Multiplication rate variation in the human malaria parasite Plasmodium falciparum

Murray, Lee G.; Stewart, Lindsay B.; Tarr, Sarah J.; Ahouidi, Ambroise D.; Diakité, Mahamadou; Amambua-Ngwa, Alfred; Conway, David J.

doi:10.1038/s41598-017-06295-9

Cited by 45 publications

(55 citation statements)

References 42 publications

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“…Substantial variation in multiplication rates have also been shown among seven P. falciparum clones from Southeast Asian isolates 20 , further indicating the likely importance of within-population variation. Multiplication rates of four of the West African isolates cultured for up to three months remained lower than in older laboratory adapted control strains 19 , although adaptation might occur over a longer period as novel alleles take time to increase to high frequencies in culture 21 .…”

Section: Introductionmentioning

confidence: 79%

“…However, such assays are subject to potentially confounding determinants, including effects on parasite viability by host inflammatory responses or sample handling prior to laboratory culture. More precise multiplication rate estimates can be obtained for laboratory-adapted parasite strains or clinical isolates after the first few weeks of culture ex vivo , using replicate exponential growth assays in different donor erythrocytes, which has demonstrated a wide range of multiplication rates among eleven West African P. falciparum clinical isolates tested 19 . Substantial variation in multiplication rates have also been shown among seven P. falciparum clones from Southeast Asian isolates 20 , further indicating the likely importance of within-population variation.…”

Section: Introductionmentioning

confidence: 99%

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Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

et al. 2020

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Pathogen multiplication rate is theoretically an important determinant of virulence, although often poorly understood and difficult to measure accurately. We show intrinsic asexual blood stage multiplication rate variation of the major human malaria parasite Plasmodium falciparum to be associated with blood-stage infection intensity in patients. A panel of clinical isolates from a highly endemic West African population was analysed repeatedly during five months of continuous laboratory culture, showing a range of exponential multiplication rates at all timepoints tested, mean rates increasing over time. All isolates had different genome sequences, many containing within-isolate diversity that decreased over time in culture, but increases in multiplication rates were not primarily attributable to genomic selection. New mutants, including premature stop codons emerging in a few isolates, did not attain sufficiently high frequencies to substantially affect overall multiplication rates. Significantly, multiplication rate variation among the isolates at each of the assayed culture timepoints robustly correlated with parasite levels seen in patients at clinical presentation, indicating innate parasite control of multiplication rate that contributes to virulence.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

et al. 2020

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“…In the past, it was hypothesized that parasites carrying pfhrp3 gene have a competitive advantage in the laboratory conditions or in the chimpanzee host used in the genetic crosses A C C E P T E D M A N U S C R I P T (Wellems et al, 1987). A recent study has reported evidence for similar distributions of multiplication rates between 3D7 and HB3 in lab cultures (Murray et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

Sepúlveda

Phelan

Benavente

et al. 2018

Infection, Genetics and Evolution

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Many rapid diagnostic tests (RDT) used on suspected malaria cases are based on the detection of the protein encoded by the Plasmodium falciparum histidine-rich protein-2 (pfhrp2) gene, which shares a high sequence homology with pfhrp3 in the 3D7 reference genome. Parasite isolates showing pfhrp2 and pfhrp3 gene deletions have been emerging over the years, but a comprehensive genetic analysis of these variants is still lacking. With this purpose, genomic data from experimental P. falciparum genetic crosses between different laboratory lines (3D7, HB3, DD2, 7G8 and GB4) were first analysed (n = 98). The frequency of pfhrp2 deletions was consistent with a Mendelian prediction in HB3 × DD2 (56.7%; 95%CI = (39.5%-72.9%)). Moreover, the pfhrp2 and pfhrp3 deletions segregated independently of each other in the same genetic cross. Analysis of 3D7 × HB3 and 7G8 × GB4 estimated the probability of spontaneously generating a pfhrp2 deletion during sexual recombination to be up to 6.2%. Next, whole genome sequence data from 1970 P. falciparum isolates collected globally were analysed. Nine samples displayed depth of coverage consistent with pfhrp2 deletions (0.5%), but the corresponding split-read analysis could not confirm deletions in seven of these samples. Twenty-eight isolates had evidence of pfhrp3 deletions (1.4%), which are widespread in Southeast Asia. Finally, a meta-analysis of published data revealed a positive mean association between the frequencies of pfhrp2 and pfhrp3 deletions in Africa and South America. This result suggested a shared selective pressure acting on these genetic variants. In conclusion, evidence of genetic selection on both pfhrp2 and pfhrp3 deletions was presented, but experimental crosses do not provide evidence of a fitness cost of these variants. Further work is urgently needed to accurately determine the prevalence and the degree of association between these genetic variants, and the respective impact on diagnostic accuracy of many in-use RDT.

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“…These observed differences, 21 together with the results observed for South America therefore support an effect of transmission 22 history on the submicroscopic reservoir which is distinct from the age structure of the infected 23 population and unlikely to be driven by geographical bias. 24 A number of hypotheses could explain these results, including systematic variation in asexual blood 1 stage multiplication rate of Plasmodium falciparum 46 or various haemoglobinopathies and human 2 genetic traits that have been linked to lower average parasite densities 41,47 . It is also not possible to 3 definitively preclude systematic variation in diagnostic quality across settings, although this is perhaps 4 unlikely: for example, a recent analysis found that whilst microscopy quality varies across settings, it 5 does not do so systematically with transmission intensity 48 .…”

Section: Discussionmentioning

confidence: 99%

Global & Temporal Patterns of Submicroscopic Plasmodium falciparum Malaria Infection

Whittaker

Slater

Bousema

et al. 2019

Preprint

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Background: Adoption of molecular techniques to detect Plasmodium falciparum infection has revealed many 11 previously undetected (yet transmissible) low-density infections in areas of low malaria transmission. In a world 12 where numerous countries are approaching elimination, additional data from low transmission areas are 13 required to better understand the determinants of submicroscopic infection and their potential relevance in 14 these settings. 15Methods: We updated a systematic review of studies assessing asexual P. falciparum prevalence by microscopy 16 and PCR in the same population. PubMed and Web of Science databases were searched up to July 2017. Bayesian Research in Context:1 Evidence before this study: Cross-sectional studies of malaria prevalence in endemic populations have revealed 2 the widespread presence of infections with parasite densities lower than the threshold of detection by 3 microscopy. Previous systematic reviews of these surveys have highlighted that the fraction of P.falciparum 4 infections missed by microscopy can be substantial (~45% of all infections detected by PCR on average), that 5 submicroscopic infection is more likely in adults than in children (a phenomenon attributed to increased levels 6 of immunity), and that this missed fraction (the "submicroscopic reservoir") is typically highest in areas with low 7 transmission intensity. Although further work is required, a number of studies have also demonstrated the 8 capacity of these submicroscopic, low density infections to infect mosquitoes and therefore contribute to 9 onwards transmission. 10Added value of this study: Although previous studies have found that infections in older, more immune 11 individuals are more likely to be submicroscopic, in lower transmission settings where individuals generally 12 develop less immunity, a larger proportion of infections are also typically submicroscopic. Here we present an 13 updated systematic review to explore this apparent paradox across a range of transmission settings and define 14 contexts in which submicroscopic infections are likely to be most relevant to malaria control efforts. Leveraging 15 the substantial increase in the availability of malaria cross-sectional surveys reporting prevalence by molecular 16 methods, we explore the association of submicroscopic infection with a number of novel factors -these include

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Multiplication rate variation in the human malaria parasite Plasmodium falciparum

Cited by 45 publications

References 42 publications

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

Global & Temporal Patterns of Submicroscopic Plasmodium falciparum Malaria Infection

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