Genetics of cerebral malaria: pathogenesis, biomarkers and emerging therapeutic interventions.

BACKGROUND: Cerebral malaria (CM) is a preeminent cause of severe disease and premature deaths in Sub-Saharan Africa, where an estimated 90% of cases occur. The key features of CM are a deep, unarousable coma that persists for longer than 1 h in patients with peripheral Plasmodium falciparum and no other explanation for encephalopathy. Significant research efforts on CM in the last few decades have focused on unravelling the molecular underpinnings of the disease pathogenesis and the identification of potential targets for therapeutic or pharmacologic intervention. These efforts have been greatly aided by the generation and study of mouse models of CM, which have provided great insights into key events of CM pathogenesis, revealed an interesting interplay of host versus parasite factors that determine the progression of malaria to severe disease and exposed possible targets for therapeutic intervention in severe disease. MAIN BODY: This paper reviews our current understanding of the pathogenic and immunologic factors involved in CM. We present the current view of the roles of certain gene products e.g., the var gene, ABCA-1, ICAM-1, TNF-alpha, CD-36, PfEMP-1 and G6PD, in CM pathogenesis. We also present alterations in the blood-brain barrier as a consequence of disease proliferation as well as complicated host and parasite interactions, including the T-cell immune reaction, reduced deformation of erythrocytes and cytoadherence. We further looked at recent advances in cerebral malaria treatment interventions by emphasizing on biomarkers, new diagnostic tools and emerging therapeutic options. CONCLUSION: Finally, we discuss how the current understanding of some of these pathogenic and immunologic factors could inform the development of novel therapeutic interventions to fight CM.

Low incidence of COVID-19 case severity and mortality in Africa; Could malaria co-infection provide the missing link?

BACKGROUND: Despite reports of malaria and coronavirus diseases 2019 (COVID-19) co-infection, malaria-endemic regions have so far recorded fewer cases of COVID-19 and deaths from COVID-19, indicating a probable protection from the poor outcome of COVID-19 by malaria. On the contrary, other evidence suggests that malaria might contribute to the death caused by COVID-19. Hence, this paper reviewed existing evidence hypothesizing poor outcome or protection of COVID-19 patients when co-infected with malaria. METHODS: PRISMA guidelines for systematic review were employed in this study. Published articles from December 2019 to May 2021on COVID-19 and malaria co-infection and outcome were systematically searched in relevant and accessible databases following a pre-defined strategy. Studies involving human, in vivo animal studies, and in vitro studies were included. RESULTS: Twenty three (23) studies were included in the review out of the 3866 records identified in the selected scientific databases. Nine (9) papers reported on co-infection of COVID-19 and malaria. Five (5) papers provided information about synergism of malaria and COVID-19 poor prognosis, 2 papers reported on syndemic of COVID-19 and malaria intervention, and 7 studies indicated that malaria protects individuals from COVID-19. CONCLUSIONS: Low incidence of COVID-19 in malaria-endemic regions supports the hypothesis that COVID-19 poor prognosis is prevented by malaria. Although further studies are required to ascertain this hypothesis, cross-immunity and common immunodominant isotopes provide strong evidence to support this hypothesis. Also, increase in co-inhibitory receptors and atypical memory B cells indicate synergy between COVID-19 and malaria outcome, though, more studies are required to make a definite conclusion.

Effects of in utero exposure to monosodium glutamate on locomotion, anxiety, depression, memory and KCC2 expression in offspring.

In pregnancy, there is a significant risk for developing embryos to be adversely affected by everyday chemicals such as food additives and environmental toxins. In recent times, several studies have documented the detrimental effect of exposure to such chemicals on the behaviour and neurodevelopment of the offspring. This study evaluated the influence of the food additive, monosodium glutamate (MSG), on behaviour and development in mice. Pregnant dams were exposed to MSG 2 or 4 g/kg or distilled water from gestation day 10-20. On delivery, postnatal day 1 (PN 1), 3 pups were sacrificed and whole brain samples assayed for KCC2 expression by western blot. The remaining pups were housed until PN 43 before commencing behavioural assessment. Their weights were measured at birth and at 3 days intervals until PN 42. The impact of prenatal exposure to MSG on baseline exploratory, anxiety and depression behaviours as well as spatial and working memory was assessed. In utero exposure to 4 g/kg MSG significantly reduced exploratory drive and increased depression-like behaviours but did not exert any significant impact on anxiety-like behaviours (p < 0.01). Additionally, there was a two-fold increase in KCC2 expression in both 2 and 4 g/kg MSG-exposed offspring. CONCLUSION: This study indicates that, in utero exposure to MSG increases the expression of KCC2 and causes significant effect on locomotion and depression-like behaviours but only marginally affects memory function.

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice.

BACKGROUND: Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect. METHODS: Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg-1), artesunate (ART: 1, 2, 4, 8, 16 mg kg-1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg-1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded. RESULTS: ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg-1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss. CONCLUSION: Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.