Describing the current status of
            Plasmodium falciparum
            population structure and drug resistance within mainland Tanzania using molecular inversion probes

ABSTRACTHigh-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programs, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania country-wide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, roughly separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from geographically close districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts, and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared.SIGNIFICANCEDocumenting dynamics of malaria parasite genomics in high-transmission settings at scale in sub-Saharan Africa is critical for policy and decision making to support ongoing malaria elimination initiatives. Using molecular inversion probes, we genotyped over 1,000 Tanzanian Plasmodium falciparum samples collected country-wide in 2017 at hundreds of variable polymorphic positions across the genome. Frequencies of known drug resistance mutations were higher in northern districts of the country compared to the south. Results also showed a distinct isolation-by-distance pattern (whereby increasing geographic distance was correlated with decreasing genetic relatedness), as well as signals of higher genetic sharing between several southern districts. These results provide, for the first time, a picture of current within-country diversity of Tanzanian P. falciparum populations.

Download Full-text

Drug-Resistance and Population Structure of Plasmodium falciparum Across the Democratic Republic of Congo Using High-Throughput Molecular Inversion Probes

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy223 ◽

2018 ◽

Vol 218 (6) ◽

pp. 946-955 ◽

Cited By ~ 28

Author(s):

Ozkan Aydemir ◽

Mark Janko ◽

Nick J Hathaway ◽

Robert Verity ◽

Melchior Kashamuka Mwandagalirwa ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Population Structure ◽

High Throughput ◽

Democratic Republic ◽

Democratic Republic Of Congo ◽

Republic Of Congo ◽

Molecular Inversion Probes

Download Full-text

History and current status of Plasmodium falciparum antimalarial drug resistance in Madagascar

Scandinavian Journal of Infectious Diseases ◽

10.3109/00365540903289670 ◽

2010 ◽

Vol 42 (1) ◽

pp. 22-32 ◽

Cited By ~ 9

Author(s):

Valérie Andriantsoanirina ◽

Didier Ménard ◽

Luciano Tuseo ◽

Rémy Durand

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Current Status ◽

Antimalarial Drug Resistance

Download Full-text

The question of Plasmodium falciparum population structure

Trends in Parasitology ◽

10.1016/s1471-4922(01)02034-7 ◽

2001 ◽

Vol 17 (8) ◽

pp. 351-353 ◽

Cited By ~ 23

Author(s):

Philip Awadalla ◽

David Walliker ◽

Hamza Babiker ◽

Margaret Mackinnon

Keyword(s):

Plasmodium Falciparum ◽

Population Structure ◽

Falciparum Population

Download Full-text

Local differentiation in Plasmodium falciparum drug resistance genes in Sudan

Parasitology ◽

10.1017/s0031182003003020 ◽

2003 ◽

Vol 126 (5) ◽

pp. 391-400 ◽

Cited By ~ 88

Author(s):

A. A. ABDEL-MUHSIN ◽

M. J. MACKINNON ◽

P. AWADALLA ◽

E. ALI ◽

S. SULEIMAN ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Population Structure ◽

Resistance Genes ◽

Microsatellite Loci ◽

Balancing Selection ◽

Dry Season ◽

Chloroquine Resistance ◽

Multi Drug Resistance ◽

Eastern Region

Studies of population genetic structure of parasites can be used to infer which parasite genes are under selection. Here, the population structure of 4 genes associated with drug resistance of Plasmodium falciparum (the chloroquine resistance transporter, pfcrt, dihydrofolate reductase, dhfr, dihydropteroate synthase, dhps, and multi-drug resistance, pfmdr-1) were examined in parasite populations in 3 villages in eastern Sudan and in an urban area of Khartoum, the capital. In order to differentiate the effects of drug selection from neutral influences on population structure, parasites were also genotyped for 3 putatively neutral microsatellite loci (polyα, TA81 and pfg377), and for 2 antigenic loci that are either under balancing selection or neutral, merozoite surface protein 1 and 2, (MSP-1 and MSP-2). Cross-sectional surveys were carried out during the peak transmission (wet) season and in the ensuing dry season. No significant variation in frequencies of MSP-1 and MSP-2 alleles was seen among villages in the eastern region and between the villages and Khartoum, nor between the wet and dry season. However, the drug resistance genes, pfmdr-1, pfcrt and dhfr and to a lesser extent the microsatellite loci showed high FST values when comparing villages with Khartoum, indicating strong geographical differentiation at these loci. Moreover, variation in frequencies of the drug resistance genes, pfmdr-1, pfcrt and dhfr, was observed between the wet and dry season. These differences most probably reflect the variation in drug pressure between each region, and in drug usage between the wet and dry season in a given region.

Download Full-text

Plasmodium falciparum population structure in Sudan post artemisinin-based combination therapy

Acta Tropica ◽

10.1016/j.actatropica.2015.04.013 ◽

2015 ◽

Vol 148 ◽

pp. 97-104 ◽

Cited By ~ 8

Author(s):

Amani M.A. Bakhiet ◽

Abdel-Muhsin A. Abdel-Muhsin ◽

Salah-Eldin G. Elzaki ◽

Zainab Al-Hashami ◽

Hamida S. Albarwani ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Population Structure ◽

Combination Therapy ◽

Falciparum Population

Download Full-text

Antimalarial Drug Resistance Profiling of Plasmodium falciparum Infections in Ghana Using Molecular Inversion Probes and Next-Generation Sequencing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01423-19 ◽

2020 ◽

Vol 64 (4) ◽

Cited By ~ 4

Author(s):

Benedicta A. Mensah ◽

Ozkan Aydemir ◽

James L. Myers-Hansen ◽

Millicent Opoku ◽

Nicholas J. Hathaway ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Next Generation Sequencing ◽

Antimalarial Drug ◽

Next Generation ◽

Cape Coast ◽

Antimalarial Drug Resistance ◽

Content Type ◽

Molecular Inversion Probes ◽

Generation Sequencing

ABSTRACT A key drawback to monitoring the emergence and spread of antimalarial drug resistance in sub-Saharan Africa is early detection and containment. Next-generation sequencing methods offer the resolution, sensitivity, and scale required to fill this gap by surveilling for molecular markers of drug resistance. We performed targeted sequencing using molecular inversion probes to interrogate five Plasmodium falciparum genes (pfcrt, pfmdr1, pfdhps, pfdhfr, and pfk13) implicated in chloroquine, sulfadoxine-pyrimethamine (SP), and artemisinin resistance in two sites in Ghana. A total of 803 dried blood spots from children aged between 6 months and 14 years presenting with uncomplicated P. falciparum malaria at the Begoro District Hospital in Begoro and the Ewim Polyclinic in Cape Coast, Ghana, from 2014 to 2017 were prepared on filter paper. Thirteen years after the removal of drug pressure, chloroquine-sensitive parasite strains with pfcrt K76 have increased nearly to fixation in Begoro, in the forest area (prevalence = 95%), but at a lower rate in Cape Coast, in the coastal region (prevalence = 71%, Z = −3.5, P < 0.001). In addition, pfmdr1 184F-bearing parasites are under strong selection. The pfdhfr/pfdhps quadruple genotype (IRNGK), associated with SP resistance, is near saturation. Our study identified at a 2 to 10% prevalence pfdhps 581G, which is a sulfadoxine resistance marker that correlates with the failure of SP prophylaxis in pregnancy and which has not been observed in Ghana. The differences in the reexpansion of chloroquine-sensitive strains observed at the two study sites, the stronger SP resistance, and the high prevalence of pfmdr1 184F should be further monitored to inform malaria control strategies in Ghana.

Download Full-text