A role for neutrophils and type I interferon in pediatric cerebral malaria

Abstract

Malaria remains a significant global burden. Infection with P. falciparum can cause a range of disease presentations from asymptomatic malaria to severe disease syndromes. Risk for severe disease is associated with host genetic backgrounds, transmission intensity and other factors; however, the host mechanisms that mediate severe illness are poorly understood. Thus, this thesis project set out to discover novel host factors associated with cerebral malaria (CM), one of the most severe forms of malaria. CM has two subtypes; the more common subtype is associated with a massive sequestration of infected red blood cells (iRBC) to the microvasculature throughout the body including the brain and this can be detected in life by visualizing vascular abnormalities in the retina, termed Ret+CM. Ret+CM is associated with 20% mortality; whereas, the second subtype of CM without massive iRBC sequestration (Ret-CM) is associated with 5% mortality. In Chapter 2, to identify host factors and potential disease mechanisms associated with these two clinical phenotypes of CM, we compared the peripheral whole blood transcriptomes of Malawian children with Ret+CM to children with Ret-CM. We identified a higher neutrophil activation state and upregulation of extracellular matrix and coagulation cascade pathways in Ret+CM. In contrast, children with Ret-CM demonstrated lower levels of inflammation, higher levels of alpha-interferon and upregulation of toll-like receptor pathways. In Chapter 3, we reported our unpublished observation that the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant-response pathway is also upregulated in Ret-CM. In Chapter 4, we further characterized the observation that genetic polymorphisms in the type I interferon receptor (IFNAR1) are associated with severe malaria. To identify IFNAR1 variants associated with CM, we compared 21 variants in Malawian children with either CM or mild malaria. We confirmed one variant previously associated with CM and identified two novel variants: rs12626750 and rs914142. Both rs12626750 and rs914142 are predicted to be involved in gene regulation and more functional studies on the effect of IFNAR1 variants in CM are merited. This thesis work identifies potential new molecular mechanisms in CM pathogenesis associated with iRBC sequestration and vasculopathy and a potentially protective role for type I IFN and Nrf2.