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Fatal cerebral malaria: a venous efflux problem.

ABSTRACT: Most Plasmodium falciparum-infected children with cerebral malaria (CM) die from respiratory arrest, but the underlying pathology is unclear. Here we present a model in which the ultimate cause of death from CM is severe intracranial hypertension. Dynamic imaging of mice infected with P. berghei ANKA, an accepted model for experimental CM, revealed that leukocyte adhesion impairs the venous blood flow by reducing the functional lumen of postcapillary venules (PCV). The resulting increase in intracranial pressure (ICP) exacerbates cerebral edema formation, a hallmark of both murine and pediatric CM. We propose that two entirely different pathogenetic mechanisms-cytoadherence of P. falciparum-infected erythrocytes in pediatric CM and leukocyte arrest in murine CM-result in the same pathological outcome: a severe increase in ICP leading to brainstem herniation and death from respiratory arrest. The intracranial hypertension (IH) model unifies previous hypotheses, applies to human and experimental CM alike, eliminates the need to explain any selective recognition mechanism Plasmodium might use to target multiple sensitive sites in the brain, and explains how an intravascular parasite can cause so much neuronal dysfunction.

SUBMITTER: Frevert U

PROVIDER: S-EPMC4222339 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Fatal cerebral malaria: a venous efflux problem.

Frevert Ute U Nacer Adéla A

Frontiers in cellular and infection microbiology 20141106

Most Plasmodium falciparum-infected children with cerebral malaria (CM) die from respiratory arrest, but the underlying pathology is unclear. Here we present a model in which the ultimate cause of death from CM is severe intracranial hypertension. Dynamic imaging of mice infected with P. berghei ANKA, an accepted model for experimental CM, revealed that leukocyte adhesion impairs the venous blood flow by reducing the functional lumen of postcapillary venules (PCV). The resulting increase in intr ...[more]

PMID: 25414834

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Project description:BackgroundThe sequestration of Plasmodium falciparum-infected erythrocytes in brain microvasculature through cytoadherence to endothelium, is the hallmark of the definitive diagnosis of cerebral malaria and plays a critical role in malaria pathogenesis. The complex pathophysiology, which leads each patient to the final outcome of cerebral malaria, is multifaceted and thus, metrics to delineate specific patterns within cerebral malaria are needed to further parse patients.MethodsA method was developed for quantification utilizing counts of capillary contents (early-stage parasites, late-stage parasites and fibrin) from histological preparations of brain tissue after death, and compared it to the standard approach, in which the percentage of parasitized vessels in cross-section is determined.ResultsWithin the initial cohort of 50 patients, two different observers agreed closely on the percentage of vessels parasitized, pigmented parasites and pigment globules (ICC?=?0.795-0.970). Correlations between observers for correct diagnostic classification were high (Kendall's tau-b?=?0.8779, Kappa?=?0.8413). When these methods were applied prospectively to a second set of 50 autopsy samples, they revealed a heterogeneous distribution of sequestered parasites in the brain with pigmented parasites and pigment globules present in the cerebellum?>?cortex?>?brainstem. There was no difference in the distribution of early stages of parasites or in the percentage of vessels parasitized across the same sites. The second cohort of cases was also used to test a previously published classification and regression tree (CART) analysis; the quantitative data alone were able to accurately classify and distinguish cerebral malaria from non-cerebral malaria. Classification errors occurred within a subclassification of cerebral malaria (CM1 vs CM2). A repeat CART analysis for the second cohort generated slightly different classification rules with more accurate subclassification, although misclassification still occurred.ConclusionsThe traditional measure of parasite sequestration in falciparum malaria, the percentage of vessels parasitized, is the most reliable and consistent for the general diagnosis of cerebral malaria. Methods that involve quantitative measures of different life cycle stages are useful for distinguishing patterns within the cerebral malaria population; these subclassifications may be important for studies of disease pathogenesis and ancillary treatment.

Project description:Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV(+)) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV(+) and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV(+) children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV(+) children exacerbates the pathological features associated with CM. IMPORTANCE?: There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV(+)) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV(+) than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV(+) children. Our findings raise the possibility that HIV(+) children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.

Project description:Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-?, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen-dependent interactions with cerebrovasculature.

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Fatal cerebral malaria: a venous efflux problem.

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Fatal cerebral malaria: a venous efflux problem.

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