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The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

ABSTRACT: Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.

SUBMITTER: Slater HC

PROVIDER: S-EPMC6440965 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

Slater Hannah C HC Ross Amanda A Felger Ingrid I Hofmann Natalie E NE Robinson Leanne L Cook Jackie J Gonçalves Bronner P BP Björkman Anders A Ouedraogo Andre Lin AL Morris Ulrika U Msellem Mwinyi M Koepfli Cristian C Mueller Ivo I Tadesse Fitsum F Gadisa Endalamaw E Das Smita S Domingo Gonzalo G Kapulu Melissa M Midega Janet J Owusu-Agyei Seth S Nabet Cécile C Piarroux Renaud R Doumbo Ogobara O Doumbo Safiatou Niare SN Koram Kwadwo K Lucchi Naomi N Udhayakumar Venkatachalam V Mosha Jacklin J Tiono Alfred A Chandramohan Daniel D Gosling Roly R Mwingira Felista F Sauerwein Robert R Paul Richard R Riley Eleanor M EM White Nicholas J NJ Nosten Francois F Imwong Mallika M Bousema Teun T Drakeley Chris C Okell Lucy C LC

Nature communications 20190329 1

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasi ...[more]

PMID: 30926893

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Project description:BackgroundDeep sequencing of targeted genomic regions is becoming a common tool for understanding the dynamics and complexity of Plasmodium infections, but its lower limit of detection is currently unknown. Here, a new amplicon analysis tool, the Parallel Amplicon Sequencing Error Correction (PASEC) pipeline, is used to evaluate the performance of amplicon sequencing on low-density Plasmodium DNA samples. Illumina-based sequencing of two Plasmodium falciparum genomic regions (CSP and SERA2) was performed on two types of samples: in vitro DNA mixtures mimicking low-density infections (1-200 genomes/μl) and extracted blood spots from a combination of symptomatic and asymptomatic individuals (44-653,080 parasites/μl). Three additional analysis tools-DADA2, HaplotypR, and SeekDeep-were applied to both datasets and the precision and sensitivity of each tool were evaluated.ResultsAmplicon sequencing can contend with low-density samples, showing reasonable detection accuracy down to a concentration of 5 Plasmodium genomes/μl. Due to increased stochasticity and background noise, however, all four tools showed reduced sensitivity and precision on samples with very low parasitaemia (< 5 copies/μl) or low read count (< 100 reads per amplicon). PASEC could distinguish major from minor haplotypes with an accuracy of 90% in samples with at least 30 Plasmodium genomes/μl, but only 61% at low Plasmodium concentrations (< 5 genomes/μl) and 46% at very low read counts (< 25 reads per amplicon). The four tools were additionally used on a panel of extracted parasite-positive blood spots from natural malaria infections. While all four identified concordant patterns of complexity of infection (COI) across four sub-Saharan African countries, COI values obtained for individual samples differed in some cases.ConclusionsAmplicon deep sequencing can be used to determine the complexity and diversity of low-density Plasmodium infections. Despite differences in their approach, four state-of-the-art tools resolved known haplotype mixtures with similar sensitivity and precision. Researchers can therefore choose from multiple robust approaches for analysing amplicon data, however, error filtration approaches should not be uniformly applied across samples of varying parasitaemia. Samples with very low parasitaemia and very low read count have higher false positive rates and call for read count thresholds that are higher than current default recommendations.

Dataset Information

The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

Publications

The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

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