Plasmodium falciparum remains a relevant global health pathogen with high levels of genomic variation and gene flow that could undermine malaria elimination strategies, especially in the high burden regions of Africa. Infections with P. falciparum remain complex across most of sub-Saharan Africa. SNP variants from 2263 isolates from 24 malaria endemic settings within 15 African countries classified into western, central and eastern ancestry, plus a divergent Ethiopian population. The parasite populations are interbred and share genomic haplotypes especially across drug resistance loci. Haplotypes across drug resistance associated loci showed the strongest recent identity-by-descent between populations and endogenous haplotypes have spread to and from all populations. A recent signature of selection on chromosome 12 with candidate resistance loci against artemisinin derivatives is evident in Ghana and Malawi. Such selection and emerging sub-structure may affect intervention strategies and the efficacy of drugs and vaccines for malaria elimination. Formatted: Font: +Body (Calibri) Formatted: Line spacing: Multiple 1.15 li
Understanding the mechanisms of vaccine-elicited protection contributes to the development of new vaccines. The emerging field of systems vaccinology provides detailed information on host responses to vaccination and has been successfully applied to study the molecular mechanisms of several vaccines. Long noncoding RNAs (lncRNAs) are crucially involved in multiple biological processes, but their role in vaccine-induced immunity has not been explored. We performed an analysis of over 2,000 blood transcriptome samples from 17 vaccine cohorts to identify lncRNAs potentially involved with antibody responses to influenza and yellow fever vaccines. We have created an online database where all results from this analysis can be accessed easily. We found that lncRNAs participate in distinct immunological pathways related to vaccine-elicited responses. Among them, we showed that the expression of lncRNA FAM30A was high in B cells and correlates with the expression of immunoglobulin genes located in its genomic vicinity. We also identified altered expression of these lncRNAs in RNA-sequencing (RNA-seq) data from a cohort of children following immunization with intranasal live attenuated influenza vaccine, suggesting a common role across several diverse vaccines. Taken together, these findings provide evidence that lncRNAs have a significant impact on immune responses induced by vaccination.
Genome sequences of 247 Plasmodium falciparum isolates collected in The Gambia in 2008 and 2014 were analysed to identify changes possibly related to the scale-up of antimalarial interventions that occurred during this period. Overall, there were 15 regions across the genomes with signatures of positive selection. Five of these were sweeps around known drug resistance and antigenic loci. Signatures at antigenic loci such as thrombospodin related adhesive protein (Pftrap) were most frequent in eastern Gambia, where parasite prevalence and transmission remain high. There was a strong temporal differentiation at a non-synonymous SNP in a cysteine desulfarase (Pfnfs) involved in iron-sulphur complex biogenesis. During the 7-year period, the frequency of the lysine variant at codon 65 (Pfnfs-Q65K) increased by 22% (10% to 32%) in the Greater Banjul area. Between 2014 and 2015, the frequency of this variant increased by 6% (20% to 26%) in eastern Gambia. IC50 for lumefantrine was significantly higher in Pfnfs-65K isolates. This is probably the first evidence of directional selection on Pfnfs or linked loci by lumefantrine. Given the declining malaria transmission, the consequent loss of population immunity, and sustained drug pressure, it is important to monitor Gambian P. falciparum populations for further signs of adaptation.
Highlights d Upregulated mucosal interferon prior to vaccination leads to reduced LAIV shedding d Asymptomatic respiratory viral infections were seen in 42% of children d Other respiratory viral infections contribute to higher interferon gene expression
Background Artemether/lumefantrine is the most commonly used artemisinin-based combination treatment (ACT) for malaria in sub-Saharan Africa. Drug resistance to ACT components is a major threat to malaria elimination efforts. Therefore, rigorous monitoring of drug efficacy is required for adequate management of malaria and to sustain the effectiveness of ACTs. Objectives This study identified and described genomic loci that correlate with differences in ex vivo responses of natural Plasmodium falciparum isolates from The Gambia to antimalarial drugs. Methods Natural P. falciparum isolates from The Gambia were assayed for IC50 responses to four antimalarial drugs (artemether, dihydroartemisinin, amodiaquine and lumefantrine). Genome-wide SNPs from 56 of these P. falciparum isolates were applied to mixed-model regression and network analyses to determine linked loci correlating with drug responses. Genomic regions of shared haplotypes and positive selection within and between Gambian and Cambodian P. falciparum isolates were mapped by identity-by-descent (IBD) analysis of 209 genomes. Results SNPs in 71 genes, mostly involved in stress and drug resistance mechanisms correlated with drug responses. Additionally, erythrocyte invasion and permeability loci, including merozoite surface proteins (Pfdblmsp, Pfsurfin), and high-molecular-weight rhoptry protein 2 (Pfrhops2) were correlated with responses to multiple drugs. Haplotypes of pfdblmsp2 and known drug resistance loci (pfaat1, pfcrt and pfdhfr) from The Gambia showed high IBD with those from Cambodia, indicating co-ancestry, with significant linkage disequilibrium between their alleles. Conclusions Multiple linked genic loci correlating with drug response phenotypes suggest a genomic backbone may be under selection by antimalarials. This calls for further analysis of molecular pathways to drug resistance in African P. falciparum.
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