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Malaria Infection (malaria + infection)
Selected AbstractsExpression of immune responsive genes in cell lines from two different Anopheline speciesINSECT MOLECULAR BIOLOGY, Issue 6 2006C. Luna Abstract Malaria infection results in increased expression of immune responsive genes, including those encoding antimicrobial peptides such as Gambicin (Gam1) and Cecropin A (Cec1). Understanding how these genes are regulated will provide insights how the mosquito immune system is activated by Plasmodium. We previously have shown that Cec1 was primarily regulated by the Imd-Relish (REL2) pathway in the Anopheles gambiae Sua1B cell line. We show here that expression of Defensin A (Def1) and Gam1 was reduced after RNA interference against components of the Imd- REL2 pathway in An. gambiae cell lines. Interestingly, promoter reporters of these antimicrobial peptides were expressed at very low level in the cell line MSQ43 from Anopheles stephensi. Surprisingly, over-expression of either NF-,B transcription factor REL1 or REL2 alone is sufficient to induce the expression of Cec1, Gam1 and Def1. These results suggest that expression of these antimicrobial peptides (AMP) in vivo may be regulated by both the Toll and Imd pathways. We also show here for the first time that Tep4, a gene encoding a thioester containing protein, is regulated by REL2. Taken together, these results suggest that there are significant overlaps of genes regulated by the Toll-Rel1 and Imd-Rel2 pathways. Further, the different expression patterns in two different Anopheline cell lines provide a platform to identify other key positive and negative regulators of the antimicrobial peptide genes. [source] Multiple functions of human T cells generated by experimental malaria challengeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Stephen M. Todryk Abstract Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-,, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum -infected RBC (iRBC) Ag, 28 and 90,days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-, cultured ELISPOT, were low and unstable over time, despite CD4+ T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-,, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-, measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed. [source] Synthesis of "Trioxaquantel"® Derivatives as Potential New Antischistosomal DrugsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 5 2008Sophie A.-L. Abstract Over the past 20 years, praziquantel, a pyrazinoisoquinoline derivative, has become the mainstay for morbidity control of human and animal schistosomiasis. From early in their lives in vertebrate hosts, schistosomes ingest hemoglobin and aggregate the released heme as a dark pigment very similar to the hemozoin produced by Plasmodium in malaria infection. The antimalarial artemisinin derivatives have real, though low, schistosomicide activity. Because of the complementarity of the two drug classes , praziquantel and artemisinin derivatives , we designed new molecules, named trioxaquantels®, that combine the 1,2,4-trioxane unit responsible for the activity of artemisinin, and the pyrazinoisoquinoline moiety of praziquantel within a single drug. The synthesis of these new drugs and their preliminary evaluation in mice infected with Schistosoma mansoni is reported here.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Associations Between Helicobacter pylori Infection, Co-Morbid Infections, Gastrointestinal Symptoms, and Circulating Cytokines in African ChildrenHELICOBACTER, Issue 2 2010Sarah Cherian Abstract Background:, Refugee children have complex medical needs and often have multiple infections. The relationship between infection, gastrointestinal symptoms, and systemic inflammation is poorly understood. We investigated these parameters in refugee children with a high prevalence of Helicobacter pylori, helminth, and malaria infection. Materials and Methods:, African refugee children were recruited at resettlement health screening. Data were collected on demography, gastrointestinal symptoms, co-morbid infection, and serum for peripheral cytokine levels. Helicobacter pylori infection was diagnosed by a fecal-based immunoassay. Results:, Data from 163 children were analyzed, of which 84.0% were positive for H. pylori. Infected children were significantly older (9.2 years ± 3.7 vs 7.1 years ± 3.9, p = .01). Half the cohort (84/163, 51.5%) described gastrointestinal symptoms but these were not strongly associated with co-morbid infections. Helicobacter pylori -infected children had significantly lower circulating log-interleukin-8 (IL-8) (odds ratio 0.61, 95% confidence interval (CI) 0.40, 0.94, p = .025). Helminth infections were common (75/163, 46%) and associated with elevated log-IL-5 (,: 0.42, 95% CI 0.077, 0.76). Children with malaria (15/163, 9.2%) had elevated log-tumor necrosis factor-, (TNF,) and log-IL-10 (,: 0.67, 95% CI 0.34, 1.0 and ,: 1.3, 95% CI 0.67, 1.9, respectively). IL-10 : IL-12 ratios were increased in H. pylori- infected children with malaria or helminth infections. Symptoms were generally not associated with levels of circulating peripheral cytokines irrespective of co-morbid infection diagnosis. Conclusions:, There is a high prevalence of asymptomatic H. pylori infection in recently resettled African refugee children. Gastrointestinal symptoms were not predictive of H. pylori nor of helminth infections. Serum cytokines, particularly IL-5, IL-10, and TNF,, were significantly elevated in children with malaria and helminth infections but not in those with H. pylori infection. [source] Functional genomics studies on the innate immunity of disease vectorsINSECT SCIENCE, Issue 1 2008Luke A. Baton Abstract The increasing availability of genome sequences and the development of high-throughput techniques for gene expression profiling and functional characterization are transforming the study of innate immunity and other areas of insect biology. Already, functional genomic approaches have enabled a quantum advance in the characterization of mosquito immune responses to malaria parasite infection, and similar high-throughput functional genomic studies of other vector-pathogen interactions can be expected in the near future. The application of microarray-based and other expression analyses provide genome-wide transcriptional profiles that can be used to identify insect immune system components that are differentially regulated upon exposure to various classes of pathogens, including many important etiologic agents of human and animal diseases. The role of infection-responsive or other candidate immune genes identified through comparative genomic approaches can then be functionally characterized, either in vivo, for instance in adult mosquitoes, or in vitro using cell lines. In most insect vectors of human pathogens, germ-line transgenesis is still technically difficult and maintenance of multiple transgenic lines logistically demanding. Consequently, transient RNA interference (RNAi)-mediated gene-silencing has rapidly become the method of choice for functional characterization of candidate innate immune genes. The powerful combination of transcriptional profiling in conjunction with assays using RNAi to determine gene function, and identify regulatory pathways, together with downstream cell biological approaches to determine protein localization and interactions, will continue to provide novel insights into the role of insect innate immunity in a variety of vector-pathogen interactions. Here we review advances in functional genomics studies of innate immunity in the insect disease vectors, over the past decade, with a particular focus on the Anopheles mosquito and its responses to malaria infection. [source] The Efficacy of Chemoprophylaxis against Malaria with Chloroquine plus Proguanil, Mefloquine, and Atovaquone plus Proguanil in Travelers from DenmarkJOURNAL OF TRAVEL MEDICINE, Issue 3 2003Kristian Kofoed Background The risk of malaria infection in travelers is seldom known in detail and neither is the efficacy of different prophylactic regimens, due to a lack of controlled trials. Surveillance of malaria diagnosed after return can provide data on risk and efficacy. Methods An open case-control study was initiated. Imported cases were notified to our department and were studied in 320 permanent residents in Denmark, returning from abroad with malaria from 1997 to 1999. These were compared with a group of 600 travelers who were not infected with malaria and matched by age, sex, and destination. Information on the use of chemoprophylaxis and the length of stay in malarious areas were obtained by questionnaire. Results Two hundred cases of Plasmodium falciparum malaria were notified of which 103 had used chloroquine and proguanil, 16 mefloquine, and 3 atovaquone and proguanil as prophylaxis, whereas the rest had taken other drugs or no prophylaxis. This study showed that the risk increased with increasing exposure and that compliance was lower especially for mefloquine users in malaria cases compared with controls. The study provided the first comprehensive data on the use of atovaquone/proguanil to travelers. The estimated efficacy of chloroquine and proguanil, mefloquine, and atovaquone and proguanil in fully compliant users was 1:599, 1:2,232, and 1:1,943, respectively, P. falciparum cases per prescription. The country specific risk data showed that the risk of getting malaria varied from 1 per 140 travelers to Ghana to almost 1 per 40,000 to Thailand, providing data that allow the use of prophylaxis to be restricted to high-risk areas. Conclusion There was a considerable variation in risk between the countries with the highest risk in tropical Africa. Chloroquine and proguanil was less efficient compared with mefloquine. Atovaquone/proguanil (Malarone) was at least as efficient as mefloquine, but breakthroughs were observed. [source] A clash to conquer: the malaria parasite liver infectionMOLECULAR MICROBIOLOGY, Issue 6 2006Sebastian A. Mikolajczak Summary All mammalian malaria parasite species have an initial tissue stage in liver cells. The liver stage produces new parasite forms that can enter and live inside red blood cells. Accordingly, the first place of residence provides parasites with a radically different cellular and molecular environment from their subsequent red blood cell home. Liver stages have remained refractory to reveal their secrets, yet the last few years have seen several advances in elucidating their biology. This review looks at the more recent findings concerning the liver stage,host hepatocyte association, some of which may become powerful weapons in the prevention of malaria infection. We also outline areas of liver stage research and technological development that provide promising foci to accelerate a better understanding of this most elusive of the parasites many life cycle stages. [source] The development of the RTS,S malaria vaccine candidate: challenges and lessonsPARASITE IMMUNOLOGY, Issue 9 2009W. R. BALLOU Summary RTS,S is the world's most advanced malaria vaccine candidate and is intended to protect infants and young children living in malaria endemic areas of sub-Saharan Africa against clinical disease caused by Plasmodium falciparum. Recently, a pivotal Phase III efficacy trial of RTS,S began in Africa. The goal of the programme has been to develop a vaccine that will be safe and effective when administered via the Expanded Program for Immunization (EPI) and significantly reduce the risk of clinically important malaria disease during the first years of life. If a similar reduction in the risk of severe malaria and other important co-morbidities associated with malaria infection can be achieved, then the vaccine could become a major new tool for reducing the burden of malaria in sub-Saharan Africa. Encouraging data from the ongoing phase II programme suggest that these goals may indeed be achievable. This review discusses some of the unique challenges that were faced during the development of this vaccine, highlights the complexity of developing new vaccine technologies and illustrates the power of partnerships in the ongoing fight against this killer disease. [source] Early treatment during a primary malaria infection modifies the development of cross immunityPARASITE IMMUNOLOGY, Issue 1 2004M. Legorreta-Herrera SUMMARY We have used a murine model to study the kinetics of cross-protection when a primary infection is halted at different times. We analysed how parasitaemia is modified during a second infection with the homologous parasite, a heterologous parasite, or a mixture of the two. In addition, possible mechanisms involved in cross-protection were analysed. Results show that treatment with pyrimethamine on day 5 during a primary infection with P. chabaudi AS (non-lethal), prevents the generation of cross-protection to a new challenge with lethal P. yoelii 17XL. In contrast, when treatment is on day 7, mice survive a P. yoelii infection. Differences between both groups suggest that in order for ,preimmune' mice to survive a lethal challenge, a predominantly TH2-type response is required, with a higher mRNA expression level of IL-4 and IL-10, and a lower mRNA expression of IFN-,. This work shows that an early treatment of a malaria infection produced by a non-lethal parasite drives the immune response towards a loss of cross-protection to further infections, in particular with more virulent parasites. This finding should be taken into account for the development of effective malaria vaccines. [source] Differential immunoglobulin E and cytokine responses in BALB/c and C57Bl/6 mice during repeated infections with blood-stage Plasmodium chabaudi malariaPARASITE IMMUNOLOGY, Issue 4 2000Helena Helmby Repeated blood-stage Plasmodium chabaudi chabaudi AS challenge infections in BALB/c and C57Bl/6 mice result in increased serum immunoglobulin (Ig) E levels and splenic cytokine production. The genetic background of the host influences both the cytokine response as well as the development of IgE antibodies. BALB/c mice showed high interleukin (IL)-4 secretion from splenocytes after in-vitro stimulation with malaria antigen after repeated P. chabaudi challenges and this was closely followed by higher levels of total IgE. Despite slightly elevated serum IgE levels, splenocytes from C57Bl/6 mice did not secrete any detectable IL-4 but produced interferon (IFN)-, in response to malaria antigen-stimulation in vitro. These data suggest that induction of IgE antibodies during murine malaria infection is genetically regulated. [source] Malaria during pregnancy in endemic areas: A lens for examining maternal,fetal conflict,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 5 2009Elizabeth T. Abrams Most of our knowledge about maternal,fetal conflict derives from the battle over scarce nutritional resources. How do other stressors like infectious diseases alter the maternal,fetal relationship? In this article, we use the example of malaria infection during pregnancy to explore the altered maternal,fetal relationship in the presence of an infectious disease. While adults living in regions endemic to Plasmodium falciparum malaria are generally immune, pregnant women experience significantly more frequent and severe infections. These infections generally resolve within a few days of birth and rarely cross the placenta, but the infants often experience poor birth outcomes, particularly low birth weight. This article summarizes what is known about the proximate, or physiological, mechanisms by which malaria causes more severe or frequent infections for pregnant versus nonpregnant women in endemic regions and then utilizes an evolutionary approach to focus on the altered maternal,fetal relationship during malaria-infected pregnancy. Am. J. Hum. Biol. 2009. © 2009 Wiley-Liss, Inc. [source] Antimalarial drugs , host targets (re)visitedBIOTECHNOLOGY JOURNAL, Issue 3 2006Margarida Cunha-Rodrigues Abstract Every year, forty percent of the world population is at risk of contracting malaria. Hopes for the erradication of this disease during the 20th century were dashed by the ability of Plasmodium falciparum, its most deadly causative agent, to develop resistance to available drugs. Efforts to produce an effective vaccine have so far been unsuccessful, enhancing the need to develop novel antimalarial drugs. In this review, we summarize our knowledge concerning existing antimalarials, mechanisms of drug-resistance development, the use of drug combination strategies and the quest for novel anti-plasmodial compounds. We emphasize the potential role of host genes and molecules as novel targets for newly developed drugs. Recent results from our laboratory have shown Hepatocyte Growth Factor/MET signaling to be essential for the establishment of infection in hepatocytes. We discuss the potential use of this pathway in the prophylaxis of malaria infection. [source] ,+ -Thalassaemia and pregnancy in a malaria endemic region of Papua New GuineaBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2006A. O'Donnell Summary The effect of maternal ,+ -thalassaemia on pregnancy was assessed in the north coastal region of Papua New Guinea (PNG), where malaria is hyperendemic and ,+ -thalassaemia is extremely common. In a prospective study of 987 singleton hospital deliveries, we correlated maternal , -globin genotype with markers of reproductive fitness (age in primigravidae, gravidity, pregnancy interval and the number of miscarriages and stillbirths), Plasmodium falciparum(P. falciparum) infection of the mother and placenta, maternal haemoglobin, preterm delivery and birthweight. The frequency of the ,, genotype in mothers was 0·61. Markers of reproductive fitness were similar in women with and without ,+ -thalassaemia. Median haemoglobin concentration during pregnancy and after delivery was about 1·0 g/dl lower in homozygous ,+ -thalassaemia than in women with a normal , - globin genotype (P , 0·001). The frequency of placental P. falciparum infection and systemic malaria infection after delivery showed no consistent relationship to , -globin genotype. The frequency of preterm delivery and low birthweight did not vary significantly according to maternal , -globin genotype. Maternal ,+ -thalassaemia does not affect reproductive fitness or susceptibility to malaria during pregnancy. Although median haemoglobin concentration was significantly lower in mothers homozygous for ,+ -thalassaemia than those with a normal , -globin genotype, this did not result in an adverse outcome of pregnancy. [source] Kupffer cells are obligatory for Plasmodium yoelii sporozoite infection of the liverCELLULAR MICROBIOLOGY, Issue 2 2007Kerstin Baer Summary Previous studies suggested Plasmodium sporozoites infect hepatocytes after passing through Kupffer cells, but proof has been elusive. Here we present new information strengthening that hypothesis. We used homozygous op/op mice known to have few Kupffer cells because they lack macrophage colony stimulating factor 1 required for macrophage maturation due to a deactivating point mutation in the osteopetrosis gene. We found these mice to have 77% fewer Kupffer cells and to exhibit reduced clearance of colloidal carbon particles compared with heterozygous phenotypically normal littermates. Using a novel quantitative reverse transcription polymerase chain reaction assay for P. yoelii 18S rRNA, we found liver infection of op/op mice to be decreased by 84% compared with controls. However, using another way of limiting Kupffer cells, treatment with liposome-encapsulated clodronate, infection of normal mice was enhanced seven- to 15-fold. This was explained by electron microscopy showing temporary gaps in the sinusoidal cell layer caused by this treatment. Thus, Kupffer cell deficiency in op/op mice decreases sporozoite infection by reducing the number of portals to the liver parenchyma, whereas clodronate increases sporozoite infection by opening portals and providing direct access to hepatocytes. Together these data provide strong support for the hypothesis that Kupffer cells are the portal for sporozoites to hepatocytes and critical for the onset of a malaria infection. [source] Plasmodium falciparum infection of the placenta affects newborn immune responsesCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2003J. ISMAILI SUMMARY The effects of exposure to placental malaria infection on newborn immunological responses, in particular Th1/Th2 cytokines and antigen-presenting cell (APC) function, were compared between cord blood mononuclear cells (CBMC) from parasitized and non-parasitized placentas of Gambian women. Cells were analysed in vitro for their ability to respond to mitogens [phorbol myristate acetate (PMA)/ionomycin, phytohaemagglutinin (PHA)], a malaria-unrelated test antigen [purified protein derivative of Mycobacterium tuberculin[purified protein derivative (PPD)] and Plasmodium falciparum schizont extracts. Mitogens induced strong proliferation and secretion of high concentrations of both IL-13 and sCD30 in CBMC from both groups. Conversely, significantly lower amounts of IFN- , were induced in the parasitized group in response to low doses of PHA. Protein antigens induced very low amounts of all tested cytokines, in particular IFN- ,. However, a significantly higher release of sCD30 was observed in response to schizont extracts in the parasitized group. Addition of LPS to activate APC to low doses of PHA or schizont extracts increased the IFN- , production in both groups but levels remained lower in CBMC from the parasitized group. This result correlates with the lower production of IL-12 found following lipopolysaccharide (LPS) stimulation in this group. Taken together, these data show that placental infection with P. falciparum affects Th1 differentiation and sCD30 priming of neonatal lymphocytes and that the probable mode of action is via APC. [source] | |||||||||||||