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Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread.

ABSTRACT: Although drug resistance in Plasmodium falciparum typically evolves in regions of low transmission, resistance spreads readily following introduction to regions with a heavier disease burden. This suggests that the origin and the spread of resistance are governed by different processes, and that high transmission intensity specifically impedes the origin. Factors associated with high transmission, such as highly immune hosts and competition within genetically diverse infections, are associated with suppression of resistant lineages within hosts. However, interactions between these factors have rarely been investigated and the specific relationship between adaptive immunity and selection for resistance has not been explored. Here, we developed a multiscale, agent-based model of Plasmodium parasites, hosts, and vectors to examine how host and parasite dynamics shape the evolution of resistance in populations with different transmission intensities. We found that selection for antigenic novelty ("immune selection") suppressed the evolution of resistance in high transmission settings. We show that high levels of population immunity increased the strength of immune selection relative to selection for resistance. As a result, immune selection delayed the evolution of resistance in high transmission populations by allowing novel, sensitive lineages to remain in circulation at the expense of the spread of a resistant lineage. In contrast, in low transmission settings, we observed that resistant strains were able to sweep to high population prevalence without interference. Additionally, we found that the relationship between immune selection and resistance changed when resistance was widespread. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistant parasites in the population by allowing them to proliferate, even in untreated hosts, when resistance was linked to a novel epitope. Our results suggest that immune selection plays a role in the global pattern of resistance evolution.

SUBMITTER: Whitlock AOB

PROVIDER: S-EPMC8321109 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundArtemisinin-resistant genotypes of Plasmodium falciparum have now emerged a minimum of six times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy. We aimed to model and evaluate the long-term effects of high levels of partner-drug resistance on the early emergence of artemisinin-resistant genotypes.MethodsUsing a consensus modelling approach, we used three individual-based mathematical models of Plasmodium falciparum transmission to evaluate the effects of pre-existing partner-drug resistance and ACT deployment on the evolution of artemisinin resistance. Each model simulates 100 000 individuals in a particular transmission setting (malaria prevalence of 1%, 5%, 10%, or 20%) with a daily time step that updates individuals' infection status, treatment status, immunity, genotype-specific parasite densities, and clinical state. We modelled varying access to antimalarial drugs if febrile (coverage of 20%, 40%, or 60%) with one primary ACT used as first-line therapy: dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (ASAQ), or artemether-lumefantrine (AL). The primary outcome was time until 0·25 580Y allele frequency for artemisinin resistance (the establishment time).FindingsHigher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all models, a 10-fold increase in the frequency of partner-drug resistance genotypes on average corresponded to loss of artemisinin efficacy 2-12 years earlier. Most reductions in time to artemisinin resistance establishment were observed after an increase in frequency of the partner-drug resistance genotype from 0·0 to 0·10.InterpretationPartner-drug resistance in ACTs facilitates the early emergence of artemisinin resistance and is a major public health concern. Higher-grade partner-drug resistance has the largest effect, with piperaquine resistance accelerating the early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.FundingSchmidt Science Fellowship in partnership with the Rhodes Trust; Bill & Melinda Gates Foundation; Wellcome Trust.

Project description:In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.

Project description:BackgroundCape Verde is an archipelago located off the West African coast and is in a pre-elimination phase of malaria control. Since 2010, fewer than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks and sources of infection, including parasite importation.MethodsEnrolled subjects involved malaria patients admitted to Dr Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real-time PCR was used to identify SNPs in genes associated with drug resistance (e.g., pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data were generated to investigate the population structure of P. falciparum parasites.ResultsThe study analysed 190 parasite samples, 187 indigenous and 3 from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine-resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%).ConclusionsPolymorphisms in pfk13 associated with artemisinin-based combination therapy (ACT) tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and anti-malarial-associated mutations in the the pfcrt and pfdhfr genes. The first whole genome sequencing (WGS) was performed for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.

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Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread.

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