Severity of Retinopathy Parallels the Degree of Parasite Sequestration in the Eyes and Brains of Malawian Children With Fatal Cerebral Malaria

Barrera, Valentina; Hiscott, Paul; Craig, Alister G.; White, Valerie A.; Milner, Danny A.; Beare, Nicholas A. V.; MacCormick, Ian J. C.; Kamiza, Steve; Taylor, Terrie E.; Molyneux, Malcolm E.; Harding, Simon

doi:10.1093/infdis/jiu592

Cited by 53 publications

(66 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also called vasogenic oedema, this process is consistent with the description of ring haemorrhages, a characteristic sign of BBB disruption, in pediatric CM (Taylor et al, 2004; Dorovini-Zis et al, 2011). In addition, these ring hemorrhages correlate positively between retinal and cerebral tissues, owing to their common embryological origin from the neuroectoderm (Barrera et al, 2015; Greiner et al, 2015). Malaria retinopathies seen in pediatric CM are therefore a direct reflection of the neurovascular disease process, and the high frequency of ring haemorrhages both in the brain and in the retina in fatal disease point towards the occurrence of vasogenic oedema.…”

Section: Clinical Consequences Of Bbb Opening In Cm: Vasogenic Oedmentioning

confidence: 98%

Severe malaria: what’s new on the pathogenesis front?

Wassmer

Grau

2017

International Journal for Parasitology

117

102

View full text Add to dashboard Cite

Plasmodium falciparum causes the most severe and fatal form of malaria in humans with over half a million deaths each year. Cerebral malaria (CM), a complex neurological syndrome of severe falciparum malaria, is often fatal and represents a major public health burden. Despite vigorous efforts, the pathophysiology of CM remains to be elucidated, thereby hindering the development of adjunctive therapies. In recent years, multidisciplinary and collaborative approaches have led to groundbreaking progress both in the laboratory and in the field. Here we review the latest breakthroughs in severe malaria pathogenesis, with a specific focus on new pathogenetic mechanisms leading to CM. The most recent findings point towards specific parasite phenotypes targeting brain microvasculature, endothelial dysfunction and subsequent oedema-induced brain swelling.

show abstract

Section: Clinical Consequences Of Bbb Opening In Cm: Vasogenic Oedmentioning

confidence: 98%

Severe malaria: what’s new on the pathogenesis front?

Wassmer

Grau

2017

International Journal for Parasitology

117

102

View full text Add to dashboard Cite

show abstract

“…Future studies with a better resolution of cerebral manifestations, e.g., qualified by examination for retinopathy (43), are required to elucidate the suggested increased risk of development of cerebral complications when parasites can bind both EPCR and ICAM-1. However, our results suggest that circumstances relating to the patient, such as the expression of EPCR in different parts of the vasculature, regulation of the local inflammatory response, or prior immune priming, may be more important determinants of disease manifestation than the subtype of the EPCR-binding PfEMP1 gene that is being expressed.…”

Section: Figmentioning

confidence: 99%

The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

et al. 2017

View full text Add to dashboard Cite

By attaching infected erythrocytes to the vascular lining, Plasmodium falciparum parasites leave blood circulation and avoid splenic clearance. This sequestration is central to pathogenesis. Severe malaria is associated with parasites expressing an antigenically distinct P. falciparum erythrocyte membrane protein 1 (PfEMP1) subset mediating binding to endothelial receptors. Previous studies indicate that PfEMP1 adhesins with so-called CIDR␣1 domains capable of binding endothelial protein C receptor (EPCR) constitute the PfEMP1 subset associated with severe pediatric malaria. To analyze the relative importance of different subtypes of CIDR␣1 domains, we compared Pfemp1 transcript levels in children with severe malaria (including 9 fatal and 114 surviving cases), children hospitalized with uncomplicated malaria (n ϭ 42), children with mild malaria not requiring hospitalization (n ϭ 10), and children with parasitemia and no ongoing fever (n ϭ 12). High levels of transcripts encoding EPCR-binding PfEMP1 were found in patients with symptomatic infections, and the abundance of these transcripts increased with disease severity. The compositions of CIDR␣1 subtype transcripts varied markedly between patients, and none of the subtypes were dominant. Transcript-level analyses targeting other domain types indicated that subtypes of DBL␤ or DBL domains might mediate binding phenomena that, in conjunction with EPCR binding, could contribute to pathogenesis. These observations strengthen the rationale for targeting the PfEMP1-EPCR interaction by vaccines and adjunctive therapies. Interventions should target EPCR binding of all CIDR␣1 subtypes. KEYWORDS Plasmodium falciparum, antigenic variation, gene expression, malaria, PfEMP1 B ased on simple clinical observations, malaria patients can be divided into a smaller group with severe manifestations and a much larger group with uncomplicated disease (1). In areas of Africa with high to moderate rates of malaria transmission, severe malaria is seen almost only in children below 5 years of age (2). At the first entry point for health care, the majority of African children diagnosed with Plasmodium falciparum malaria suffer from uncomplicated febrile disease and are treated as outpatients. Downloaded fromHowever, based on the initial assessment, the examining physician hospitalizes some patients with more manifest symptoms. These children are not well, but based on simple triage, they can be further divided into a large group with uncomplicated disease, who, upon correct treatment, will be very likely to survive the disease, and a smaller group with severe disease, where a proportion will die despite the administration of what is currently considered optimal care (3). It is estimated that around 10 million children suffer from severe malaria every year and that 5 to 10% of these children die (4). Even though most children in areas where malaria is endemic are expected to experience several bouts of malaria during childhood, only one to three of these bouts are likely to ca...

show abstract

“…Several studies suggest that malaria retinopathy reflects pathological processes in the central nervous system. For instance, the severity of the retinopathy is associated with a higher risk of patient death [70] and parallels the extent of parasite sequestration in retina and brain microvasculature [71, 72]. In addition, there is a correlation between retinal and brain hemorrhages and the presence of fibrinogen leakage in the retinal and brain microvasculature, indicative of barrier breakdown [73, 74].…”

Section: Parasite Sequestration Microvascular Obstruction and Metabomentioning

confidence: 99%

“…This novel technique showed that non-perfused capillaries overlapped with areas of retinal whitening observed by ocular fundoscopy [75]. 40% of retinopathy-positive patients present brain swelling assessed by magnetic resonance imaging (MRI) [68] and the degree of sequestration in the retina is associated with the degree of brain swelling [71]. The demonstration that retinal changes are directly associated with parasite sequestration provides valuable information about neurovascular pathology, and reveals that damage induced by parasite factors is one of the main contributors to cerebral disease.…”

Section: Parasite Sequestration Microvascular Obstruction and Metabomentioning

confidence: 99%

EPCR and Malaria Severity: The Center of a Perfect Storm

Bernabeu

Smith

2017

Trends in Parasitology

View full text Add to dashboard Cite

Severe malaria due to Plasmodium falciparum infection causes nearly half a million deaths per year. The different symptomatology and disease manifestations among patients have hampered understanding of severe malaria pathology and complicated efforts to develop targeted disease interventions. Infected erythrocyte sequestration in the microvasculature plays a critical role in the development of severe disease and there is increasing evidence that cytoadherent parasites interact with host factors to enhance the damage caused by the parasite. The recent discovery that parasite binding to endothelial protein C receptor (EPCR) is associated with severe disease has suggested new mechanisms of pathology and provided new avenues for severe malaria adjunctive therapy research.

show abstract

Severity of Retinopathy Parallels the Degree of Parasite Sequestration in the Eyes and Brains of Malawian Children With Fatal Cerebral Malaria

Cited by 53 publications

References 29 publications

Severe malaria: what’s new on the pathogenesis front?

Severe malaria: what’s new on the pathogenesis front?

The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

EPCR and Malaria Severity: The Center of a Perfect Storm

Contact Info

Product

Resources

About