Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection with Plasmodium berghei ANKA (PbA) leads, in susceptible strains of mice, to the development of cerebral malaria (CM), a lethal syndrome that reproduces some features of human CM. To study a possible relationship between genetic susceptibility to CM and the cytokine expression pattern, we quantitatively evaluated gene expression on RNA extracted from various organs of malaria-infected mice, using strains that are susceptible and resistant to CM. Northern blot analysis and semi-quantitative PCR showed that CM is associated with an increased TNF-alpha mRNA accumulation in the brain of mice developing the neurologic complications of CM. An increased IFN-gamma mRNA accumulation and a decreased expression of IL-4 and TGF-beta genes were also observed in mice susceptible to CM. In vitro restimulation studies using crude malarial Ag showed that lymphoid cell proliferation was higher in CM-susceptible than in CM-resistant infected mice. Moreover, susceptible mice produced large amounts of IFN-gamma, in a dose-dependent manner, in response to PbA Ag, whereas cells from resistant mice failed to produce significant amounts of this cytokine. Conversely, IL-2 and IL-4 production was significantly higher in infected CM-resistant mouse cells. No difference was seen in the production of IL-3 and IL-5 between resistant and susceptible PbA-infected mice. Upon stimulation with various malarial Ag, comparable amounts of TNF-alpha were produced by macrophages of either strain of mice. Taken together, these findings indicate that susceptibility to CM resides at the level of T cells rather than macrophages. Furthermore, the cytokine production profile is consistent with a predominant Th1-like response in mice developing cerebral complications of malaria.
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PMID:Profiles of cytokine production in relation with susceptibility to cerebral malaria. 840 39

Pregnant women, especially primigravidas, are highly susceptible to malaria infection, resulting in maternal anemia and low birth weight infants. Because circulating parasitemia is rare in the newborn, the cause of poor fetal outcomes has been unclear. We measured cytokine concentrations in placentas collected from women delivering in urban hospitals in malaria-holoendemic or nonendemic areas of Kenya. Normal placentas displayed a bias toward type 2 cytokines; type 1 cytokines IFN-gamma and IL-2 were absent in placentas not exposed to malaria but present in a large proportion of placentas from a holoendemic area. TNF-alpha and TGF-beta concentrations were significantly higher, and IL-10 concentrations significantly lower, in placentas from the holoendemic area. Among primigravidas, placental TNF-alpha concentrations were significantly higher in the presence of severe maternal anemia, and both IFN-gamma and TNF-alpha were significantly elevated when a low birth weight, rather than normal weight, infant was delivered. We conclude that maternal malaria decreases IL-10 concentrations and elicits IFN-gamma, IL-2, and TNF-alpha in the placenta, shifting the balance toward type 1 cytokines. This is the first demonstration that these placental cytokine changes are associated with poor pregnancy outcomes in humans.
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PMID:Malaria elicits type 1 cytokines in the human placenta: IFN-gamma and TNF-alpha associated with pregnancy outcomes. 949 98

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.
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PMID:Transforming growth factor beta production is inversely correlated with severity of murine malaria infection. 965 82

Evidence from clinical studies and murine models supports a role for cytokines in the pathogenesis of human cerebral malaria (CM). In this study, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate expression of mRNA for transforming growth factor (TGF)-beta, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha in human postmortem tissue. Immunohistochemistry was used to examine the distribution of cytokine protein. TGF-beta was expressed in normal brain, in CM, and in meningitis and encephalitis. IL-1beta was absent from normal brain but was detected in CM and other cerebral infections. TNF-alpha mRNA was expressed only in CM, although TNF-alpha protein was also seen in meningitis. Cytokine mRNA expression in the brain did not correlate with the density of parasitized erythrocytes detected using RT-PCR for major surface protein-2. This report of RT-PCR on postmortem human tissues infected with CM demonstrates induction of the proinflammatory cytokines TNF-alpha and IL-1beta in the brain.
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PMID:Cytokine expression in the brain in human cerebral malaria. 1051 46

We have isolated the first mosquito member of the TGF-beta superfamily, As60A. As60A is a single copy gene, approximately 5 kb in length and encodes eight exons. Here we report the isolation and characterization of two of four transcripts produced from this gene. The transcripts As60A(1)and As60A(2)encode related 5'UTR/exon 1 sequences. As60A is most similar to the 60A genes from Drosophila and is thus a member of the Dpp/BMP subfamily of the TGF-beta superfamily. The splice junction of intron 2 is conserved among As60A, BMP2, BMP4, Tc-Dpp, Bm-tgh-1, TGF-beta1 and Dpp. Intron 2 also contains three putative binding sites for a Dorsal/Gambif1 transcription factor. The large number of introns and the conservation of intron 2 indicate that As60A is relatively ancient compared to the other arthropod TGF-beta genes. We also propose that As60A plays a role in the mosquito immune response to Plasmodium infection.
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PMID:Isolation and characterization of As60A, a transforming growth factor-beta gene, from the malaria vector Anopheles stephensi. 1114 45

During pregnancy, a local and systemic Th2 bias of maternal immunity favors Th1-dependent infections such as malaria. This study measured cytokines secreted in cultures of chorionic villi, placental blood cells (PBC), and serum in term placentas from 88 malaria-infected and -noninfected Cameroon women. Interleukin (IL)--2 and --4 were consistently low; IL-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)--beta 2 were highest in villi cultures. Tumor necrosis factor (TNF)--alpha, interferon (IFN)--gamma, and IL-10 were highest in PBC cultures. Malaria placental infection increased Th1-type cytokines, whereas Th2-type cytokines and TGF-beta 2 were unchanged. Addition of lipopolysaccharide or infected erythrocytes to cultures increased TNF-alpha, IL-1 beta, IL-6, and IL-10 secretions but not those of IFN-gamma and IL-4. Overall, Plasmodium falciparum induced a placental immune response involving both Th1- and Th2-type cell activation. Although the Th1 pathway was favored, IL-10 secretion was also increased, and this increase should be effective in protecting the placenta by controlling the negative effects of Th1 cytokines on pregnancy.
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PMID:Plasmodium falciparum induces a Th1/Th2 disequilibrium, favoring the Th1-type pathway, in the human placenta. 1131 91

This was a prospective study conducted at the Moi Teaching and Referral Hospital, Eldoret, Kenya. Twenty-three children admitted to the hospital with cerebral (CM) and 10 children with non-cerebral malaria (NCM) were studied. The aim of the study was to establish and compare levels of tumour necrosis factor (TNF-alpha) and transforming growth factor (TGF-beta1) in these children. Serum and cerebrospinal fluid (CSF) cytokine levels were assayed using ELISA kits. In serum, TGF-beta1 and TNF-alpha decreased over 5 days after admission to the hospital in both groups of patients with CM and NCM. In the CSF of cerebral cases the levels of TNF-alpha and TGF-beta1 were low and inversely related. Children in deeper coma had lower levels in serum of TGF-beta and higher levels of TNF-alpha than those in lighter levels of coma. The serum TNF-alpha levels in CM children were the same irrespective of the duration of illness before admission, but children with NCM who had been sick for a shorter duration before admission tended to have higher serum levels of TNF-alpha and higher levels of TGF-beta than those with a longer duration of illness before admission. In conclusion, this study shows that TNF-alpha and TGF-beta1 may not be useful in predicting the outcome for CM. They may, however, be useful in detecting children at risk of developing deep coma. TNF-alpha and TGF-beta levels were inversely related both in serum and CSF.
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PMID:Cerebral malaria in children: serum and cerebrospinal fluid TNF-alpha and TGF-beta levels and their relationship to clinical outcome. 1292 82

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.
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PMID:Differential induction of TGF-beta regulates proinflammatory cytokine production and determines the outcome of lethal and nonlethal Plasmodium yoelii infections. 1460 47

Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon gamma, and tumor necrosis factor alpha), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-beta plays a crucial role in preventing the severe pathology of malaria in mice and TGF-beta production is associated with reduced risk of clinical malaria in humans. Here we show that serum-free preparations of Plasmodium falciparum, Plasmodium yoelii 17XL, and Plasmodium berghei schizont-infected erythrocytes, but not equivalent preparations of uninfected erythrocytes, are directly able to activate latent TGF-beta (LatTGF-beta) in vitro. Antibodies to thrombospondin (TSP) and to a P. falciparum TSP-related adhesive protein (PfTRAP), and synthetic peptides from PfTRAP and P. berghei TRAP that represent homologues of TGF-beta binding motifs of TSP, all inhibit malaria-mediated TGF-beta activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-beta than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-beta by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-beta represents a novel mechanism for direct modulation of the host response by malaria parasites.
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PMID:Activation of transforming growth factor beta by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule. 1467 96

Malaria and schistosomiasis are the two major parasite diseases present in developing countries. The epidemiological co-infection with schistosomiasis could influence the development of the physiological reaction associated with Plasmodium falciparum infection in human. Most studies have demonstrated the association of circulating levels of interferon-gamma (IFN-gamma), tumour necrosis factor-a (TNF-alpha), interleukin-10 (IL-10), transforming growth factor (TGF-beta) and soluble Tumour Necrosis Factor Receptors (sTNF-RI and sTNF-RII) with the morbidity of malaria. In the present study, we showed that Schistosoma haematobium co-infection influences, in an age-dependent manner, the unbalance between pro- and anti-inflammatory circulating cytokines that play a key role during malaria infection. Indeed, children co-infected by S. haematobium have higher levels of IFN-gamma and sTNF-RII than children infected only by P. falciparum. In contrast, co-infected adults presented a significant increase of IFN-gamma, IL-10, TGF-beta, sTNF-RI and sTNF-RII rates and IL-10/TNF-alpha ratio. Taken together, this study indicates that schistosomiasis co-infection can unbalance the regulation of inflammatory factors in uncomplicated P. falciparum malaria. The possible consequences of the schistosomiasis co-infection for age-dependent malaria morbidity are discussed.
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PMID:Schistosomiasis co-infection in humans influences inflammatory markers in uncomplicated Plasmodium falciparum malaria. 1567 34


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