Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure
- University of California, San Francisco, United States
- Infectious Diseases Research Collaboration, Uganda
- Stanford University, United States
- Makerere University College of Health Sciences, Uganda
- Infectious Diseases Resarch Collaboration, Uganda
- London School of Hygiene and Tropical Medicine, United Kingdom
- University of Washington, United States
Abstract
Fundamental gaps remain in our understanding of how immunity to malaria develops. We used detailed clinical and entomological data from parallel cohort studies conducted across the malaria transmission spectrum in Uganda to quantify the development of immunity against symptomatic P. falciparum as a function of age and transmission intensity. We focus on: anti-parasite immunity (i.e; ability to control parasite densities) and anti-disease immunity (i.e; ability to tolerate higher parasite densities without fever). Our findings suggest a strong effect of age on both types of immunity, not explained by cumulative-exposure. They also show an independent effect of exposure, where children living in moderate/high transmission settings develop immunity faster as transmission increases. Surprisingly, children in the lowest transmission setting appear to develop immunity more efficiently than those living in moderate transmission settings. Anti-parasite and anti-disease immunity develop in parallel, reducing the probability of experiencing symptomatic malaria upon each subsequent P. falciparum infection.
Data availability
All the data used for these analyses as well as the R code used to reproduce the main study findings are available at https://github.com/isabelrodbar/immunity. Complete data from the 3 cohort studies are available at the CliEpiDB website (https://clinepidb.org/ce/app/record/dataset/DS_0ad509829e).
Article and author information
Author details
Isabel Rodriguez-Barraquer
Prasanna Jagannathan
Funding
National Institutes of Health (2U19AI089674)
- Isabel Rodriguez-Barraquer
- Emmanuel Arinaitwe
- Prasanna Jagannathan
- Moses R Kamya
- Phillip J Rosenthal
- John Rek
- Grant Dorsey
- Joaniter Nankabirwa
- Sarah G Staedke
- Maxwell Kilama
- Chris Drakeley
- Isaac Ssewanyana
- David L Smith
- Bryan Greenhouse
Bill and Melinda Gates Foundation (OPP1110495)
- David L Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study protocol was reviewed and approved by the Makerere University School of Medicine Research and Ethics Committee (Identification numbers 2011-149 and 2011-167, the Uganda National Council for Science and Technology, , the London School of Hygiene and Tropical Medicine Ethics Committee (Identification numbers 5943 and 5944), the Durham University School of Biological and Biomedical Sciences Ethics Committee (PRISM Entomology Uganda), and the University of California, San Francisco, Committee on Human Research (Identification numbers 11-05539 and 11-05995) and the Uganda National Council for Science and Technology (Identification numbers HS350 and HS-1019).. All parents/guardians were asked to provide written informed consent at the time of enrollment.
Copyright
© 2018, Rodriguez-Barraquer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure
eLife 7:e35832.
https://doi.org/10.7554/eLife.35832
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Background: The role of circulating metabolites on child development is understudied. We investigated associations between children's serum metabolome and early childhood development (ECD).
Methods: Untargeted metabolomics was performed on serum samples of 5,004 children aged 6-59 months, a subset of participants from the Brazilian National Survey on Child Nutrition (ENANI-2019). ECD was assessed using the Survey of Well-being of Young Children's milestones questionnaire. The graded response model was used to estimate developmental age. Developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Partial least square regression selected metabolites with a variable importance projection ≥ 1. The interaction between significant metabolites and the child's age was tested.
Results: Twenty-eight top-ranked metabolites were included in linear regression models adjusted for the child's nutritional status, diet quality, and infant age. Cresol sulfate (β = -0.07; adjusted-p < 0.001), hippuric acid (β = -0.06; adjusted-p < 0.001), phenylacetylglutamine (β = -0.06; adjusted-p < 0.001), and trimethylamine-N-oxide (β = -0.05; adjusted-p = 0.002) showed inverse associations with DQ. We observed opposite directions in the association of DQ for creatinine (for children aged -1 SD: β = -0.05; p =0.01; +1 SD: β = 0.05; p =0.02) and methylhistidine (-1 SD: β = - 0.04; p =0.04; +1 SD: β = 0.04; p =0.03).
Conclusion: Serum biomarkers, including dietary and microbial-derived metabolites involved in the gut-brain axis, may potentially be used to track children at risk for developmental delays.
Funding: Supported by the Brazilian Ministry of Health and the Brazilian National Research Council.
