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• W1512421493 abstract "Cerebral malaria (CM) attributable to Plasmodium falciparum infection is estimated to affect 575,000 children in sub-Saharan Africa every year1Murphy SC Breman JG Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy.Am J Trop Med Hyg. 2001; 64: 57-67PubMed Google Scholar and is among the deadliest forms of malaria, with an average estimated mortality rate of 18.6%.2Newton CR Krishna S Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment.Pharmacol Ther. 1998; 79: 1-53Crossref PubMed Scopus (286) Google Scholar 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.3Hunt NH Golenser J Chan-Ling T Parekh S Rae C Potter S Medana IM Miu J Ball HJ Immunopathogenesis of cerebral malaria.Int J Parasitol. 2006; 36: 569-582Crossref PubMed Scopus (192) Google Scholar 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 colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar 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.5Boivin MJ Bangirana P Byarugaba J Opoka RO Idro R Jurek AM John CC Cognitive impairment after cerebral malaria in children: a prospective study.Pediatrics. 2007; 119: e360-e366Crossref PubMed Scopus (191) Google Scholar, 6Carter JA Mung'ala-Odera V Neville BG Murira G Mturi N Musumba C Newton CR Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children.J Neurol Neurosurg Psychiatry. 2005; 76: 476-481Crossref PubMed Scopus (151) Google Scholar 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 conducted in malaria endemic areas, most notably the studies conducted in Malawi by Taylor and colleagues.7Taylor TE Fu WJ Carr RA Whitten RO Mueller JS Fosiko NG Lewallen S Liomba NG Molyneux ME Differentiating the pathologies of cerebral malaria by postmortem parasite counts.Nat Med. 2004; 10: 143-145Crossref PubMed Scopus (525) Google Scholar These studies have added significantly to our understanding of pathological processes that occur in human CM, but even in the best of these studies, the number of autopsy specimens studied has been fairly small. In addition, these studies have not been able to assess the changes that occur before death or the changes that are present in children who survive CM. For these reasons, murine studies have been an important source of additional insight into the pathogenesis of CM. However, there are important differences between murine CM models and human CM. The most important difference is that P. falciparum, the Plasmodium species that causes CM in humans, is not infectious in mice, so murine malaria models generally use either the rodent malaria species Plasmodium berghei ANKA (PbA) or Plasmodium yoelii. A key difference between these parasites and P. falciparum is that P. berghei and P. yoelii infection in mice primarily induces adherence of leukocytes to vascular endothelium,8Neill AL Hunt NH Pathology of fatal and resolving Plasmodium berghei cerebral malaria in mice.Parasitology. 1992; 105: 165-175Crossref PubMed Scopus (123) Google Scholar whereas P. falciparum infection in humans primarily induces adherence of infected red blood cells to vascular endothelium.9Aikawa M Iseki M Barnwell JW Taylor D Oo MM Howard RJ The pathology of human cerebral malaria.Am J Trop Med Hyg. 1990; 43: 30-37PubMed Google Scholar Murine models of CM are also not invariably associated with the human clinical picture of neurological impairment and coma. Using a combination of a specific Plasmodium species (PbA) and specific mouse strains (C57BL or CBA), researchers have developed fatal murine CM models in which the mice develop neurological impairment and coma, and sequestration of leukocytes and some red blood cells is seen.10Medana IM Chaudhri G Chan-Ling T Hunt NH Central nervous system in cerebral malaria: “innocent bystander” or active participant in the induction of immunopathology?.Immunol Cell Biol. 2001; 79: 101-120Crossref PubMed Scopus (62) Google Scholar However, 100% of mice in these fatal murine CM models die after contracting CM, whereas mortality rates in humans with CM are generally less than 40%. A resolving CM model has also been devised, in which DBA mice inoculated with PbA develop neurological symptoms, such as disturbed gait and transient limb paralysis, but recover from these symptoms. However, these mice never develop coma, the hallmark criterion for human CM.8Neill AL Hunt NH Pathology of fatal and resolving Plasmodium berghei cerebral malaria in mice.Parasitology. 1992; 105: 165-175Crossref PubMed Scopus (123) Google Scholar The imperfect clinical approximation of the murine CM model, the difference in infecting Plasmodium species, and the differences between the murine and human immune system all suggest that caution must be exercised when attempting to extrapolate the results from murine CM models to human CM. Murine models can nonetheless provide us with a useful starting point for investigation of potential mechanisms of CM pathogenesis in humans. The hallmark of human CM pathology is the presence of infected red blood cells and leukocyte sequestration in the postcapillary venules of the brain.9Aikawa M Iseki M Barnwell JW Taylor D Oo MM Howard RJ The pathology of human cerebral malaria.Am J Trop Med Hyg. 1990; 43: 30-37PubMed Google Scholar The presence of local ischemia or hypoxia resulting from sequestration was long thought to be the cause of the symptoms of CM, but this would be expected to result in stroke-like events and does not satisfactorily explain the coma seen in CM or the often rapid recovery noted. Murine models provided early evidence that the host's immune response to the parasite played a critical role in the pathogenesis of murine CM. Throughout the past 2 decades there has been increasing evidence that a number of immune-related mechanisms first noted in murine CM, such as tumor necrosis factor (TNF)-α production,11Grau GE Fajardo LF Piguet PF Allet B Lambert PH Vassalli P Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria.Science. 1987; 237: 1210-1212Crossref PubMed Scopus (626) Google Scholar blood-brain barrier breakdown,12Neill AL Chan-Ling T Hunt NH Comparisons between microvascular changes in cerebral and non-cerebral malaria in mice, using the retinal whole-mount technique.Parasitology. 1993; 107: 477-487Crossref PubMed Scopus (41) Google Scholar and endothelial cell damage,12Neill AL Chan-Ling T Hunt NH Comparisons between microvascular changes in cerebral and non-cerebral malaria in mice, using the retinal whole-mount technique.Parasitology. 1993; 107: 477-487Crossref PubMed Scopus (41) Google Scholar are also involved in the pathogenesis of human CM.13Brown H Rogerson S Taylor T Tembo M Mwenechanya J Molyneux M Turner G Blood-brain barrier function in cerebral malaria in Malawian children.Am J Trop Med Hyg. 2001; 64: 207-213PubMed Google Scholar, 14Brown H Turner G Rogerson S Tembo M Mwenechanya J Molyneux M Taylor T Cytokine expression in the brain in human cerebral malaria.J Infect Dis. 1999; 180: 1742-1746Crossref PubMed Scopus (156) Google Scholar, 15Combes V Taylor TE Juhan-Vague I Mege JL Mwenechanya J Tembo M Grau GE Molyneux ME Circulating endothelial microparticles in Malawian children with severe falciparum malaria complicated with coma.JAMA. 2004; 291: 2542-2544PubMed Google Scholar, 16Grau GE Piguet PF Vassalli P Lambert PH Tumor-necrosis factor and other cytokines in cerebral malaria: experimental and clinical data.Immunol Rev. 1989; 112: 49-70Crossref PubMed Scopus (234) Google Scholar 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-1.3Hunt NH Golenser J Chan-Ling T Parekh S Rae C Potter S Medana IM Miu J Ball HJ Immunopathogenesis of cerebral malaria.Int J Parasitol. 2006; 36: 569-582Crossref PubMed Scopus (192) Google Scholar, 17Hunt NH Grau GE Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria.Trends Immunol. 2003; 24: 491-499Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar 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.3Hunt NH Golenser J Chan-Ling T Parekh S Rae C Potter S Medana IM Miu J Ball HJ Immunopathogenesis of cerebral malaria.Int J Parasitol. 2006; 36: 569-582Crossref PubMed Scopus (192) Google Scholar 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.”18Microarray policy.Nat Immunol. 2002; 4: 93Google Scholar 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. In this regard, the inclusion of a gene-gene interaction network to create an “interactome” that identified hubs of interconnectivity is a major strength of the study by Lovegrove and colleagues,4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar allowing them to identify factors that appear to be particularly important in directing the overall transcriptional response to PbA infection. The finding that expression of several genes involved in regulation of IFN were up-regulated in CM-susceptible mice led to assessment of brain tissue by quantitative real-time reverse transcriptase (RT)-PCR directed at a number of immune-related genes. Expression microarray and PCR analyses correlated well for most genes, and the majority of up-regulated genes documented by RT-PCR were either involved in IFN signaling or were IFN-inducible.4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In addition, the identification of several caspase genes and Fas (CD95) as prominent hubs in the interactome led the investigators to assess the brains of CM-susceptible and CM-resistant mice for evidence of apoptosis by terminal dUTP nick-end labeling immunohistochemistry. The expression microarray findings were again confirmed: CM-susceptible mice showed a higher number of terminal dUTP nick-end labeling-positive cells, primarily in the neurons of the cerebral cortex and cells of the leptomeninges.4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The corroborative studies performed by Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar add significantly to the data from initial microarray analysis and convincingly suggest a role for IFN-related processes and neuronal apoptosis in murine CM pathogenesis. Although other studies have suggested the importance of IFN, particularly IFN-γ, in murine CM,19Grau GE Heremans H Piguet PF Pointaire P Lambert PH Billiau A Vassalli P Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor.Proc Natl Acad Sci USA. 1989; 86: 5572-5574Crossref PubMed Scopus (284) Google Scholar only two very recent studies have documented neuronal apoptosis in murine CM.20Lackner P Burger C Pfaller K Heussler V Helbok R Morandell M Broessner G Tannich E Schmutzhard E Beer R Apoptosis in experimental cerebral malaria: spatial profile of cleaved caspase-3 and ultrastructural alterations in different disease stages.Neuropathol Appl Neurobiol. 2007; 33: 560-571PubMed Google Scholar, 21Wiese L Kurtzhals JA Penkowa M Neuronal apoptosis, metallothionein expression and proinflammatory responses during cerebral malaria in mice.Exp Neurol. 2006; 200: 216-226Crossref PubMed Scopus (64) Google Scholar Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar confirm these findings of neuronal apoptosis in murine CM and also provide, through microarray analysis, a number of potential pathways by which neuronal apoptosis may occur. The study findings of Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar nicely demonstrate the potential for microarray analysis to lead to significant new discoveries in murine CM pathogenesis. The report by Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar is not the first to use microarray analysis to assess murine brain responses to CM, and indeed there are differences between this study and the previous studies that will require further investigations for resolution. The previously published studies of brain tissue gene expression microarray analysis in murine CM had slightly different foci than the study by Lovegrove and colleagues,4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Sexton and colleagues22Sexton AC Good RT Hansen DS D'Ombrain MC Buckingham L Simpson K Schofield L Transcriptional profiling reveals suppressed erythropoiesis, up-regulated glycolysis, and interferon-associated responses in murine malaria.J Infect Dis. 2004; 189: 1245-1256Crossref PubMed Scopus (76) Google Scholar focused primarily on gene expression in splenic tissue, noting, however, that IFN-γ was present in brains of Balb/C mice at days 3 and 5 after infection and observing an increase in many IFN-inducible gene transcripts in the brain and splenic tissue of infected mice. In the study by Sexton and colleagues,22Sexton AC Good RT Hansen DS D'Ombrain MC Buckingham L Simpson K Schofield L Transcriptional profiling reveals suppressed erythropoiesis, up-regulated glycolysis, and interferon-associated responses in murine malaria.J Infect Dis. 2004; 189: 1245-1256Crossref PubMed Scopus (76) Google Scholar only C57BL/6 (CM-susceptible) mice were assessed; there was no comparison to CM-resistant mice. Delahaye and colleagues23Delahaye NF Coltel N Puthier D Flori L Houlgatte R Iraqi FA Nguyen C Grau GE Rihet P Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice.J Infect Dis. 2006; 193: 312-321Crossref PubMed Scopus (47) Google Scholar tested brain tissue gene expression in two strains of CM-resistant mice (BALB/c and DBA/2) and two strains of CM-susceptible mice (C57BL/6 and CBA/J) to evaluate the contribution of strain differences to differences in gene expression. Mice in this study were tested only at day 6, after development of CM symptoms in the susceptible mice. The study identified 28 genes for which expression differed strongly between the susceptible and resistant mice, regardless of strain, but also identified several genes for which expression differed between the two different susceptible strains or the two different resistant strains.23Delahaye NF Coltel N Puthier D Flori L Houlgatte R Iraqi FA Nguyen C Grau GE Rihet P Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice.J Infect Dis. 2006; 193: 312-321Crossref PubMed Scopus (47) Google Scholar The majority of genes that differed in level of expression between CM-susceptible and CM-resistant mice in the study by Delahaye and colleagues23Delahaye NF Coltel N Puthier D Flori L Houlgatte R Iraqi FA Nguyen C Grau GE Rihet P Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice.J Infect Dis. 2006; 193: 312-321Crossref PubMed Scopus (47) Google Scholar were not “hub” genes in the interactome described by Lovegrove and colleagues,4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar but IFN-regulating genes were an important component of both gene expression sets. The findings of Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar thus confirm the findings in the two previous murine CM microarray studies that IFN and IFN-regulating processes play a major role in murine CM pathogenesis. Interestingly, although earlier murine studies have implicated TNF-α in CM pathogenesis,10Medana IM Chaudhri G Chan-Ling T Hunt NH Central nervous system in cerebral malaria: “innocent bystander” or active participant in the induction of immunopathology?.Immunol Cell Biol. 2001; 79: 101-120Crossref PubMed Scopus (62) Google Scholar and TNF-related or TNF-induced genes were among the genes up-regulated in CM-susceptible but not CM-resistant mice in the study by Delahaye and colleagues,23Delahaye NF Coltel N Puthier D Flori L Houlgatte R Iraqi FA Nguyen C Grau GE Rihet P Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice.J Infect Dis. 2006; 193: 312-321Crossref PubMed Scopus (47) Google Scholar TNF-α-related genes were not a major part of the interactome hubs in the study by Lovegrove and colleagues.4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In contrast, neither any of the caspase genes nor Fas (Cd95) was noted to be up-regulated in the studies by Delahaye and colleagues23Delahaye NF Coltel N Puthier D Flori L Houlgatte R Iraqi FA Nguyen C Grau GE Rihet P Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice.J Infect Dis. 2006; 193: 312-321Crossref PubMed Scopus (47) Google Scholar or Sexton and colleagues.22Sexton AC Good RT Hansen DS D'Ombrain MC Buckingham L Simpson K Schofield L Transcriptional profiling reveals suppressed erythropoiesis, up-regulated glycolysis, and interferon-associated responses in murine malaria.J Infect Dis. 2004; 189: 1245-1256Crossref PubMed Scopus (76) Google Scholar The brain tissue microarray studies performed thus far in murine CM show a number of similarities and most strikingly point to IFN-regulating and IFN-regulated processes as critical to CM, but they also differ in their findings. There are a number of reasons why the findings may differ, including differing cDNA libraries used in the microarrays, differences across and within mouse strains, different methods and cutoffs for choosing statistical significance, and different analytic techniques. The similar findings provide a strong case for the importance of IFN-related processes in murine CM. The differences suggest a need for greater consistency in murine CM models and microarray statistical analyses and models if results are to be compared or considered generalizable. The differences also demonstrate the importance of corroborative data in these models, as evidence that up-regulation of gene expression does lead to the predicted outcomes. The differences in murine CM gene expression microarray studies indicate that further caution is required when attempting to extrapolate from murine findings, particularly from a single study, to human CM. The murine studies are best thought of as a launching pad for hypotheses and testing in human CM. For example, the study by Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar again suggests a role for IFN-regulated or IFN-related processes, including IFN-γ production, in murine CM. Are type I and type II IFN expression important in humans with CM? The study by Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and two other recent studies20Lackner P Burger C Pfaller K Heussler V Helbok R Morandell M Broessner G Tannich E Schmutzhard E Beer R Apoptosis in experimental cerebral malaria: spatial profile of cleaved caspase-3 and ultrastructural alterations in different disease stages.Neuropathol Appl Neurobiol. 2007; 33: 560-571PubMed Google Scholar, 21Wiese L Kurtzhals JA Penkowa M Neuronal apoptosis, metallothionein expression and proinflammatory responses during cerebral malaria in mice.Exp Neurol. 2006; 200: 216-226Crossref PubMed Scopus (64) Google Scholar strongly suggest a role for neuronal apoptosis in murine CM. Could neuronal apoptosis be a cause of the neurological and, in particular, the long-term cognitive deficits seen in children with CM? The study by Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar also demonstrates up-regulation of the gene regulating endothelin-1 production. Might endothelin-1 production leading to local vasospasm be part of the pathogenesis of human CM? Finally, earlier studies, but not the study by Lovegrove and colleagues,4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar suggest a role for TNF-α in murine CM. Is TNF-α truly a mediator of murine CM or a marker for other processes? Does TNF-α play a role in human CM? Testing these hypotheses in humans will not be easy. Autopsies remain the only way of assessing brain tissue in humans with CM and present the insoluble problem of providing tissue only from those with terminal disease. Microarray analysis of brain tissue could provide important information but might primarily reflect terminal responses to CM, as opposed to the responses that occur in all children with CM, including survivors. Measuring certain factors, such as endothelin-1 or TNF-α, in cerebrospinal fluid might provide an indication of their production in the CNS,24Kessler IM Pacheco YG Lozzi SP de Araujo Jr, AS Onishi FJ de Mello PA Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.Surg Neurol. 2005; 64: S2-S5Abstract Full Text Full Text PDF Scopus (53) Google Scholar although local production may be missed with these measurements. Assessment of vasospasm may be aided by imaging technologies such as magnetic resonance angiography,25Tamatani S Sasaki O Takeuchi S Fujii Y Koike T Tanaka R Detection of delayed cerebral vasospasm, after rupture of intracranial aneurysms, by magnetic resonance angiography.Neurosurgery. 1997; 40: 744-753Crossref Scopus (32) Google Scholar but such technologies are rarely available in malaria endemic countries. Microarray analysis of gene expression in peripheral mononuclear cells could give a picture of the systemic response to P. falciparum infection that leads to CM, but gene expression in the brain may be very different from that in other tissues such as the liver or spleen, as Lovegrove and colleagues26Lovegrove FE Pena-Castillo L Mohammad N Liles WC Hughes TR Kain KC Simultaneous host and parasite expression profiling identifies tissue-specific transcriptional programs associated with susceptibility or resistance to experimental cerebral malaria.BMC Genomics. 2006; 7: 295Crossref PubMed Scopus (53) Google Scholar have demonstrated in an earlier murine CM study. Future studies of human CM will require increased support of scientific and clinical infrastructure in malaria-endemic countries and increased support of research specifically assessing CM and its complications in these countries. Attempts should be made to determine what putative factors can be assessed in human studies, whether directly, by brain tissue microarray analysis, immunohistochemistry, real-time RT-PCR, or other methods, or indirectly, by methods such as CSF analyte measurement. There are enough differences between murine and human CM that going directly to human therapeutic trials from murine data seems premature, but murine CM studies may provide the basis for human studies that lead to therapeutic trials. Assessment for factors such as neuronal apoptosis in human CM may provide new insights into the pathogenesis of long-term morbidity from CM and lead to therapeutic trials to decrease not only mortality but also morbidity. Support for both human and murine studies of CM is clearly necessary if we are to advance our understanding of CM pathogenesis and move on to successful adjunctive therapy that will decrease CM morbidity and mortality. Thoughtfully designed and carefully performed gene expression microarray analyses like those in the report by Lovegrove and colleagues4Lovegrove FE Gharib SA Patel SN Hawkes CA Kain KC Liles WC Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria.Am J Pathol. 2007; 171: 1894-1903Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar in this issue tell us something new about murine CM pathogenesis and may well lead to a better understanding of human CM pathogenesis. Expression Microarray Analysis Implicates Apoptosis and Interferon-Responsive Mechanisms in Susceptibility to Experimental Cerebral MalariaThe American Journal of PathologyVol. 171Issue 6PreviewSpecific local brain responses, influenced by parasite sequestration and host immune system activation, have been implicated in the development of cerebral malaria. This study assessed whole-brain transcriptional responses over the course of experimental cerebral malaria by comparing genetically resistant and susceptible inbred mouse strains infected with Plasmodium berghei ANKA. Computational methods were used to identify differential patterns of gene expression. Overall, genes that showed the most transcriptional activity were differentially expressed in susceptible mice 1 to 2 days before the onset of characteristic symptoms of cerebral malaria. Full-Text PDF" @default.
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