscosity for shear rates revealed that the blood viscosity of the infected patients was significantly greater than that of the non-infected individuals. The viscosity of the blood was greater in the infected individuals than in the non-infected subjects. The serum from individuals with P. vivax infections exhibited higher IFN-γ and IL-17 concentrations and lower TGF-β levels. Incubation of the blood from infected individuals with IL-17 or IL-17 associated with IFN-γ reduced the viscosity to rates equivalent to the blood from non-infected individuals. Independently of cytokine modulation, no correlation was found between the parasitemia and blood viscosity of the infected patients. These data suggest that the alterations of blood viscosity are relevant as an auxiliary tool for the clinical diagnosis of disease. In malaria, erythrocytes are more sensitive to osmotic shock, and the reduction of viscosity by IL-17 may be related to a possible immunomodulator agent during infection.

Topics: Adult; Blood Viscosity; Cross-Sectional Studies; Cytokines; Female; Humans; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-4; Malaria; Malaria, Vivax; Male; Middle Aged; Parasitemia; Plasmodium vivax; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Malaria still infects many Malawian children, and it is a cause of death in some of them. Regulatory T cells (Tregs) help in negating immune-related pathology, it but can also favor multiplication of malaria parasites. The question remains whether children recovering from uncomplicated malaria (UCM) have higher Tregs and interleukin (IL)-10 levels in convalescence.. We recruited children between the ages of 6 and 60 months presenting with acute UCM in Blantyre (low transmission area) and Chikwawa (high transmission area). We observed the children after 1 month and 3 months and analyzed their blood samples for parasitemia, lymphocyte subsets, and levels of the cytokines interferon (IFN)-γ, IL-10, and transforming growth factor (TGF)-β. Blood samples from age-matched controls were also analyzed for the same parameters.. Compared with controls, acute UCM was associated with mild lymphopenia, splenomegaly, and high levels of IFN-γ, tumor necrosis factor-α, and IL-10, which normalized in convalescence. In Chikwawa, Treg counts were significantly (P < .0001) higher in convalescence compared with acute disease, whereas in Blantyre, these were as low as in healthy controls both during acute disease and in convalescence. Blantyre had a higher percentage of parasiteamic children (15% versus 12%) in convalescence compared with Chikwawa, but none of these developed symptomatic malaria during the study duration. Concentrations of TGF-β were higher at time points for the study participants and in controls from Blantyre compared with those recruited in Chikwawa.. The high transmission area was associated with high Tregs counts and IL-10 concentrations in convalescence, which could have an effect on parasite clearance. We recommend that children recovering from UCM, especially those from high transmission area, should sleep under insecticide-treated nets, be screened for parasitemia, and a provision of antimalarial prophylaxis should be considered.

Topics: Child, Preschool; Cohort Studies; Convalescence; Cytokines; Disease Transmission, Infectious; Female; HIV; HIV Infections; Humans; Infant; Interferon-gamma; Interleukin-10; Malaria; Malawi; Male; Parasitemia; Pre-Exposure Prophylaxis; Prospective Studies; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Host immune responses in disease including malaria are finely regulated by the opposing effects of Th17 and T regulatory (Treg) cells. Here we have examined the role of Treg cells and Th17 cells during malaria infection and find that low levels of Treg cells possibly influence the outcome of infections with the lethal strain of Plasmodium berghei ANKA (PbA). In contrast, high level of Treg cells may influence the outcome of nonlethal Plasmodium yoelii NXL (P. yoelii) infections. We observed decreased expressions of key regulators of Treg inductions-TGF-β, CD4IL-2 and IL-10 during PbA infection, whereas their expression remains high during P. yoelii infection. On the other hand TNF-α, IL-6, IFN-γ and IL-23 expression is high during PbA infection and lower during P. yoelii infection. Thus, results from this study suggest that the differential expression of Treg and Th17 might have a key role on host pathogenesis during malaria infection. The high level of IL-6 and low level of TGF-β may composite of the advantaged local microenvironment for the production of Th17 cells in the spleen of the PBA infected mice and vice verse during nonlethal P. yoelii.

Topics: Animals; CD4-CD8 Ratio; Erythrocytes; Forkhead Transcription Factors; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-6; Malaria; Malaria, Cerebral; Male; Mice; Parasitemia; Plasmodium berghei; Plasmodium yoelii; RNA, Messenger; Spleen; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Streptomyces sp LK-3 (JF710608) mediated Gold nanoparticles (Au-N-LK3) were found within the size range of 5-50 nm. Au-N-LK3 treatment in Plasmodium berghei ANKA (PbA) infected mice delayed the parasitemia rise (~6%) compared to PbA infection on 8 days post infection. Survivability of mice increases to ~85% in Au-N-LK3 treated mice in contrast to in PbA (~50%) infected mice in 8 dpi with respect to control. During Au-N-LK3 treatment in PbA infection, histomorphological analysis revealed as such no change in spleen and liver tissue during 8 dpi. Our results confirmed up-regulation of TGF-β and down-regulation of TNF-α in tissue and serum level in PbA infected Au-N-LK3 treated mice compared to PbA infection. No significant changes were found in the hatchability of Artemia embryos upto 8 mg. The results obtained suggest that the Au-N-LK3 possess anti-malarial activity and could be considered as a potential source for anti-malarial drug development.. These investigators present a method of marine actinobacteria mediated synthesis of gold nanoparticles, resulting in nanoparticles that possess anti-malarial activity and could be considered in future anti-malarial drug development.

Topics: Animals; Antimalarials; Cell Death; Gold; Liver; Malaria; Male; Metal Nanoparticles; Mice; Plasmodium berghei; Seawater; Spleen; Streptomyces; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; X-Ray Diffraction

Cerebral malaria is associated with the circulating levels of tumour necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β), but association between these two cytokines and implications in splenocyte apoptosis remain largely obscured. We have evaluated the outcome of TGF-β and TNF-α production in the context of splenocyte apoptosis during Plasmodium berghei ANKA (PbA) infection. Blood-stage PbA infection confirmed blood-brain barrier disruption, disarray of white pulp, increase in percentage of sub-G0/G1 and splenocyte apoptosis. Flow cytometric analysis reveals up-regulation of Fas-L followed by caspase-8 and caspase-3 activation and signifies possible involvement of Fas-L-mediated splenocyte apoptosis. We have observed down-regulation of TGF-β and up-regulation of TNF-α in tissue and serum level, respectively, during PbA infection. Association between the production of TGF-β and the severity of malaria infection in splenocytes was verified with TGF-β inhibitor that exacerbated the apoptotic process. In contrary, TNF-α inhibitor causes significant delay in apoptotic process, but could not alter the lethality of parasite. Thus, results from this study suggest that the critical balance between TGF-β and TNF-α might have a key role on Fas-L-mediated splenocyte apoptosis during experimental cerebral malaria.

Topics: Animals; Apoptosis; Benzamides; Cell Survival; Dioxoles; Fas Ligand Protein; Flow Cytometry; Gene Expression Regulation; Histocytochemistry; Malaria; Male; Membrane Potential, Mitochondrial; Mice; Parasitemia; Pentoxifylline; Plasmodium berghei; Spleen; Statistics, Nonparametric; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Cytokines play an important role in the defense against malaria and some have long been documented to influence the course of malaria infection in rodents and humans. The present study was conducted to determine the mRNA expression pattern of a few prominent cytokines at different time points during the course of infection with a nonlethal and lethal Plasmodium vinckei rodent malaria parasite, using highly sensitive real-time PCR. Analysis of mRNA expression of cytokines in spleen from infected mice revealed that the principal difference was an early depletion in pro-inflammatory cytokine's mRNA expression in mice infected with lethal P. vinckei (PvAS) parasites. In addition, an increase in anti-inflammatory cytokines particularly IL-10 mRNA expression levels was found in the same group of mice. In contrast, the significant rise in pro-inflammatory cytokine's mRNA expression levels was recorded at day 1 onwards after infection with nonlethal P. vinckei (PvAR). The maximum fold change was recorded for IFN-γ and IL-10, when compared to baseline value. TGF-β did not seem to play any major role in P. vinckei infection.

Topics: Animals; Interferon-gamma; Interleukin-10; Malaria; Mice; Mice, Inbred AKR; Plasmodium yoelii; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sequence Analysis, RNA; Spleen; Transforming Growth Factor beta

Transforming growth factor (TGF-β1) is a pleiotropic cytokine, secreted by immune and nonhematopoietic cells. TGF-β is involved in many different critical processes, such as embryonal development, cellular maturation and differentiation, wound healing, and immune regulation. It maintains immune homeostasis by acting as a potent immune suppressor through inhibition of proliferation, differentiation, activation, and effector function of immune cells. Paradoxically, depending on the context, it displays proinflammatory properties by being a potent chemoattractant for neutrophils and promoting inflammation. In addition, it does not only induce differentiation into the anti-inflammatory Treg cells, but also into the proinflammatory Th17 and Th9 cells and inhibits Th22 differentiation. TGF-β has been demonstrated to be involved in multiple pathologies. In infections, it protects against collateral damages caused by the immune system, but it also promotes immune evasion and chronic infections. In autoimmune diseases, a TGF-β dysfunction leads to the loss of tolerance to self-antigens. In cancer, TGF-β is a potent inhibitor of cell proliferation and acts as a tumor suppressor at the beginning of tumorogenesis. However, once the cells become resistant to TGF-β, it mainly supports tumor growth and metastasis by promoting immune evasion and angiogenesis. In asthma, it is assumed to promote allergen tolerance, but plays a detrimental role in irreversible remodeling of the airways. Despite the high numbers of TGF-β-targeted pathways, it is a promising drug target for treatment of autoimmunity, cancer, fibrosis, if cell specificity can be achieved.This review summarizes the progresses that have been accomplished on the understanding of TGF-β's signaling in the immune homeostasis and its role in pathogenesis.

Topics: Arthritis, Rheumatoid; Base Sequence; CD8 Antigens; Cells, Cultured; Cytokines; Diabetes Mellitus, Type 1; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Immune Tolerance; Interleukin-2; Interleukin-4; Malaria; Molecular Sequence Data; Multiple Sclerosis; Promoter Regions, Genetic; Signal Transduction; Transcription Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Placental infections with Plasmodium falciparum are associated with fetal growth restriction resulting in low birth weight (LBW). The mechanisms that mediate these effects have yet to be completely described; however, they are likely to involve inflammatory processes and dysregulation of angiogenesis. Soluble endoglin (sEng), a soluble receptor of transforming growth factor (TGF)-β previously associated with preeclampsia in pregnant women and with severe malaria in children, regulates the immune system and influences angiogenesis. We hypothesized that sEng may play a role in development of LBW associated with placental malaria (PM). Plasma levels of sEng were measured in women (i) followed prospectively throughout pregnancy in Cameroon (n = 52), and (ii) in a case-control study at delivery in Malawi (n = 479). The relationships between sEng levels and gravidity, peripheral and placental parasitemia, gestational age, and adverse outcomes of PM including maternal anemia and LBW were determined. In the longitudinal cohort from Cameroon, 28 of 52 women (54%) experienced at least one malaria infection during pregnancy. In Malawi we enrolled two aparasitemic gravidity-matched controls for every case with PM. sEng levels varied over the course of gestation and were significantly higher in early and late gestation as compared to delivery (P<0.006 and P<0.0001, respectively). Circulating sEng levels were higher in primigravidae than multigravidae from both Cameroon and Malawi, irrespective of malarial infection status (p<0.046 and p<0.001, respectively). Peripheral parasitemia in Cameroonian women and PM in Malawian women were each associated with elevated sEng levels following correction for gestational age and gravidity (p = 0.006 and p = 0.033, respectively). Increased sEng was also associated with the delivery of LBW infants in primigravid Malawian women (p = 0.017); the association was with fetal growth restriction (p = 0.003) but not pre-term delivery (p = 0.286). Increased circulating maternal sEng levels are associated with P. falciparum infection in pregnancy and with fetal growth restriction in primigravidae with PM.

Topics: Adolescent; Adult; Antigens, CD; Cameroon; Case-Control Studies; Endoglin; Female; Fetal Growth Retardation; Gestational Age; Humans; Malaria; Malawi; Neovascularization, Physiologic; Placenta; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Prospective Studies; Receptors, Cell Surface; Transforming Growth Factor beta

Circulation CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) have been associated with the delicate balancing between control of overwhelming acute malaria infection and prevention of immune pathology due to disproportionate inflammatory responses to erythrocytic stage of the parasite. While the role of Tregs has been well-documented in murine models and P. falciparum infection, the phenotype and function of Tregs in P. vivax infection is still poorly characterized. In the current study, we demonstrated that patients with acute P. vivax infection presented a significant augmentation of circulating Tregs producing anti-inflammatory (IL-10 and TGF-beta) as well as pro-inflammatory (IFN-gamma, IL-17) cytokines, which was further positively correlated with parasite burden. Surface expression of GITR molecule and intracellular expression of CTLA-4 were significantly upregulated in Tregs from infected donors, presenting also a positive association between either absolute numbers of CD4(+)CD25(+)FoxP3(+)GITR(+) or CD4(+)CD25(+)FoxP3(+)CTLA-4(+) and parasite load. Finally, we demonstrate a suppressive effect of Treg cells in specific T cell proliferative responses of P. vivax infected subjects after antigen stimulation with Pv-AMA-1. Our findings indicate that malaria vivax infection lead to an increased number of activated Treg cells that are highly associated with parasite load, which probably exert an important contribution to the modulation of immune responses during P. vivax infection.

Topics: Adult; Antigens, CD; CD4-Positive T-Lymphocytes; Cell Proliferation; CTLA-4 Antigen; Forkhead Transcription Factors; Humans; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-2 Receptor alpha Subunit; Malaria; Middle Aged; Phenotype; Plasmodium vivax; Transforming Growth Factor beta

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

Immunization with Plasmodium yoelii merozoite surface protein (PyMSP)-8 protects mice from lethal malaria but does not prevent infection. Using this merozoite surface protein-based vaccine model, we investigated vaccine- and infection-induced immune responses that contribute to protection. Analysis of prechallenge sera from rPyMSP-8-immunized C57BL/6 and BALB/c mice revealed high and comparable levels of Ag-specific IgG, but differences in isotype profile and specificity for conformational epitopes were noted. As both strains of mice were similarly protected against P. yoelii, we could not correlate vaccine-induced responses with protection. However, passive immunization studies suggested that protection resulted from differing immune responses. Studies with cytokine-deficient mice showed that protection was induced by immunization of C57BL/6 mice only when IL-4 and IFN-gamma were both present. In BALB/c mice, the absence of either IL-4 or IFN-gamma led to predictable shifts in the IgG isotype profile but did not reduce the magnitude of the Ab response induced by rPyMSP-8 immunization. Immunized IL-4-/- BALB/c mice were solidly protected against P. yoelii. To our surprise, immunized IFN-gamma-/- BALB/c mice initially controlled parasite growth but eventually succumbed to infection. Analysis of cytokine production revealed that P. yoelii infection induced two distinct peaks of IFN-gamma that correlated with periods of controlled parasite growth in intact, rPyMSP-8-immunized BALB/c mice. Maximal parasite growth occurred during a period of sustained TGF-beta production. Combined, the data indicate that induction of protective responses by merozoite surface protein-based vaccines depends on IL-4 and IFN-gamma-dependent pathways and that vaccine efficacy is significantly influenced by host responses elicited upon infection.

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Interferon-gamma; Interleukin-4; Malaria; Malaria Vaccines; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Plasmodium yoelii; Protozoan Proteins; Transforming Growth Factor beta; Vaccination

Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 Abs, but there has been considerable debate about the effectiveness of this strategy. In this study, we have compared the depletion and repopulation of CD4+CD25+Foxp3+ Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 Abs. We find that numbers and percentages of CD25(high) cells, but not Foxp3+ cells, are transiently reduced after 7D4 treatment, whereas treatment with PC61 alone or in combination with 7D4 (7D4 plus PC61) reduces but does not eliminate Foxp3+ cells for up to 2 wk. Importantly, all protocols fail to eliminate significant populations of CD25-Foxp3+ or CD25(low)Foxp3+ cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25(high)Foxp3+ cells results from the re-expression of CD25 on peripheral populations of CD25-Foxp3+ but not from the conversion of peripheral Foxp3-) cells. CD25(high)Foxp3+ repopulation occurs more rapidly in 7D4-treated mice than in 7D4 plus PC61-treated mice, reflecting ongoing clearance of emergent CD25+Foxp3+ cells by persistent PC61 Ab. However, in 7D4 plus PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25+Foxp3+ cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4+CD25-Foxp3+ cells and/or conversion of CD4+CD25-Foxp3- cells. Finally, we reveal an essential role for IL-2 for the re-expression of CD25 by Foxp3+ cells after anti-CD25 treatment and observe that TGF-beta is required, in the absence of CD25 and IL-2, to maintain splenic Foxp3+ cell numbers and a normal ratio of Treg:non-Treg cells.

Topics: Animals; Antibodies, Monoclonal; CD4 Antigens; Disease Models, Animal; Forkhead Transcription Factors; Immunoglobulin G; Immunoglobulin M; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphocyte Depletion; Malaria; Mice; Mice, Inbred C57BL; Plasmodium yoelii; Regeneration; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

During an acute blood-stage malaria infection, T cell responses to malaria and other bystander antigens are inhibited. Plasmodium infection induces strong cytokine responses that facilitate parasite clearance but may interfere with T cell functions, as some of the soluble immune mediators induced are also general inhibitors of T cell responses. Using a malaria mouse model, we have analyzed the cytokines produced by dendritic cells in response to P. yoelii infection that have potential T cell inhibitory activity. We found that during acute infection DC migrate to the spleen and secrete TGF-beta, prostaglandin E2 (PGE2) and IL-10. We have analyzed the role of these general T cell inhibitors in a particular T cell response of evident importance in malaria infections: the CD8+ T cells generated against the liver-stage of the disease. During blood-stage infection, inhibition of the activity of TGF-beta and PGE2 restores the CD8+ T cell responses generated by sporozoites, increasing protection against re-infection. Our findings suggest that the strong cytokine response induced by blood-stage P. yoelii infection affects host T cell responses, inhibiting protective CD8+ T cells against the liver-stage of the disease.

Topics: 16,16-Dimethylprostaglandin E2; Adoptive Transfer; Animals; Antibodies, Monoclonal; Antigens, Protozoan; CD11c Antigen; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dendritic Cells; Dinoprostone; Erythrocytes; Interleukin-10; Malaria; Mice; Mice, Inbred BALB C; Peptide Fragments; Plasmodium yoelii; Receptors, CCR7; Receptors, Chemokine; Receptors, Transforming Growth Factor beta; Spleen; T-Lymphocytes; Transforming Growth Factor beta; Vaccination

The natural killer complex (NKC) is a genetic region of highly linked genes encoding several receptors involved in the control of NK cell function. The NKC is highly polymorphic, and allelic variability of various NKC loci has been demonstrated in inbred mice. Making use of BALB.B6-Cmv1r congenic mice, in which the NKC from disease-susceptible C57BL/6 mice has been introduced into the disease-resistant BALB/c background, we show here that during murine malaria infection, the NKC regulates a range of pathophysiological syndromes such as cerebral malaria, pulmonary edema, and severe anemia, which contribute to morbidity and mortality in human malaria. Parasitemia levels were not affected by the NKC genotype, indicating that control of malarial fatalities by the NKC cells does not operate through effects on parasite growth rate. Parasite-specific antibody responses and the proinflammatory gene transcription profile, as well as the TH1/TH2 balance, also appeared to be influenced by NKC genotype, providing evidence that this region, known to control innate immune responses via NK and/or NK T-cell activation, can also significantly regulate acquired immunity to infection. To date, NKC-encoded innate system receptors have been shown mainly to regulate viral infections. Our data provide evidence for critical NKC involvement in the broad immunological responses to a protozoan parasite.

Topics: Anemia; Animals; Antibodies, Protozoan; Brain; Gene Expression Profiling; Interferon-gamma; Killer Cells, Natural; Malaria; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmodium berghei; Pulmonary Edema; Transforming Growth Factor beta

Helminthiases, which are highly prevalent in areas where malaria is endemic, have been shown to modulate or suppress the immune response to unrelated antigens or pathogens. In this study, we established a murine model of coinfection with a gastrointestinal nematode parasite, Heligmosomoides polygyrus, and the blood-stage malaria parasite Plasmodium chabaudi AS in order to investigate the modulation of antimalarial immunity by concurrent nematode infection. Chronic infection with the nematode for 2, 3, or 5 weeks before P. chabaudi AS infection severely impaired the ability of C57BL/6 mice to control malaria, as demonstrated by severe mortality and significantly increased malaria peak parasitemia levels. Coinfected mice produced significantly lower levels of gamma interferon (IFN-gamma) during P. chabaudi AS infection than mice infected with malaria alone. Concurrent nematode infection also suppressed production of type 1-associated, malaria-specific immunoglobulin G2a. Mice either infected with the nematode alone or coinfected with the nematode and malaria had high transforming growth factor beta1 (TGF-beta1) levels, and concurrent nematode and malaria infections resulted in high levels of interleukin-10 in vivo. Splenic CD11c(+) dendritic cells (DC) from mice infected with malaria alone and coinfected mice showed similarly increased expression of CD40, CD80, and CD86, but DC from coinfected mice were unable to induce CD4(+) T-cell proliferation and optimal IFN-gamma production in response to the malaria antigen in vitro. Importantly, treatment of nematode-infected mice with an anthelmintic drug prior to malaria infection fully restored protective antimalarial immunity and reduced TGF-beta1 levels. These results demonstrate that concurrent nematode infection strongly modulates multiple aspects of immunity to blood-stage malaria and consequently impairs the development of protective antimalarial immunity.

Topics: Animals; Antibodies, Protozoan; Cytokines; Dendritic Cells; Erythrocytes; Female; Interleukin-4; Malaria; Male; Mice; Mice, Inbred BALB C; Nematospiroides dubius; Plasmodium chabaudi; Strongylida Infections; Transforming Growth Factor beta

Our previous observation that B-cell-deficient JH-/- mice utilize T cell-dependent immunity to suppress acute Plasmodium chabaudi adami-induced malaria but then develop chronic low-level parasitemia prompted this study of control mechanisms for chronic parasitemia. When we infected JH-/- mice with blood-stage parasites, chronic parasitemia exacerbated after the 6th month and persisted for up to 17 months. This exacerbation of parasitemia could not be attributed to host aging because the time-course of acute infection in naïve aged mice was nearly identical to that seen in young mice. Nor could exacerbated parasitemia be attributed to mutation in the parasite genome resulting in increased virulence; when subinoculated into naïve JH-/- mice, parasites from chronically infected JH-/- mice with exacerbated parasitemia produced acute stage parasitemia profiles in most recipients comparable to those seen in JH-/- mice upon infection with the original stabilate material. Of the pro-inflammatory cytokines measured, including IFNgamma, TNFalpha, IL-12p70, and MCP-1beta, none were significantly different in the sera of mice with exacerbated parasitemia compared to uninfected controls. Levels of IL-6 were significantly (P=0.002) less in the sera of mice with exacerbated parasitemia. Serum levels of the anti-inflammatory cytokine, TGFbeta, were significantly depressed in chronically infected JH-/- mice compared to uninfected controls. In contrast, IL-10 levels were markedly increased. These findings suggest that the cytokine balance may be disturbed during chronic malaria, thereby impacting on mechanisms that modulate levels of parasitemia.

Topics: Aging; Animals; B-Lymphocytes; Chronic Disease; Cytokines; Female; Immunity, Cellular; Interleukin-10; Malaria; Male; Mice; Mice, Inbred C57BL; Parasitemia; Plasmodium chabaudi; T-Lymphocytes; Time Factors; Transforming Growth Factor beta; Virulence

The participation of a divergent mosquito transforming growth factor-beta (TGF-beta) and mammalian TGF-beta1 in the Anopheles stephensi response to malaria parasite development [Infect. Genet. Evol. 1 (2001) 131-141; Infect. Immun. 71 (2003) 3000-3009] suggests that a network of Anopheles TGF-beta ligands and signaling pathways figure prominently in immune defense of this important vector group. To provide a basis for identifying the roles of these proteins in Anopheles innate immunity, we identified six predicted TGF-beta ligand-encoding genes in the Anopheles gambiae genome, including two expressed, diverged copies of 60A, the first evidence of ligand gene duplication outside of chordates. In addition to five predicted type I and II receptors, we identified three Smad genes in the A. gambiae genome that would be predicted to support both TGF-beta/Activin- and bone morphogenetic protein (BMP)-like signaling. All three Smad genes are expressed in an immunocompetent A. stephensi cell line and in the A. stephensi midgut epithelium, confirming that a conserved signaling architecture is in place to support signaling by divergent exogenous and endogenous TGF-beta superfamily proteins.

Topics: Amino Acid Sequence; Animals; Base Sequence; Culicidae; Humans; Ligands; Malaria; Molecular Sequence Data; Phylogeny; Plasmodium; Sequence Alignment; Signal Transduction; Transforming Growth Factor beta

During the process of bloodfeeding by Anopheles stephensi, mammalian latent transforming growth factor beta1 (TGF-beta1) is ingested and activated rapidly in the mosquito midgut. Activation may involve heme and nitric oxide (NO), agents released in the midgut during blood digestion and catalysis of L-arginine oxidation by A. stephensi NO synthase (AsNOS). Active TGF-beta1 persists in the mosquito midgut to extended times postingestion and is recognized by mosquito cells as a cytokine. In a manner analogous to the regulation of vertebrate inducible NO synthase and malaria parasite (Plasmodium) infection in mammals by TGF-beta1, TGF-beta1 regulates AsNOS expression and Plasmodium development in A. stephensi. Together, these observations indicate that, through conserved immunological cross talk, mammalian and mosquito immune systems interface with each other to influence the cycle of Plasmodium development.

Topics: Animals; Anopheles; Humans; Intestinal Mucosa; Malaria; Nitric Oxide; Nitric Oxide Synthase; Penicillamine; Peroxynitrous Acid; Plasmodium falciparum; Transforming Growth Factor beta; Transforming Growth Factor beta1

Interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice infected with Plasmodium chabaudi (AS) suffer a more severe disease and exhibit a higher rate of mortality than control C57BL/6 mice. Here, we show that a drop in body temperature to below 28 degrees C and pronounced hypoglycemia of below 3 mM are reliable indicators of a lethal infection. Elevated inflammatory responses have been shown to accompany pathology in infected IL-10(-/-) mice. We show that neutralization of tumor necrosis factor alpha (TNF-alpha) in IL-10(-/-) mice abolishes mortality and ameliorates the hypothermia, weight loss, and anemia but does not affect the degree of hypoglycemia. These data suggest that TNF-alpha is involved in some of the pathology associated with a P. chabaudi infection in IL-10(-/-) mice but other factors play a role. IL-10(-/-) mice that survive a primary infection have been shown to control gamma interferon (IFN-gamma) and TNF-alpha production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor beta (TGF-beta), a cytokine with such properties, are present in the plasma of infected IL-10(-/-) mice at a time that coincides with the disappearance of IFN-gamma and TNF-alpha from the blood. Neutralization of TGF-beta in IL-10(-/-) mice resulted in higher circulating amounts of TNF-alpha and IFN-gamma, and all treated IL-10(-/-) mice died within 12 days with increased pathology but with no obvious increase in parasitemia. Our data suggest that a tight regulation of the balance between regulatory cytokines such as IL-10 and TGF-beta and inflammatory cytokines such as IFN-gamma and TNF-alpha is critical for survival in a mouse malaria infection.

Topics: Animals; Antibodies; Female; Inflammation Mediators; Interferon-gamma; Interleukin-10; Malaria; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutralization Tests; Plasmodium chabaudi; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Transforming growth factor-beta is an essential moderator of malaria-induced inflammation in mice. In this study, we show that the virulence of malaria infections is dependent upon the cellular source of TGF-beta and the timing of its production. C57BL/6 mice infected with a nonlethal (Py17X) strain of Plasmodium yoelii produce TGF-beta from 5 days postinfection; this correlates with resolution of parasitemia, down-regulation of TNF-alpha, and full recovery. In contrast, infection with the lethal strain Py17XL induces high levels of circulating TGF-beta within 24 h; this is associated with delayed and blunted IFN-gamma and TNF-alpha responses, failure to clear parasites, and 100% mortality. Neutralization of early TGF-beta in Py17XL infection leads to a compensatory increase in IL-10 production, while simultaneous neutralization of TGF-beta and IL-10R signaling leads to up-regulation of TNF-alpha and IFN-gamma, prolonged survival in all, and ultimate resolution of infection in 40% of Py17XL-infected animals. TGF-beta production can be induced in an Ag-specific manner from splenocytes of infected mice, and by cross-linking surface CTLA-4. CD25(+) and CD8(+) cells are the primary source of TGF-beta following Py17X stimulation of splenocytes, whereas Py17XL induces significant production of TGF-beta from adherent cells. In mice immunized against Py17XL, the early TGF-beta response is inhibited and is accompanied by significant up-regulation of IFN-gamma and TNF-alpha and rapid resolution of challenge infections.

Topics: Animals; Cell Adhesion; Cells, Cultured; Cytokines; Down-Regulation; Epitopes, T-Lymphocyte; Immune Sera; Inflammation Mediators; Interferon-gamma; Malaria; Malaria Vaccines; Mice; Mice, Inbred C57BL; Parasitemia; Plasmodium yoelii; Receptors, Interleukin-2; Spleen; T-Lymphocyte Subsets; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Antigen-presenting cells (APC) play a key role in orchestrating immune responses. T-cell proliferative responses are inhibited during the erythrocyte stages of malaria infection, and a number of studies have suggested that APC are responsible for this phenomenon. In the present studies we examine individual components of the T-cell-activating function of APC: expression of costimulatory and major histocompatibility complex (MHC) class II proteins, the ability to process and present antigen to T cells, and the ability to support cytokine production. We find that during the acute phases of Plasmodium yoelii erythrocyte stage infection, APC upregulate the expression of class II MHC and CD80, maintain expression of CD86, process and present antigen, and support gamma interferon production. However the CD11b(+) subpopulation produces a soluble factor or factors that specifically inhibit interleukin-2 (IL-2) production by responding CD4 T cells. This factor is distinct from prostaglandin E(2), NO, or transforming growth factor beta. The data suggest that IL-2 suppression observed during malaria infection is not due to functional defects of APC but is triggered by production of a factor(s) that actively suppresses production of IL-2 by T cells.

Topics: Animals; Antigen-Presenting Cells; Antigens, CD; B7-1 Antigen; B7-2 Antigen; Cell Division; Cells, Cultured; Dinoprostone; Disease Models, Animal; Female; Histocompatibility Antigens Class II; Interferon-gamma; Interleukin-2; Malaria; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Plasmodium yoelii; T-Lymphocytes; Transforming Growth Factor beta

Topics: Animals; Humans; Immunity, Active; Interleukin-12; Malaria; Malaria Vaccines; Mice; Transforming Growth Factor beta

The role of transforming growth factor beta (TGF-beta) in infection with Plasmodium chabaudi was investigated with resistant and susceptible mouse models. C57BL/10 mice produced gamma interferon (IFN-gamma) and nitric oxide (NO) shortly after infection and cleared the parasite spontaneously. In contrast, BALB/c mice showed a transient enhancement of TGF-beta production, followed by a relative lack of IFN-gamma and NO production, and succumbed to the infection. However, there was no correlation between levels of serum TGF-beta and splenic TGF-beta mRNA in both mouse strains before and after infection. Administration of recombinant TGF-beta (rTGF-beta) rendered resistant mice susceptible because of suppression of subsequent production of IFN-gamma and NO. Administration of anti-TGF-beta antibody to the infected BALB/c mice resulted in remarkable increases in serum IFN-gamma and NO, and the mice resisted the infection. Splenic CD4(+) T and CD11b+ cells of C57BL/10 mice were significantly activated after infection, but this was completely abrogated by administration of rTGF-beta. These results suggested that, in the P. chabaudi-susceptible but not resistant mice, production of TGF-beta was promoted, and subsequent failure of IFN-gamma- and NO-dependent resistance to the parasite was induced. This study is the first to indicate that TGF-beta production was the key event in failure of resistance to mouse malaria.

Topics: Animals; Antibodies, Monoclonal; Base Sequence; CD4-Positive T-Lymphocytes; DNA Primers; Female; Interferon-gamma; Kinetics; Lymphocyte Activation; Macrophage-1 Antigen; Malaria; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Plasmodium chabaudi; Recombinant Proteins; RNA, Messenger; Spleen; Transforming Growth Factor beta

We have examined the role of the immunomodulatory cytokine transforming growth factor (TGF)-beta in the resolution and pathology of malaria in BALB/c mice. Circulating levels of TGF-beta, and production of bioactive TGF-beta by splenocytes, were found to be low in lethal infections with Plasmodium berghei. In contrast, resolving infections with P. chabaudi chabaudi or P. yoelii were accompanied by significant TGF-beta production. A causal association between the failure to produce TGF-beta and the severity of malaria infection was demonstrated by treatment of infected mice with neutralizing antibody to TGF-beta, which exacerbated the virulence of P. berghei and transformed a resolving P. chabaudi chabaudi infection into a lethal infection, but had little effect on the course of P. yoelii infection. Parasitemia increased more rapidly in anti-TGF-beta-treated mice but this did not seem to be the explanation for the increased pathology of infection as peak parasitemias were unchanged. Treatment of P. berghei-infected mice with recombinant TGF-beta (rTGF-beta) slowed the rate of parasite proliferation and prolonged their survival from 15 to up to 35 d. rTGF-beta treatment was accompanied by a significant decrease in serum tumor necrosis factor alpha and an increase in interleukin 10. Finally, we present evidence that differences in TGF-beta responses in different malaria infections are due to intrinsic differences between species of malaria parasites in their ability to induce production of TGF-beta. Thus, TGF-beta seems to induce protective immune responses, leading to slower parasite growth, early in infection, and, subsequently, appears to downregulate pathogenic responses late in infection. This duality of effect makes TGF-beta a prime candidate for a major immunomodulatory cytokine associated with successful control of malaria infection.

Topics: Animals; Antibodies, Monoclonal; Cytokines; Disease Models, Animal; Interleukin-10; Malaria; Male; Mice; Mice, Inbred BALB C; Monocytes; Plasmodium; Recombinant Proteins; Spleen; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha