Immunopathogenesis of cerebral malaria

Hunt, Nicholas H.; Golenser, Jacob; Chan‐Ling, Tailoi; Parekh, Sapan; Rae, Caroline; Potter, Sarah M.; Medana, Isabelle M.; Miu, Jenny; Ball, Helen J.

doi:10.1016/j.ijpara.2006.02.016

Cited by 217 publications

(201 citation statements)

References 145 publications

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“…Nevertheless, years of studies on malaria have progressively shown an important role for proinflammatory cytokines in disease pathogenesis (34,35). It is currently known that parasite sequestration is exacerbated by cytokine-mediated up-regulation of host endothelial receptors that bind to parasitized erythrocytes (i.e., intracellular adhesion molecule-1, vascular cellular adhesion molecule) (15,33,35,36). Studies in mice with deficiency in several inflammatory mediators (e.g., TNF-α) (37), other cytokines, and chemokines (38) suggest that the ECM model used in this study is mainly a cytokine-associated encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

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Section: Discussionmentioning

confidence: 99%

“…P.c., P. chabaudi. shown to affect blood-brain barrier (BBB) permeability, leading to leak and infiltration of mononuclear cells contributing to ECM (33). Because of its inhibitory effect on cytokine production in mouse cells (Fig.…”

Section: E6446 Prevents Hyperresponsiveness Of Tlrs and Lps-induced Smentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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“…[13][14][15][16] Human and murine data also suggest a potential role for other immunological or inflammatory factors in CM pathogenesis, including vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), heme oxygenase-1, nitric oxide, kynurenic acid metabolites, and endothelin-1. 3,17 Current models of human CM postulate a contribution of multiple factors, including microvascular sequestration and blockage leading to local ischemia; cytopathic hypoxia, in which oxygen supply is adequate but cellular use of oxygen is not; and up-regulation of numerous immune or immune-related responses, all of which combine to lead to blood-brain-barrier breakdown, microglial and astrocyte activation, and damage or death of microglia, astrocytes, and neurons. 3 The best studies done with microarray analysis provide new insights: as stated in a Nature Immunology editorial, there is nothing wrong in starting with a "fishing expedition" if the discoveries from that expedition are further characterized with nonmicroarray tools in a way that provides "fresh mechanistic insight into the immunological process being examined."…”

Section: What Can Microarray Analysis Tell Us About Murine CM Pathogementioning

confidence: 99%

“…3,17 Current models of human CM postulate a contribution of multiple factors, including microvascular sequestration and blockage leading to local ischemia; cytopathic hypoxia, in which oxygen supply is adequate but cellular use of oxygen is not; and up-regulation of numerous immune or immune-related responses, all of which combine to lead to blood-brain-barrier breakdown, microglial and astrocyte activation, and damage or death of microglia, astrocytes, and neurons. 3 The best studies done with microarray analysis provide new insights: as stated in a Nature Immunology editorial, there is nothing wrong in starting with a "fishing expedition" if the discoveries from that expedition are further characterized with nonmicroarray tools in a way that provides "fresh mechanistic insight into the immunological process being examined." 18 The methods of microarray analysis are as important as the microarray testing itself: appropriate and rigorous statistical analysis is key to accurate interpretation of results, and the methods and presentation of data analysis can make a big difference in communicating the main findings from within the many.…”

Section: What Can Microarray Analysis Tell Us About Murine CM Pathogementioning

confidence: 99%

“…Studies to date suggest that CM is attributable to a combination of local brain tissue damage from microvascular ischemia and hypoxia and more global brain injury caused by the host immune response to the parasite. 3 A deficiency of most murine and human CM studies is that assessment has been restricted to specific predefined factors hypothesized to be of importance. These studies address specific hypotheses but cannot provide a systemic evaluation of the potential factors in the pathogenesis of CM.…”

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Cerebral Malaria Pathogenesis

John

2007

The American Journal of Pathology

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Cerebral malaria (CM) attributable to Plasmodium falciparum infection is estimated to affect 575,000 children in sub-Saharan Africa every year 1 and is among the deadliest forms of malaria, with an average estimated mortality rate of 18.6%. 2 Although extensive studies have been conducted in murine models of CM and in human populations with CM, the pathogenesis of CM is still incompletely understood. Studies to date suggest that CM is attributable to a combination of local brain tissue damage from microvascular ischemia and hypoxia and more global brain injury caused by the host immune response to the parasite. 3 A deficiency of most murine and human CM studies is that assessment has been restricted to specific predefined factors hypothesized to be of importance. These studies address specific hypotheses but cannot provide a systemic evaluation of the potential factors in the pathogenesis of CM.Systems biology, in particular the decoding of the human and murine genome, development of microarray analysis, and application of more sophisticated computational technology to assess the results of this analysis, has moved us ahead in our understanding of numerous diseases. In an elegant and carefully designed series of experiments in this issue of The American Journal of Pathology, Lovegrove and colleagues 4 use microarray analysis of whole brain tissue gene expression in CM-susceptible and CM-resistant mice to define potential pathways involved in murine CM pathogenesis. Their microarray analysis and confirmatory quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry studies demonstrate that interferon (IFN)-regulated processes and neuronal apoptosis appear to be important in murine CM pathogenesis. These findings, particularly the findings about neuronal apoptosis, are novel and add significantly to our understanding of murine CM pathogenesis. Although there are important differences between murine CM models and human CM, these findings may also provide clues about human CM pathogenesis and, in particular, suggest potential mechanisms for the long-term cognitive sequelae that occur in children with CM. 5,6 Differences between Murine CM Models and Human CM As is the case for many diseases affecting the brain, far more is known about the pathogenesis of murine CM than human CM. The most obvious reason for this is that sizeable numbers of murine brains can be studied at different phases of the illness, but human brain studies of CM are limited to those done at autopsy. Another reason for the paucity of information on human CM pathogenesis is that human CM occurs almost exclusively in low-and middle-income countries. The resources in these countries for investigating CM pathogenesis are severely limited, and the resources provided by wealthier countries for such studies in malaria endemic areas have to date been relatively meager. Despite these limitations, in addition to cultural problems with acceptance of autopsies in children who die of CM, remarkable human brain autopsy studies have been con...

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Experimental Asexual Blood Stage Malaria Immunity

2011

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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.

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Immunopathogenesis of cerebral malaria

Cited by 217 publications

References 145 publications

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Cerebral Malaria Pathogenesis

Experimental Asexual Blood Stage Malaria Immunity

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