Biology subjects

Okell, L. C.

Publications and source records attributed to Okell, L. C..

3 recordsLinked to original sources

bioRxiv2020

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

Resistance to artemisinin combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. Whilst resistance manifests as delayed asexual parasite clearance in patients following ACT treatment, the phenotype can only spread geographically via the sexual cycle and subsequent transmission through the mosquito. Artemisinin and its derivatives (such as dihydroartemisinin, DHA) as well as killing the asexual parasite form are known to sterilize male, sexual-stage gametes from activation. Whether resistant parasites overcome this artemisinin-dependent sterilizing effect has not, however, been fully tested. Here, we analysed five P. falciparum clinical isolates from the Greater Mekong Subregion, each of which demonstrated delayed clinical clearance and carried known resistance-associated polymorphisms in the Kelch13 gene (PfK13var). As well as demonstrating reduced sensitivity to artemisinin-derivates in in vitro asexual growth assays, certain PfK13var isolates also demonstrated a marked reduction in sensitivity to these drugs in an in vitro male gamete activation assay compared to a sensitive control. Importantly, the same reduction in sensitivity to DHA was observed when the most resistant isolate was assayed by standard membrane feeding assays using Anopheles stephensi mosquitoes. These results indicate that ACT use can favour resistant over sensitive parasite transmission. A selective advantage for resistant parasite transmission could also favour acquisition of further polymorphisms, such as mosquito host-specificity or antimalarial partner-drug resistance in mixed infections. Favoured transmission of resistance under ACT coverage could have profound implications for the spread of multidrug resistant malaria beyond Southeast Asia. ONE SENTENCE SUMMARYArtemisinin-resistant clinical isolates can also demonstrate resistance to the transmission-blocking effects of artemisinin-based drugs, favouring resistance transmission to the mosquito.

microbiology↗

bioRxiv2019

Evaluating the performance of malaria genomics for inferring changes in transmission intensity using transmission modelling

Advances in genetic sequencing and accompanying methodological approaches have resulted in pathogen genetics being used in the control of infectious diseases. To utilise these methodologies for malaria we first need to extend the methods to capture the complex interactions between parasites, human and vector hosts, and environment. Here we develop an individual-based transmission model to simulate malaria parasite genetics parameterised using estimated relationships between complexity of infection and age from 5 regions in Uganda and Kenya. We predict that cotransmission and superinfection contribute equally to within-host parasite genetic diversity at 11.5% PCR prevalence, above which superinfections dominate. Finally, we characterise the predictive power of six metrics of parasite genetics for detecting changes in transmission intensity, before grouping them in an ensemble statistical model. The best performing model successfully predicted malaria prevalence with mean absolute error of 0.055, suggesting genetic tools could be used for monitoring the impact of malaria interventions.

genetics↗

bioRxiv2019

Variation in the Prevalence of Submicroscopic Malaria Infections: Historical Transmission Intensity and Age as Key Determinants

Molecular detection of Plasmodium falciparum infection has revealed large numbers of individuals with low-density (yet transmissible) infections undetectable by microscopy. Here we present an updated systematic review of cross-sectional malaria surveys to explore the prevalence and drivers of these submicroscopic infections and define where they are likely to be relevant to malaria control efforts. Our results show that submicroscopic infections predominate in low transmission settings, but also reveal marked geographical variation in their prevalence, being highest in South American surveys and lowest in West African studies. Whilst current transmission levels partly explain these results, we find that historical transmission intensity also represents a crucial determinant of the size of the submicroscopic reservoir. Submicroscopic infection was more likely in adults than children, although we did not observe a statistically significant influence of seasonality. Our results suggest that the contribution of submicroscopic infections to transmission likely varies substantially across settings, potentially warranting different approaches to their targeting in the approach to elimination.

epidemiology↗