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    Evolution of drug-resistance genes in the asymptomatic Plasmodium falciparum reservoir of infection in Ghana
    Narh, Charles Akugbey ( 2019)
    Ghana is one of the 11 countries in the world with the highest malaria burden. Like many other African countries, the majority of individuals of all ages harbour asymptomatic Plasmodium falciparum infections, which sustain malaria transmission. Yet these infections are largely undiagnosed and untreated. Chloroquine (CQ) was the main drug for treating clinical malaria in Africa until it was replaced with artemisinin-based combination therapies (ACTs) in the early 2000s due to treatment failures. At the same time, sulphadoxine-pyrimethamine (SP) was adopted for intermittent preventative treatment in pregnancy (IPTp). In order to inform future malaria control strategies in Ghana, I investigated the asymptomatic P. falciparum reservoir in Bongo District (BD), where malaria transmission is both high and seasonal. To evaluate the reservoir of asymptomatic P. falciparum infections including antimalarial drug-resistance markers in BD, a cross-sectional Pilot survey of ~700 participants (≥ 1 year) was undertaken at the end of the dry season in June 2012. Following the completion of this Pilot investigation a larger serial cross-sectional study (~2,000 participants) involving six seasonally timed surveys was completed between 2012 and 2016. This study was designed to evaluate the impact of indoor residual spraying with insecticides (IRS) on the prevalence and diversity of asymptomatic P. falciparum infections in BD before, during, and after the IRS intervention. At the end of the dry season in 2012 I showed that 38.3% of the population across all ages (1-85 year) carried asymptomatic P. falciparum infections. The majority (>70%) of these infections harboured CQ sensitive alleles (Pfcrt K76 and Pfmdr1 N86) and/or alleles associated with reduced response to SP (Pfdhfr I51R59N108/Pfdhps G437) and/or the ACT partner-drug, lumefantrine (Pfmdr1 N86F184). There was no evidence of selection of multilocus haplotypes (i.e. Pfcrt- Pfmdr1- Pfdhfr- Pfdhps) with predicted resistance to both CQ and SP, nor was there any evidence of artemisinin resistance based on Pfk13 genotyping. To further understand this rebound of CQ sensitivity in BD further analyses of the microsatellite loci flanking Pfcrt and Pfmdr1 indicated that the CQ sensitive alleles spread through the asymptomatic parasite reservoir via soft selective sweeps. They may have expanded from CQ sensitive lineages that survived CQ drug pressure, i.e. before Ghana switched to ACTs. Following the completion of the 3-rounds of IRS in BD, undertaken between 2013 and 2014, both the prevalence and multiplicity of asymptomatic P. falciparum infections among children (1-10 years) reduced significantly compared to the pre-IRS surveys. Interestingly, despite these reductions, parasite diversity as assessed by msp2 heterozygosity remained high and stable from the pre-IRS through to the post-IRS surveys. My findings suggest that the asymptomatic P. falciparum reservoir in BD poses a threat to malaria elimination and plays a role in the evolution of antimalarial resistance in Ghana. Therefore, strategies combining IRS with population-wide antimalarial treatments, potentially using ACTs with CQ, would have to be deployed and sustained in BD. Nonetheless, continuous monitoring of the molecular markers of resistance and for changes in the parasite diversity will be crucial to inform elimination strategies in Ghana and Africa.