Identifying parasite virulence factors and host genetic and immunologic factors that contribute to severe malarial outcomes in Ugandan children

Cerebral malaria (CM) and severe malarial anemia (SMA) remain drivers of morbidity and mortality due to Plasmodium falciparum infection in children in Sub-Saharan Africa. There are currently no adjunctive therapies for severe malaria (SM), suggesting that we need a better understanding of both host and pathogen factors that contribute to SM. This dissertation attempted to identify both host and parasite factors that contribute to disease severity in malaria, factors that differentiate between CM and SMA, and those associated with mortality and neurocognitive outcomes in CM. Children between 18 months and 12 years of age, meeting the WHO definition for CM (n=269) or SMA (n=232), were recruited from the Acute Care Unit at Mulago Hospital in Kampala, Uganda. Healthy community children (CC, n=213) in the same age-range were recruited from the neighborhoods and extended households of children with SM. Whole blood was collected at enrollment and was either processed immediately for plasma or was preserved and stored accordingly for future RNA and DNA isolation. We performed genotyping for endothelial protein C receptor (EPCR) polymorphisms, quantitative reverse-transcriptase PCR to estimate transcript levels of var genes encoding P.falciparum erythrocyte membrane protein 1 (PfEMP1), and used plasma to quantify a number of cytokines, chemokines, angiogenic growth factors, soluble EPCR and erythropoietin with ELISA-based assays. The work presented in this dissertation identified both cytoadhesion of infected erythrocytes (IEs) and host immune factors as important contributors to SM pathogenesis. We have shown that polymorphisms associated with less bound and more soluble EPCR are associated with reduced risk of SM; that EPCR-binding PfEMP1 are important in SM and that their transcript levels are higher in CM than SMA; that the immune profile, while quite similar in CM and SMA, is differentiated especially by elevated levels of chemokines and IL-10 in CM. Lastly, our studies on the association of TNF-α and EPO with disease severity in CM highlight the importance of understanding both systemic and local effects of host mediators when considering targets for adjunctive therapies, and the importance of selectively inhibiting the pathogenic effects without compromising the beneficial roles of that target.

Author dc:creator

• Shabani, Estela

• immune response
• parasite virulence factors
• pediatric
• severe malaria
• severe outcomes
• Uganda

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/11299/192648

OAI identifier oai:identifier

oai:conservancy.umn.edu:11299/192648