Review Article: Blood-brain barrier in falciparum malaria*

Gitau, Evelyn; Newton, Charles R.

doi:10.1111/j.1365-3156.2004.01366.x

Cited by 31 publications

(30 citation statements)

References 53 publications

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“…CM appears as a diffuse encephalopathy commonly presenting with headache, agitation, frank psychosis, seizures and impaired consciousness, and occasionally with brainstem signs or focal neurological signs such as hemiplegia and cranial nerve palsies [8,9]. According to the World Health Organization (WHO) clinical criteria, CM is defined as a potentially reversible, diffuse encephalopathy causing a Glasgow coma score of 11/15 or less, often associated with fitting, in the absence of other factors that could cause unconsciousness such as coexistent hypoglycemia or other CNS infections [10].…”

Section: Introductionmentioning

confidence: 99%

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

Polimeni

Prato

2014

Fluids Barriers CNS

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Cerebral malaria (CM) is a life-threatening complication of falciparum malaria, associated with high mortality rates, as well as neurological impairment in surviving patients. Despite disease severity, the etiology of CM remains elusive. Interestingly, although the Plasmodium parasite is sequestered in cerebral microvessels, it does not enter the brain parenchyma: so how does Plasmodium induce neuronal dysfunction? Several independent research groups have suggested a mechanism in which increased blood–brain barrier (BBB) permeability might allow toxic molecules from the parasite or the host to enter the brain. However, the reported severity of BBB damage in CM is variable depending on the model system, ranging from mild impairment to full BBB breakdown. Moreover, the factors responsible for increased BBB permeability are still unknown. Here we review the prevailing theories on CM pathophysiology and discuss new evidence from animal and human CM models implicating BBB damage. Finally, we will review the newly-described role of matrix metalloproteinases (MMPs) and BBB integrity. MMPs comprise a family of proteolytic enzymes involved in modulating inflammatory response, disrupting tight junctions, and degrading sub-endothelial basal lamina. As such, MMPs represent potential innovative drug targets for CM.

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Section: Introductionmentioning

confidence: 99%

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

Polimeni

Prato

2014

Fluids Barriers CNS

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“…Finally, several studies also reported a crucial role for ICAM-1 in malaria pathogenesis, and notably, ICAM-1-deficient mice are protected from ECM (16). The combined effect of these pathological events is associated with disruption of the physical integrity of the blood-brain barrier (BBB) and the development of brain edema, leading to coma and, ultimately, death (2,(17)(18)(19)(20). One of the characteristic features of ECM is the increased sequestration of CD4 ϩ and CD8 ϩ T cells, which have been reported to be associated with disease pathogenesis (21,22).…”

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confidence: 99%

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

et al. 2015

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h Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized that Plasmodium HMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected with Plasmodium berghei ANKA and that in many aspects resembles human cerebral malaria elicited by P. falciparum infection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected with P. berghei ANKA lacking the hmgb2 gene (⌬hmgb2 ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM in pbhmgb2-deficient mice was restored by the administration of recombinant PbHMGB2. Protection from experimental cerebral malaria in ⌬hmgb2 ANKA-infected mice was associated with reduced sequestration in the brain of CD4؉ and CD8 ؉ T cells, including CD8 ؉ granzyme B ؉ and CD8 ؉ IFN-␥ ؉ cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-type P. berghei ANKA-infected mice. In summary, Plasmodium HMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.

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“…The sequestration may impair blood flow in the microcirculation and contribute to the CNS effects. The parasites are largely confined to the intravascular compartment, but because the blood-brain barrier is mildly impaired in severe malaria (Gitau and Newton, 2005), compounds produced by the parasite may influence neuronal function. Cytokines, in particular the proinflammatory cytokines such as tumor necrosis factor and interleukin are thought to be involved, probably effecting the CNS through nitric oxide (Clark et al, 1991).…”

Section: Cns Manifestations Of Acute Falciparum Malariamentioning

confidence: 99%

Interaction between Plasmodium falciparum and human immunodeficiency virus type 1 on the central nervous system of African children

Newton¹

2005

Journal of NeuroVirology

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Plasmodium falciparum and human immunodeficiency virus type 1 (HIV-1) infections are common in children living in sub-Saharan Africa (SSA). Both of these pathogens affect the central nervous system (CNS). Most HIV-1 infection of children in this region is acquired from infected mothers, particularly during breast-feeding and at the time of delivery. Over a third of children infected by birth will have died before their first birthday, before overt CNS manifestations have developed. The most common manifestations of primary CNS infection include neurodevelopmental delay, impaired brain growth, motor deficits, and behavioral problems. These deficits may also result from infections, neoplasm, or stroke. Cognitive impairments become more evident if the child survives for longer, but in Africa, children rarely survive past their fifth birthday. In malaria endemic areas, severe falciparum malaria usually develops after 6 months of age, and most of the CNS manifestations are more common in children over 1 year old. About 11% of children develop neurological deficits following cerebral malaria, most of which improve within 2 years of the insult. However, up to 24% of children may have neurocognitive impairments following severe malaria. The effect of milder malaria and coincidental parasitization on cognitive function is unknown. Other comorbidities that are common in SSA, such as malnutrition or micronutrient deficiencies, may influence children's neurodevelopment. The coinfection of malaria and HIV-1 may aggravate the neurodevelopmental impairments documented in these children. However, to date there are little published data, although it may have a profound effect of children living in SSA.

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Review Article: Blood-brain barrier in falciparum malaria*

Cited by 31 publications

References 53 publications

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

Interaction between Plasmodium falciparum and human immunodeficiency virus type 1 on the central nervous system of African children

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