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Science 12/2012; 338(6112):1304-5. · 31.20 Impact Factor
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ABSTRACT: A system for experimentally induced blood stage malaria infection (IBSM) with Plasmodium falciparum by direct intravenous inoculation of infected erythrocytes was developed at the Queensland Institute of Medical Research (QIMR) more than 15 years ago. Since that time, this system has been used in several studies to investigate the protective effect of vaccines, the clearance kinetics of parasites following drug treatment, and to improve understanding of the early events in blood stage infection. In this article, we will review the development of IBSM and the applications for which it is being employed. We will discuss the advantages and disadvantages of IBSM, and finish by describing some exciting new areas of research that have been made possible by this system.
Trends in Parasitology 10/2012; 28(11):515-21. · 5.14 Impact Factor
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ABSTRACT: The mononuclear phagocyte system (MPS), comprising monocytes, macrophages, and dendritic cells (DCs), plays an important role in the control of disease, but can also contribute to the establishment of persistent infections. Monocytes are derived from progenitors in the bone marrow. Once in circulation, they migrate into the tissues, differentiate into macrophages, and phagocytose microbes under inflammatory conditions. However, recent work shows they not only act as phagocytes, but are also precursors for particular types of DCs, inflammatory macrophages, and tissue macrophages. The role of monocytes during inflammation in models of bacterial and viral infections, cancer, atherosclerosis, and autoimmunity has been widely studied and reported. In this review we focus on the less understood role of monocytes in protozoan infections.
Trends in Parasitology 08/2012; 28(10):408-16. · 5.14 Impact Factor
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ABSTRACT: Dendritic cells (DCs) are highly specialized antigen-presenting cells that are crucial for initiation of immune responses. During naturally acquired malaria, DC number and function is reduced.
The timing of, parasitemia threshold of, and contribution of apoptosis to DC loss were prospectively evaluated in 10 men after experimental challenge with approximately 1800 Plasmodium falciparum-parasitized red blood cells (pRBCs) and after drug cure initiated at a parasite level of ≥ 1000 parasites/mL.
The nadir levels of total, myeloid, and plasmacytoid DCs occurred 8 days after infection. DC loss was partially attributable to apoptosis, which was first detected on day 5 (median parasite level, 238 parasites/mL) and maximal at day 7. Remaining DCs exhibited a reduced ability to uptake particulate antigen. DC numbers recovered approximately 60 hours after antimalarial drug administration. There was no loss of DC number or function before or after drug cure in 5 men inoculated with <180 pRBCs and treated on day 6, when their parasite level was approximately 200 parasites/mL.
Plasmodium causes DC loss in vivo, which is at least partially explained by apoptosis in response to blood-stage parasites. In primary infection, loss of DC number and function occurs early during the prepatent period and before or with onset of clinical symptoms. These findings may explain in part the inadequate development of immunity to blood-stage malaria infection.
The Journal of Infectious Diseases 05/2012; 206(3):333-40. · 6.41 Impact Factor
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Renee J Robb,
Katie E Lineburg,
Rachel D Kuns,
Yana A Wilson,
Neil C Raffelt,
Stuart D Olver,
Antiopi Varelias,
Kylie A Alexander,
Bianca E Teal,
Tim Sparwasser,
Gunter J Hammerling,
Kate A Markey,
Motoko Koyama,
Andrew D Clouston, Christian R Engwerda,
Geoffrey R Hill,
Kelli P A MacDonald
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ABSTRACT: FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation.
Blood 04/2012; 119(24):5898-908. · 9.90 Impact Factor
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Kate A Markey,
Motoko Koyama,
Rachel D Kuns,
Katie E Lineburg,
Yana A Wilson,
Stuart D Olver,
Neil C Raffelt,
Alistair L J Don,
Antiopi Varelias,
Renee J Robb,
Melody Cheong, Christian R Engwerda,
Raymond J Steptoe,
Hayley S Ramshaw,
Angel F Lopez,
Javier Vega-Ramos,
Andrew M Lew,
Jose A Villadangos,
Geoffrey R Hill,
Kelli P A MacDonald
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ABSTRACT: Alloreactivity after transplantation is associated with profound immune suppression, and consequent opportunistic infection results in high morbidity and mortality. This immune suppression is most profound during GVHD after bone marrow transplantation where an inflammatory cytokine storm dominates. Contrary to current dogma, which avers that this is a T-cell defect, we demonstrate that the impairment lies within conventional dendritic cells (cDCs). Significantly, exogenous antigens can only be presented by the CD8(-) cDC subset after bone marrow transplantation, and inflammation during GVHD specifically renders the MHC class II presentation pathway in this population incompetent. In contrast, both classic and cross-presentation within MHC class I remain largely intact. Importantly, this defect in antigen processing can be partially reversed by TNF inhibition or the adoptive transfer of donor cDCs generated in the absence of inflammation.
Blood 03/2012; 119(24):5918-30. · 9.90 Impact Factor
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Soraya Gaze,
Henry J McSorley,
James Daveson,
Di Jones,
Jeffrey M Bethony,
Luciana M Oliveira,
Richard Speare,
James S McCarthy, Christian R Engwerda,
John Croese,
Alex Loukas
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ABSTRACT: The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13) and regulatory (IL-10 and TGF-β) response, with some evidence of a Th1 (IFN-γ and IL-2) response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17) response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases.
PLoS Pathogens 02/2012; 8(2):e1002520. · 9.13 Impact Factor
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Motoko Koyama,
Rachel D Kuns,
Stuart D Olver,
Neil C Raffelt,
Yana A Wilson,
Alistair L J Don,
Katie E Lineburg,
Melody Cheong,
Renee J Robb,
Kate A Markey,
Antiopi Varelias,
Bernard Malissen,
Günter J Hämmerling,
Andrew D Clouston, Christian R Engwerda,
Purnima Bhat,
Kelli P A MacDonald,
Geoffrey R Hill
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ABSTRACT: The presentation pathways by which allogeneic peptides induce graft-versus-host disease (GVHD) are unclear. We developed a bone marrow transplant (BMT) system in mice whereby presentation of a processed recipient peptide within major histocompatibility complex (MHC) class II molecules could be spatially and temporally quantified. Whereas donor antigen presenting cells (APCs) could induce lethal acute GVHD via MHC class II, recipient APCs were 100-1,000 times more potent in this regard. After myeloablative irradiation, T cell activation and memory differentiation occurred in lymphoid organs independently of alloantigen. Unexpectedly, professional hematopoietic-derived recipient APCs within lymphoid organs had only a limited capacity to induce GVHD, and dendritic cells were not required. In contrast, nonhematopoietic recipient APCs within target organs induced universal GVHD mortality and promoted marked alloreactive donor T cell expansion within the gastrointestinal tract and inflammatory cytokine generation. These data challenge current paradigms, suggesting that experimental lethal acute GVHD can be induced by nonhematopoietic recipient APCs.
Nature medicine 11/2011; 18(1):135-42. · 27.14 Impact Factor
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Amanda C Stanley,
Fabian de Labastida Rivera,
Ashraful Haque,
Meru Sheel,
Yonghong Zhou,
Fiona H Amante,
Patrick T Bunn,
Louise M Randall,
Klaus Pfeffer,
Stefanie Scheu,
Michael J Hickey,
Bernadette M Saunders,
Carl Ware,
Geoff R Hill,
Koji Tamada,
Paul M Kaye, Christian R Engwerda
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ABSTRACT: LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound receptors; herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFNγ- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LTβR interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4(+) T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its receptors may be used for therapeutic advantage.
PLoS Pathogens 10/2011; 7(10):e1002279. · 9.13 Impact Factor
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Ashraful Haque,
Shannon E Best,
Anne Ammerdorffer,
Laure Desbarrieres,
Marcela Montes de Oca,
Fiona H Amante,
Fabian de Labastida Rivera,
Paul Hertzog,
Glen M Boyle,
Geoffrey R Hill, Christian R Engwerda
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ABSTRACT: During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-γ-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-α protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-γ production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T-cell-mediated parasite control.
European Journal of Immunology 06/2011; 41(9):2688-98. · 5.10 Impact Factor
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ABSTRACT: Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8(+) T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8(+) T cells expressed granzyme B (GzmB). Furthermore, gzmB(-/-) mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4(+) T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8(+) T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8(+) T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8(+) T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8(+) T cells dictates the onset of perforin/GzmB-mediated ECM.
The Journal of Immunology 06/2011; 186(11):6148-56. · 5.79 Impact Factor
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ABSTRACT: Although a link between sickle cell disease and resistance to severe malaria is well established, the biochemical relationship between the two is unknown. Ferreira et al. (2011) show that carriers of the sickle cell mutation increase expression of the heme oxygenase-1 enzyme, which produces antioxidant molecules that may prevent severe disease symptoms.
Cell 04/2011; 145(3):335-6. · 32.40 Impact Factor
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ABSTRACT: Immunity to asexual blood stages of malaria is complex, involving both humoral and cell-mediated immune mechanisms. The availability of murine models of malaria has greatly facilitated the analysis of immune mechanisms involved in resistance to the asexual blood stages. This unit details the materials and methods required for inducing protective immunity toward experimental blood stage malaria parasites by vaccination, repeated infection, and drug cure, as well as adoptive transfer of antigen-specific T cells.
Current protocols in immunology / edited by John E. Coligan ... [et al.] 04/2011; Chapter 19:Unit 19.4.
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ABSTRACT: Infection of C57BL/6 mice with Plasmodium berghei ANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological symptoms and mortality depend on pathogenic CD8(+) T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8(+) T cells accumulated in the liver following P. berghei ANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset of clinical symptoms. These data indicate that CD8(+) T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both organs during P. berghei ANKA infection. Therefore, we show that P. berghei ANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized by organ-specific CD8(+) T cell-mediated pathology.
Infection and immunity 02/2011; 79(5):1882-8. · 4.21 Impact Factor
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Henry J McSorley,
Soraya Gaze,
James Daveson,
Dianne Jones,
Robert P Anderson,
Andrew Clouston,
Nathalie E Ruyssers,
Richard Speare,
James S McCarthy, Christian R Engwerda,
John Croese,
Alex Loukas
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ABSTRACT: We present immunological data from two clinical trials where the effect of experimental human hookworm (Necator americanus) infection on the pathology of celiac disease was evaluated. We found that basal production of Interferon- (IFN-)γ and Interleukin- (IL-)17A from duodenal biopsy culture was suppressed in hookworm-infected participants compared to uninfected controls. Increased levels of CD4+CD25+Foxp3+ cells in the circulation and mucosa are associated with active celiac disease. We show that this accumulation also occurs during a short-term (1 week) oral gluten challenge, and that hookworm infection suppressed the increase of circulating CD4+CD25+Foxp3+ cells during this challenge period. When duodenal biopsies from hookworm-infected participants were restimulated with the immunodominant gliadin peptide QE65, robust production of IL-2, IFN-γ and IL-17A was detected, even prior to gluten challenge while participants were strictly adhering to a gluten-free diet. Intriguingly, IL-5 was produced only after hookworm infection in response to QE65. Thus we hypothesise that hookworm-induced TH2 and IL-10 cross-regulation of the TH1/TH17 inflammatory response may be responsible for the suppression of these responses during experimental hookworm infection.
PLoS ONE 01/2011; 6(9):e24092. · 4.09 Impact Factor
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Immunology and Cell Biology 10/2010; 88(7):692-4. · 3.66 Impact Factor
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Louise M Randall,
Enny Kenangalem,
Daniel A Lampah,
Emiliana Tjitra,
Esther D Mwaikambo,
Tjandra Handojo,
Kim A Piera,
Zhen Z Zhao,
Fabian de Labastida Rivera,
Yonghong Zhou, [......],
Amanda C Stanley,
Tonia Woodberry,
Ervi Salwati,
Donald L Granger,
Maurine R Hobbs,
Ric N Price,
J Brice Weinberg,
Grant W Montgomery,
Nicholas M Anstey, Christian R Engwerda
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ABSTRACT: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.
An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant.
No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.
These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.
Malaria Journal 10/2010; 9:302. · 3.19 Impact Factor
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Fiona H Amante,
Ashraful Haque,
Amanda C Stanley,
Fabian de Labastida Rivera,
Louise M Randall,
Yana A Wilson,
Gladys Yeo,
Christian Pieper,
Brendan S Crabb,
Tania F de Koning-Ward,
Rachel J Lundie,
Michael F Good,
Alberto Pinzon-Charry,
Mark S Pearson,
Mary G Duke,
Donald P McManus,
Alex Loukas,
Geoff R Hill, Christian R Engwerda
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ABSTRACT: Cerebral malaria is a severe complication of malaria. Sequestration of parasitized RBCs in brain microvasculature is associated with disease pathogenesis, but our understanding of this process is incomplete. In this study, we examined parasite tissue sequestration in an experimental model of cerebral malaria (ECM). We show that a rapid increase in parasite biomass is strongly associated with the induction of ECM, mediated by IFN-gamma and lymphotoxin alpha, whereas TNF and IL-10 limit this process. Crucially, we discovered that host CD4(+) and CD8(+) T cells promote parasite accumulation in vital organs, including the brain. Modulation of CD4(+) T cell responses by helminth coinfection amplified CD4(+) T cell-mediated parasite sequestration, whereas vaccination could generate CD4(+) T cells that reduced parasite biomass and prevented ECM. These findings provide novel insights into immune-mediated mechanisms of ECM pathogenesis and highlight the potential of T cells to both prevent and promote infectious diseases.
The Journal of Immunology 09/2010; 185(6):3632-42. · 5.79 Impact Factor
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Louise M Randall,
Enny Kenangalem,
Daniel A Lampah,
Emiliana Tjitra,
Esther D Mwaikambo,
Tjandra Handojo,
Kim A Piera,
Zhen Zhen Zhao,
Fabian de Labastida Rivera,
Yonghong Zhou, [......],
Amanda C Stanley,
Tonia Woodberry,
Ervi Salwati,
Donald L Granger,
Maurine R Hobbs,
Ric N Price,
J Brice Weinberg,
Grant W Montgomery,
Nicholas M Anstey, Christian R Engwerda
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ABSTRACT: Age and host genetics are important determinants of malaria severity. Lymphotoxin-alpha (LTalpha) has been associated with the development of cerebral malaria (CM) and other severe malaria (SM) syndromes. Mutations in genes regulating LTalpha production contribute to other acute vascular diseases and may contribute to malaria pathogenesis.
We tested the association between rs7291467, a single-nucleotide polymorphism (SNP) in the LTalpha-related gene encoding galectin-2 (LGALS2), disease severity, and function in a case-control study of ethnic Highland Papuan adults and children with SM (n = 380) and asymptomatic malaria-exposed controls (n = 356) originating from a non-malaria-endemic region but residing in a lowland malaria-endemic area of Papua, Indonesia.
The LGALS2 SNP showed a significant association with susceptibility to SM (including CM), in children (odds ratio, 2.02 [95% confidence interval, 1.14-3.57]) but not in adults. In SM, the C allele at rs7291467 was associated with enhanced galectin-2 transcript levels. In a separate group of Tanzanian children originating from a malaria-endemic region, we found preservation of the major ancestral LGALS2 allele and no association with susceptibility to CM.
Results suggest differences in the inflammatory contribution to the development of SM between children and adults in the same population and potential differences between individuals originating from malaria-endemic and non-malaria-endemic areas.
The Journal of Infectious Diseases 07/2010; 202(1):117-24. · 6.41 Impact Factor
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ABSTRACT: Tumor necrosis factor (TNF) has long been recognized to promote malaria parasite killing, but also to contribute to the development of severe malaria disease. The precise molecular mechanisms that influence these different outcomes in malaria patients are not well understood, but the virulence and drug-resistance phenotype of malaria parasites and the genetic background and age of patients are likely to be important determinants. In the past few years, important roles for other TNF family members in host immune responses to malaria parasites and the induction of disease pathology have been discovered. In this review, we will summarize these more recent findings and highlight major gaps in our current knowledge. We will also discuss future research strategies that may allow us to better understand the sometimes subtle and intricate effects of TNF family molecules during malaria infection.
Experimental Parasitology 04/2010; 126(3):326-31. · 2.12 Impact Factor
