CD8+ T cells target cerebrovasculature in children with cerebral malaria

Riggle, Brittany A.; Manglani, Monica; Maric, Dragan; Johnson, Kory R.; Lee, Myoung-Hwa; Neto, Osorio Lopes Abath; Tl, Taylor; Seydel, Karl B.; Nath, Avindra; Miller, Louis H.; McGavern, Dorian B.; Pierce, Susan K.

doi:10.1172/jci133474

Cited by 80 publications

(97 citation statements)

References 45 publications

(64 reference statements)

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“…In addition, increased T cell presence was observed in human CM brains with HIV co-infection [23,24]. It is likely that in co-infected patients, the HIV associated immune dysregulation further amplifies the pathological damage of CM, leading to increased T cell influx into the brain [22,24,25]. Taken together, various host factors contribute to susceptibility to severe malaria and, although there are differences among regions, factors associated with strong host-immune responses appear key.…”

Section: Host Genetic Susceptibility and Resistancementioning

confidence: 99%

Pathophysiology and neurologic sequelae of cerebral malaria

Schiess¹,

Villabona-Rueda

Cottier

et al. 2020

Malar J

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Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain lifelong post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain's vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and underinvestigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite-and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.

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Section: Host Genetic Susceptibility and Resistancementioning

confidence: 99%

Pathophysiology and neurologic sequelae of cerebral malaria

Schiess¹,

Villabona-Rueda

Cottier

et al. 2020

Malar J

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“…accompanied by sequestration of infected RBCs (iRBCs) in the brain vasculature, blood brain barrier dysfunction, brain swelling and ultimately herniation of the brain stem and death [6][7][8] . CM mortality is high, 15-25%, and tragically, approximately 25% of children who recover from CM suffer from long-term neurological sequalae, including cognitive, vision and hearing impairments 7 .…”

mentioning

confidence: 99%

“…An important tool for the study of CM is the mouse model of CM, namely experimental CM (ECM). ECM is induced by infection of susceptible mouse strains such as C57BL/6 with the ECM-causing rodent Plasmodium strain, PbANKA that recapitulates many of the features of CM in children both clinically and pathologically [7][8][9][10][11][12][13][14] . PbANKA infection results in the rapid progression of disease, leading to development of as ataxia, paralysis and coma accompanied by brain hemorrhages, iRBC sequestration in brain vessels, edema, and if left untreated, within 5-7 days post infection, death, likely by neuronal cell death in the brain stem 11,12 .…”

mentioning

confidence: 99%

Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice

Akkaya

Bansal

Sheehan

et al. 2020

Sci Rep

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Cerebral malaria (CM) is the deadliest form of severe Plasmodium infections. Currently, we have limited understanding of the mechanisms by which Plasmodium parasites induce CM. The mouse model of CM, experimental CM (ECM), induced by infection with the rodent parasite, Plasmodium berghei AnKA (PbANKA) has been extensively used to study the pathophysiology of CM. Recent genomic analyses revealed that the coding regions of PbAnKA and the closely related Plasmodium berghei NK65 (PbNK65), that does not cause ECM, differ in only 21 single nucleotide polymorphysims (SNPs). Thus, the SNP-containing genes might contribute to the pathogenesis of ECM. Although the majority of these SNPs are located in genes of unknown function, one SNP is located in the DNA binding site of a member of the Plasmodium ApiAP2 transcription factor family, that we recently showed functions as a virulence factor alternating the host's immune response to the parasite. Here, we investigated the impact of this SNP on the development of ECM. Our results using CRISPR-Cas9 engineered parasites indicate that despite its immune modulatory function, the SNP is neither necessary nor sufficient to induce ECM and thus cannot account for parasite strain-specific differences in ECM phenotypes. Malaria is a global health problem accounting for over 200 million cases each year worldwide and nearly 450,000 deaths in Africa alone, the majority of which are young children 1,2. Malaria is caused by mosquito-borne parasites belonging to genus Plasmodium that have complex life cycles involving two hosts 3. The outcome of the Plasmodium infection can vary from asymptomatic infections, to mild febrile disease, to severe malaria, the most deadly form of which is cerebral malaria (CM) 3-7. Approximately 1-2% of children with malaria develop CM that is

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“…Both the sequestration and immunopathology hypotheses have been widely tested in the mouse model for CM, P. berghei ANKA-induced ECM in C57BL/6 mice [43][44][45]. The ECM model recapitulates many of the features of CM observed in children [46,47], such as the accumulation of pRBCs and CD8 + T cells in the brain vasculature [45,46,48], and bloodbrain barrier (BBB) dysfunction and edema [46]. On the other hand, ECM is also an immune-mediated disease where CD8 + T cells and the pro-inflammatory cytokine IFN-c play central pathogenic roles [6,49,50].…”

Section: Cerebral Malariamentioning

confidence: 99%

“…On the other hand, ECM is also an immune-mediated disease where CD8 + T cells and the pro-inflammatory cytokine IFN-c play central pathogenic roles [6,49,50]. Recently, a study showed definitively the presence of CD8 + T cells in close contact with the microvasculature in brains of children that died with CM, as well as the presence of pRBC along the cerebrovasculature, which may promote endothelial antigen acquisition and cross-presentation to CD8 + T cells [47]. These findings corroborate the results obtained with the ECM model and reinforce the relevance of this experimental system to elucidate CM associated-pathogenic processes in humans and to assess new therapeutic targets for CM adjunctive therapy.…”

Section: Cerebral Malariamentioning

confidence: 99%

γδ T cells in malaria: a double‐edged sword

Pamplona

Silva‐Santos

2020

The FEBS Journal

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Malaria remains a devastating global health problem, resulting in many annual deaths due to the complications of severe malaria. However, in endemic regions, individuals can acquire 'clinical immunity' to malaria, characterized by a decrease in severe malaria episodes and an increase of asymptomatic Plasmodium falciparum infections. Recently, it has been reported that tolerance to 'clinical malaria' and reduced disease severity correlates with a decrease in the numbers of circulating Vc9Vd2 T cells, the major subset of cd T cells in the human peripheral blood. This is particularly interesting as this population typically undergoes dramatic expansions during acute Plasmodium infections and was previously shown to play antiparasitic functions. Thus, regulated cd T-cell responses may be critical to balance immune protection with severe pathology, particularly as both seem to rely on the same pro-inflammatory cytokines, most notably TNF and IFN-c. This has been clearly demonstrated in mouse models of experimental cerebral malaria (ECM) based on Plasmodium berghei ANKA infection. Furthermore, our recent studies suggest that the natural course of Plasmodium infection, mimicked in mice through mosquito bite or sporozoite inoculation, includes a major pathogenic component in ECM that depends on cd T cells and IFN-c production in the asymptomatic liver stage, where parasite virulence is seemingly set and determines pathology in the subsequent blood stage. Here, we discuss these and other recent advances in our understanding of the complex-protective versus pathogenic-functions of cd T cells in malaria.

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CD8+ T cells target cerebrovasculature in children with cerebral malaria

Cited by 80 publications

References 45 publications

Pathophysiology and neurologic sequelae of cerebral malaria

Pathophysiology and neurologic sequelae of cerebral malaria

Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice

γδ T cells in malaria: a double‐edged sword

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