Gene expression analyses reveal differences in children’s response to malaria according to their age

In Bandiagara, Mali, children experience on average two clinical malaria episodes per year. However, even in the same transmission area, the number of uncomplicated symptomatic infections, and their parasitemia, can vary dramatically among children. We simultaneously characterize host and parasite gene expression profiles from 136 Malian children with symptomatic falciparum malaria and examine differences in the relative proportion of immune cells and parasite stages, as well as in gene expression, associated with infection and or patient characteristics. Parasitemia explains much of the variation in host and parasite gene expression, and infections with higher parasitemia display proportionally more neutrophils and fewer T cells, suggesting parasitemia-dependent neutrophil recruitment and/or T cell extravasation to secondary lymphoid organs. The child’s age also strongly correlates with variations in gene expression: Plasmodium falciparum genes associated with age suggest that older children carry more male gametocytes, while variations in host gene expression indicate a stronger innate response in younger children and stronger adaptive response in older children. These analyses highlight the variability in host responses and parasite regulation during P. falciparum symptomatic infections and emphasize the importance of considering the children’s age when studying and treating malaria infections.

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Policy information about availability of of computer code Self-reported (by parent) biological sex of each individual child was considered as a covariate in our statistical models for differential expression because of previous reports of sex-based differences in the immune response to malaria.Enrollment in the cohort did not occur on the basis of sex.By chance, we obtained data from 72 male and 64 female children.In our study, we did not find a substantial number of differentially expressed genes between male and female children and biological sex was a very weak contributor to the overall variance in gene expression in our cohort.Consent was collected at the time of enrollment in the cohort to use biological information, such as sex.
Participant ethnicity was collected at enrollment in the cohort because of reported differences in malaria risk between ethnic groups in Mali, with the Fulani ethnic group having far lower risk of malaria than other ethnic groups.Because the majority of the participants in our cohort were of the Dogon ethnic group, with very small sample sizes from other ethnic groups, participant ethnicity was not included as part of our analyses.
Our cohort includes children from ages 1 to 15, with a median age of 5 years old.We identified age as one of the main drivers in gene expression during malaria infection in this cohort.Parasitemia, the number of parasites in the blood during the time of sampling, was also a main driver of gene expression, and ranged from 48 to 622,775 parasites per microliter of blood, with a median of 26,675.The total number of malaria episodes experienced in 3 years of followup and the time to the next malaria episode after our sequenced blood sample were measured for each child and weighted for the monthly risk of malaria in this seasonal transmission zone (see materials and methods for detailed calculations).
Patient samples used in this study were available at University of Maryland, Baltimore from a previous cohort study from Coulibaly et al. 2014, where consent was given for genetic and genomic analyses.Patients were not directly recruited for our presented study.This study includes transcriptomic analyses from 136 human children during a malaria episode and the parasites causing the episode.These samples were chosen from a previous incidence study described in in Coulibaly et et al., 2014 and represent one of of the largest transcriptomic studies of of human malaria infection 16 16 samples with fewer than 3 years of of available epidemiological data were excluded from analyses of of total number of of infections and time to to next infection, noted in in the text and highlighted in in Supplemental Table 1. 1.
This study includes 136 field isolates from a malaria endemic setting.Given the large sample size presented, we we expect that these samples represent the wider population of of malaria-infected children in in this transmission setting in in Mali and our results are consistent with those presented in in other field studies from similar settings.
Randomization was not relevant to to this study, as as we we analyzed gene expression changes as as they occur continuously with our chosen covariates, rather than grouping individuals into discrete categories.
Blinding was not relevant to to this study, as as we we analyzed gene expression changes as as they occur continuously with our chosen covariates, rather than grouping individuals into discrete categories.
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Institutional review boards of the Faculty of Medicine, Pharmacy and Dentistry of the University of Maryland, Baltimore and of the University of Sciences, Techniques and Technologies of Bamako, Mali (IRB numbers HCR-HP-00041382 and HP-00085882) nature portfolio | reporting summary April 2023Life sciences study designAll studies must disclose on on these points even when the disclosure is is negative.materials, systems and methodsWe We require information from authors about some types of of materials, experimental systems and methods used in in many studies.Here, indicate whether each material, system or or method listed is is relevant to to your study.If If you are not sure if if a list item applies to to your research, read the appropriate section before selecting a response.Materials & experimental systemsn/a Involved in in the study