Browsing by Author "Turnbull, Lindsey B."

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    Adipose tissue parasite sequestration drives leptin production in mice and correlates with human cerebral malaria
    (American Association for the Advancement of Science, 2021-03-24) Mejia, Pedro; Treviño-Villarreal, J. Humberto; De Niz, Mariana; Meibalan, Elamaran; Longchamp, Alban; Reynolds, Justin S.; Turnbull, Lindsey B.; Opoka, Robert O.; Roussilhon, Christian; Spielmann, Tobias; Ozaki, C. Keith; Heussler, Volker T.; Seydel, Karl B.; Taylor, Terrie E.; John, Chandy C.; Milner, Danny A.; Marti, Matthias; Mitchell, James R.; Medicine, School of Medicine
    Circulating levels of the adipokine leptin are linked to neuropathology in experimental cerebral malaria (ECM), but its source and regulation mechanism remain unknown. Here, we show that sequestration of infected red blood cells (iRBCs) in white adipose tissue (WAT) microvasculature increased local vascular permeability and leptin production. Mice infected with parasite strains that fail to sequester in WAT displayed reduced leptin production and protection from ECM. WAT sequestration and leptin induction were lost in CD36KO mice; however, ECM susceptibility revealed sexual dimorphism. Adipocyte leptin was regulated by the mechanistic target of rapamycin complex 1 (mTORC1) and blocked by rapamycin. In humans, although Plasmodium falciparum infection did not increase circulating leptin levels, iRBC sequestration, tissue leptin production, and mTORC1 activity were positively correlated with CM in pediatric postmortem WAT. These data identify WAT sequestration as a trigger for leptin production with potential implications for pathogenesis of malaria infection, prognosis, and treatment.
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    Evaluation of an ultrasensitive HRP2-based rapid diagnostic test for detection of asymptomatic Plasmodium falciparum parasitaemia among children in western Kenya
    (BMC, 2022-11-16) Turnbull, Lindsey B.; Ayodo, George; Knight, Veronicah; John, Chandy C.; McHenry, Megan S.; Tran, Tuan M.; Medicine, School of Medicine
    Background Accurate detection of asymptomatic malaria parasitaemia in children living in high transmission areas is important for malaria control and reduction programmes that employ screen-and-treat surveillance strategies. Relative to microscopy and conventional rapid diagnostic tests (RDTs), ultrasensitive RDTs (us-RDTs) have demonstrated reduced limits of detection with increased sensitivity to detect parasitaemia in symptomatic individuals. In this study, the performance of the NxTek™ Eliminate Malaria P.f test was compared with traditional microscopy and quantitative polymerase chain reaction (qPCR) testing methods of detection for P. falciparum parasitaemia among asymptomatic children aged 7–14 years living in an area of high malaria transmission intensity in western Kenya. Methods In October 2020, 240 healthy children without any reported malaria symptoms were screened for the presence of P. falciparum parasitaemia; 120 children were randomly selected to participate in a follow-up visit at 6–10 weeks. Malaria parasitaemia was assessed by blood-smear microscopy, us-RDT, and qPCR of a conserved var gene sequence from genomic DNA extracted from dried blood spots. Sensitivity, specificity, and predictive values were calculated for field diagnostic methods using qPCR as the gold standard. Comparison of detectable parasite density distributions and area under the curve were also calculated to determine the effectiveness of the us-RDT in detecting asymptomatic infections with low parasite densities. Results The us-RDT detected significantly more asymptomatic P. falciparum infections than microscopy (42.5% vs. 32.2%, P = 0.002). The positive predictive value was higher for microscopy (92.2%) than for us-RDT (82.4%). However, false negative rates were high for microscopy and us-RDT, with negative predictive values of 53.7% and 54.6%, respectively. While us-RDT detected significantly more infections than microscopy overall, the density distribution of detectable infections did not differ (P = 0.21), and qPCR detected significantly more low-density infections than both field methods (P < 0.001, for both comparisons). Conclusions Us-RDT is more sensitive than microscopy for detecting asymptomatic malaria parasitaemia in children. Though the detectable parasite density distributions by us-RDT in our specific study did not significantly differ from microscopy, the additional sensitivity of the us-RDT resulted in more identified asymptomatic infections in this important group of the population and makes the use of the us-RDT advisable compared to other currently available malaria field detection methods.
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    Sources of transcription variation in Plasmodium falciparum
    (Elsevier, 2022) Turnbull, Lindsey B.; Button-Simons, Katrina A.; Agbayani, Nestor; Ferdig, Michael T.; Pediatrics, School of Medicine
    Variation in transcript abundance can contribute to both short-term environmental response and long-term evolutionary adaptation. Most studies are designed to assess differences in mean transcription levels and do not consider other potentially important and confounding sources of transcriptional variation. Detailed quantification of variation sources will improve our ability to detect and identify the mechanisms that contribute to genome-wide transcription changes that underpin adaptive responses. To quantify innate levels of expression variation, we measured mRNA levels for more than 5000 genes in the malaria parasite, Plasmodium falciparum, among clones derived from two parasite strains across biologically and experimentally replicated batches. Using a mixed effects model, we partitioned the total variation among four sources-between strain, within strain, environmental batch effects, and stochastic noise. We found 646 genes with significant variation attributable to at least one of these sources. These genes were categorized by their predominant variation source and further examined using gene ontology enrichment analysis to associate function with each source of variation. Genes with environmental batch effect and within strain transcript variation may contribute to phenotypic plasticity, while genes with between strain variation may contribute to adaptive responses and processes that lead to parasite strain-specific survival under varied conditions.
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    Subclinical Inflammation in Asymptomatic Schoolchildren With Plasmodium falciparum Parasitemia Correlates With Impaired Cognition
    (Oxford University Press, 2024) Johnson, Alexander E.; Upadhye, Aditi; Knight, Veronicah; Gaskin, Erik L.; Turnbull, Lindsey B.; Ayuku, David; Nyalumbe, Mark; Abuonji, Emily; John, Chandy C.; McHenry, Megan S.; Tran, Tuan M.; Ayodo, George; Medicine, School of Medicine
    Background: Subclinical inflammation and cognitive deficits have been separately associated with asymptomatic Plasmodium falciparum infections in schoolchildren. However, whether parasite-induced inflammation is associated with worse cognition has not been addressed. We conducted a cross-sectional pilot study to better assess the effect of asymptomatic P. falciparum parasitemia and inflammation on cognition in Kenyan schoolchildren. Methods: We enrolled 240 children aged 7-14 years residing in high malaria transmission in Western Kenya. Children performed five fluid cognition tests from a culturally adapted NIH toolbox and provided blood samples for blood smears and laboratory testing. Parasite densities and plasma concentrations of 14 cytokines were determined by quantitative PCR and multiplex immunoassay, respectively. Linear regression models were used to determine the effects of parasitemia and plasma cytokine concentrations on each of the cognitive scores as well as a composite cognitive score while controlling for age, gender, maternal education, and an interaction between age and P. falciparum infection status. Results: Plasma concentrations of TNF, IL-6, IL-8, and IL-10 negatively correlated with the composite score and at least one of the individual cognitive tests. Parasite density in parasitemic children negatively correlated with the composite score and measures of cognitive flexibility and attention. In the adjusted model, parasite density and TNF, but not P. falciparum infection status, independently predicted lower cognitive composite scores. By mediation analysis, TNF significantly mediated ~29% of the negative effect of parasitemia on cognition. Conclusions: Among schoolchildren with PCR-confirmed asymptomatic P. falciparum infections, the negative effect of parasitemia on cognition could be mediated, in part, by subclinical inflammation. Additional studies are needed to validate our findings in settings of lower malaria transmission and address potential confounders that could affect both inflammation and cognitive performance.