Robyn E. Elphinstone

Contrasting pediatric and adult cerebral malaria: The role of the endothelial barrier

Malaria affects millions of people around the world and a small subset of those infected develop cerebral malaria. The clinical presentation of cerebral malaria differs between children and adults, and it has been suggested that age-related changes in the endothelial response may account for some of these differences. During cerebral malaria, parasites sequester within the brain microvasculature but do not penetrate into the brain parenchyma and yet, the infection causes severe neurological symptoms. Endothelial dysfunction is thought to play an important role in mediating these adverse clinical outcomes. During infection, the endothelium becomes activated and more permeable, which leads to increased inflammation, hemorrhages, and edema in the surrounding tissue. We hypothesize that post-natal developmental changes, occurring in both endothelial response and the neurovascular unit, account for the differences observed in the clinical presentations of cerebral malaria in children compared with adults.

Acute Kidney Injury Is Common in Pediatric Severe Malaria and Is Associated With Increased Mortality

Acute kidney injury is common in severe malaria and associated with short- and long-term mortality developing in 50% of cases after admission. Cystatin C and BUN are associated with the severity of AKI, are elevated at admission and predict mortality.

Alterations in Systemic Extracellular Heme and Hemopexin Are Associated With Adverse Clinical Outcomes in Ugandan Children With Severe Malaria

Background. Malaria remains a major cause of global mortality. Extracellular heme, released during malaria-induced hemolysis, mediates a number of pathogenic processes associated with vascular and organ injury. Hemopexin (hpx) facilitates the degradation of extracellular heme. In this study, we explore the hypothesis that dysregulation of the heme-hpx axis is associated with disease severity, acute kidney injury (AKI), and outcome. Methods. Plasma levels of hemin and hpx (at admission, day 3, and day 14) were assessed in children with severe malaria in Jinja, Uganda. Results. The ratio of heme to hpx was higher at admission and decreased with recovery (median, 0.043 [interquartile range {IQR}, 0.007–0.239] on day 1, 0.024 [IQR, 0.005–0.126] on day 3, and 0.008 [IQR, 0.002–0.022] on day 14; P < .001). Ratios of heme to hpx at admission were higher in children with as compared to those without severe anemia (median, 0.124 [IQR, 0.024–0.431] vs 0.016 [IQR, 0.003–0.073]; P < .0001), children with as compared to those without respiratory distress (median, 0.063 [IQR, 0.017–0.413] vs 0.020 [IQR, 0.004–0.124]; P < .01), and children with as opposed to those without stage 3 AKI (median, 0.354 [IQR, 0.123–2.481] vs 0.037 [IQR, 0.005–0.172], P < .01). The heme to hpx ratio at admission was associated with 6-month mortality (median, 0.148 [IQR, 0.042–0.500] vs 0.039 [IQR, 0.007–0.172]; P = .012). Conclusions. The ratio of heme to hpx is associated with disease severity and adverse clinical outcomes in Ugandan children, and dysregulation of the heme axis may contribute to malaria pathogenesis.

The impact of placental malaria on neurodevelopment of exposed infants: a role for the complement system?

The in utero environment can have a profound impact on early brain development and subsequent childhood school performance and behavior. Over 125 million pregnant women are at risk of malaria each year, yet the impact of in utero malaria exposure on the neurological and cognitive development of their exposed infants is unknown. Based on recent evidence supporting a role for the complement system in regulating neurodevelopment, and mediating neuroinflammation and neurodegenerative diseases, we hypothesize that excessive complement activation induced by placental malaria may disrupt normal neurodevelopment resulting in neurocognitive impairment of infants exposed to malaria in utero. Complement components may mediate these effects through the initiation of neuroinflammation, dysregulation of neurovascular angiogenesis, and the disruption of normal synaptic pruning.

S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

ABSTRACT Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P < 0.0001), despite higher parasite burdens (P < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4+ and CD8+ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.

Malaria in pregnancy alters l-arginine bioavailability and placental vascular development

Malaria in pregnancy alters l-arginine biosynthesis in Malawian women, and l-arginine supplementation improves placental vasculature and birth outcomes in a preclinical model. Malaria relief, one amino acid at a time Malaria infection during pregnancy can disrupt placental vasculature and cause complications during the pregnancy and delivery. Nitric oxide plays a key role in placental vascular function, and its synthesis requires l-arginine. Knowing that l-arginine and nitric oxide are both depleted during malaria-induced hemolysis and that many people in malaria-endemic areas lack sufficient l-arginine in their diets, McDonald et al. examined the effects of dietary l-arginine supplementation. The authors first studied a cohort of pregnant women in Malawi and showed that the blood of patients with malaria had less l-arginine and that this was associated with worse pregnancy outcomes. Conversely, l-arginine supplementation in a mouse model of malaria in pregnancy improved fetal weight and viability, indicating the potential value of this intervention. Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, l-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance l-arginine bioavailability as strategies to improve birth outcomes.

Brain-derived Neurotrophic Factor Is Associated With Disease Severity and Clinical Outcome in Ugandan Children Admitted to Hospital With Severe Malaria

Background: Malaria remains a leading cause of childhood death and neurologic disability in sub-Saharan Africa. Here, we test the hypothesis that malaria-induced alterations to circulating brain-derived neurotrophic factor (BDNF) are associated with poor clinical outcomes in children with severe malaria. Methods: We quantified BDNF (by enzyme-linked immunosorbent assay) in plasma samples collected [at presentation (day 1), day 3 and day 14], during a prospective study of Ugandan children admitted to hospital with severe malaria (n = 179). Results: BDNF concentration at presentation (day 1) was lower in children with cerebral malaria (P < 0.01), coma (P < 0.01), Lambaréné Organ Dysfunction Score >1 (P < 0.05) and respiratory distress (P < 0.01). Higher BDNF concentration at presentation was associated with shorter time to coma recovery [hazard ratio = 1.655 (1.194–2.293); P = 0.002] and a reduced odds ratio of disability [0.50 (0.27–0.94); P = 0.047] and death [0.45 (0.22–0.92); P = 0.035]. BDNF concentration was lower on day 1 and increased in children surviving severe malaria (day 14; P < 0.0001). Conclusions: Our findings provide the new evidence linking circulating BDNF with disease severity, coma recovery and clinical outcome in children with severe malaria.