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1. Temperature impacts the environmental suitability for malaria transmission by Anopheles gambiae and Anopheles stephensi

   https://doi.org/10.1002/ecy.3685  

   Villena, Oswaldo C. ; Ryan, Sadie J. ; Murdock, Courtney C. ; Johnson, Leah R. ( June 2022 , Ecology)

   Extrinsic environmental factors influence the spatiotemporal dynamics of many organisms, including insects that transmit the pathogens responsible for vector‐borne diseases (VBDs). Temperature is an especially important constraint on the fitness of a wide variety of ectothermic insects. A mechanistic understanding of how temperature impacts traits of ectotherms, and thus the distribution of ectotherms and vector‐borne infections, is key to predicting the consequences of climate change on transmission of VBDs like malaria. However, the response of transmission to temperature and other drivers is complex, as thermal traits of ectotherms are typically nonlinear, and they interact to determine transmission constraints. In this study, we assess and compare the effect of temperature on the transmission of two malaria parasites,Plasmodium falciparumandPlasmodium vivax, by two malaria vector species,Anopheles gambiaeandAnopheles stephensi. We model the nonlinear responses of temperature dependent mosquito and parasite traits (mosquito development rate, bite rate, fecundity, proportion of eggs surviving to adulthood, vector competence, mortality rate, and parasite development rate) and incorporate these traits into a suitability metric based on a model for the basic reproductive number across temperatures. Our model predicts that the optimum temperature for transmission suitability is similar for the four mosquito–parasite combinations assessed in this study, but may differ at the thermal limits. More specifically, we found significant differences in the upper thermal limit between parasites spread by the same mosquito (A. stephensi) and between mosquitoes carryingP. falciparum. In contrast, at the lower thermal limit the significant differences were primarily between the mosquito species that both carried the same pathogen (e.g.,A. stephensiandA. gambiaeboth withP. falciparum). Using prevalence data, we show that the transmission suitability metric calculated from our mechanistic model is consistent with observedP. falciparumprevalence in Africa and Asia but is equivocal forP. vivaxprevalence in Asia, and inconsistent withP. vivaxprevalence in Africa. We mapped risk to illustrate the number of months various areas in Africa and Asia predicted to be suitable for malaria transmission based on this suitability metric. This mapping provides spatially explicit predictions for suitability and transmission risk.

    

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2. Understanding work-related travel and its relation to malaria occurrence in Thailand using geospatial maximum entropy modelling

   https://doi.org/10.1186/s12936-023-04478-6  

   Memarsadeghi, Natalie ; Stewart, Kathleen ; Li, Yao ; Sornsakrin, Siriporn ; Uthaimongkol, Nichaphat ; Kuntawunginn, Worachet ; Pidtana, Kingkan ; Raseebut, Chatree ; Wojnarski, Mariusz ; Jongsakul, Krisada ; et al ( December 2023 , Malaria Journal)

   Estimating malaria risk associated with work locations and travel across a region provides local health officials with information useful to mitigate possible transmission paths of malaria as well as understand the risk of exposure for local populations. This study investigates malaria exposure risk by analysing the spatial pattern of malaria cases (primarilyPlasmodium vivax)in Ubon Ratchathani and Sisaket provinces of Thailand, using an ecological niche model and machine learning to estimate the species distribution ofP. vivaxmalaria and compare the resulting niche areas with occupation type, work locations, and work-related travel routes.

   A maximum entropy model was trained to estimate the distribution ofP. vivaxmalaria for a period between January 2019 and April 2020, capturing estimated malaria occurrence for these provinces. A random simulation workflow was developed to make region-based case data usable for the machine learning approach. This workflow was used to generate a probability surface for the ecological niche regions. The resulting niche regions were analysed by occupation type, home and work locations, and work-related travel routes to determine the relationship between these variables and malaria occurrence. A one-way analysis of variance (ANOVA) test was used to understand the relationship between predicted malaria occurrence and occupation type.

   The MaxEnt (full name) model indicated a higher occurrence ofP. vivaxmalaria in forested areas especially along the Thailand–Cambodia border. The ANOVA results showed a statistically significant difference between average malaria risk values predicted from the ecological niche model for rubber plantation workers and farmers, the two main occupation groups in the study. The rubber plantation workers were found to be at higher risk of exposure to malaria than farmers in Ubon Ratchathani and Sisaket provinces of Thailand.

   The results from this study point to occupation-related factors such as work location and the routes travelled to work, being risk factors in malaria occurrence and possible contributors to transmission among local populations.

    

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3. Remarkable similarity in Plasmodium falciparum and Plasmodium vivax geranylgeranyl diphosphate synthase dynamics and its implication for antimalarial drug design

   https://doi.org/10.1111/cbdd.13170  

   Venkatramani, Aishwarya ; Gravina Ricci, Clarisse ; Oldfield, Eric ; McCammon, J. Andrew ( February 2018 , Chemical Biology & Drug Design)

   Malaria, mainly caused byPlasmodium falciparumandPlasmodium vivax,has been a growing cause of morbidity and mortality.P. falciparumis more lethal than isP. vivax, but there is a vital need for effective drugs against both species. Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme involved in the biosynthesis of quinones and in protein prenylation and has been proposed to be a malaria drug target. However, the structure ofP. falciparumGGPPS(PfGGPPS) has not been determined, due to difficulties in crystallization. Here, we created aPfGGPPSmodel using the homologousP.vivaxGGPPSX‐ray structure as a template. We simulated the modeledPfGGPPSas well asPvGGPPSusing conventional and Gaussian accelerated molecular dynamics in bothapo‐andGGPP‐bound states. TheMDsimulations revealed a striking similarity in the dynamics of both enzymes with loop 9‐10 controlling access to the active site. We also found thatGGPPstabilizesPfGGPPSandPvGGPPSinto closed conformations andviasimilar mechanisms. Shape‐based analysis of the binding sites throughout the simulations suggests that the two enzymes will be readily targeted by the same inhibitors. Finally, we produced threeMD‐validated conformations ofPfGGPPSto be used in future virtual screenings for potential new antimalarial drugs acting on bothPvGGPPSandPfGGPPS.

    

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4. Temporal trends in molecular markers of drug resistance in Plasmodium falciparum in human blood and profiles of corresponding resistant markers in mosquito oocysts in Asembo, western Kenya

   https://doi.org/10.1186/s12936-022-04284-6  

   Zhou, Zhiyong ; Gimnig, John E. ; Sergent, Sheila B. ; Liu, Ying ; Abong’o, Bernard ; Otieno, Kephas ; Chebore, Winnie ; Shah, Monica P. ; Williamson, John ; ter Kuile, Feiko O. ; et al ( September 2022 , Malaria Journal)

   Over the last two decades, the scale-up of vector control and changes in the first-line anti-malarial, from chloroquine (CQ) to sulfadoxine-pyrimethamine (SP) and then to artemether-lumefantrine (AL), have resulted in significant decreases in malaria burden in western Kenya. This study evaluated the long-term effects of control interventions on molecular markers ofPlasmodium falciparumdrug resistance using parasites obtained from humans and mosquitoes at discrete time points.

   Dried blood spot samples collected in 2012 and 2017 community surveys in Asembo, Kenya were genotyped by Sanger sequencing for markers associated with resistance to SP (Pfdhfr, Pfdhps), CQ, AQ, lumefantrine (Pfcrt, Pfmdr1)and artemisinin (Pfk13).Temporal trends in the prevalence of these markers, including data from 2012 to 2017 as well as published data from 1996, 2001, 2007 from same area, were analysed. The same markers from mosquito oocysts collected in 2012 were compared with results from human blood samples.

   The prevalence of SPdhfr/dhpsquintuple mutant haplotype C₅₀I₅₁R₅₉N₁₀₈I₁₆₄/S₄₃₆G₄₃₇E₅₄₀A₅₈₁A₆₁₃increased from 19.7% in 1996 to 86.0% in 2012, while an increase in the sextuple mutant haplotype C₅₀I₅₁R₅₉N₁₀₈I₁₆₄/H₄₃₆G₄₃₇E₅₄₀A₅₈₁A₆₁₃containingPfdhps-436H was found from 10.5% in 2012 to 34.6% in 2017. ResistantPfcrt-76 T declined from 94.6% in 2007 to 18.3% in 2012 and 0.9% in 2017. MutantPfmdr1-86Y decreased across years from 74.8% in 1996 to zero in 2017, mutantPfmdr1-184F and wildPfmdr1-D1246 increased from 17.9% to 58.9% in 2007 to 55.9% and 90.1% in 2017, respectively.Pfmdr1haplotype N₈₆F₁₈₄S₁₀₃₄N₁₀₄₂D₁₂₄₆ increased from 11.0% in 2007 to 49.6% in 2017. No resistant mutations inPfk13were found. Prevalence ofPfdhps-436H was lower while prevalence ofPfcrt-76 T was higher in mosquitoes than in human blood samples.

   This study showed an increased prevalence ofdhfr/dhpsresistant markers over 20 years with the emergenceof Pfdhps-436H mutant a decade ago in Asembo. The reversal ofPfcrtfrom CQ-resistant to CQ-sensitive genotype occurred following 19 years of CQ withdrawal. NoPfk13markers associated with artemisinin resistance were detected, but the increased haplotype ofPfmdr1N₈₆F₁₈₄S₁₀₃₄N₁₀₄₂D₁₂₄₆was observed. The differences in prevalence ofPfdhps-436H andPfcrt-76 T SNPs between two hosts and the role of mosquitoes in the transmission of drug resistant parasites require further investigation.

    

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5. How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

   https://doi.org/10.1186/s12936-021-04017-1  

   Huber, John H. ; Koepfli, Cristian ; España, Guido ; Nekkab, Narimane ; White, Michael T. ; Alex Perkins, T. ( December 2021 , Malaria Journal)

   Plasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites.

   An analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted.

   The analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12–78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse.

   Site-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.

    

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