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Combining transgenesis with paratransgenesis to fight malaria.

ABSTRACT: Malaria is among the deadliest infectious diseases, and Plasmodium, the causative agent, needs to complete a complex development cycle in its vector mosquito for transmission to occur. Two promising strategies to curb transmission are transgenesis, consisting of genetically engineering mosquitoes to express antimalarial effector molecules, and paratransgenesis, consisting of introducing into the mosquito commensal bacteria engineered to express antimalarial effector molecules. Although both approaches restrict parasite development in the mosquito, it is not known how their effectiveness compares. Here we provide an in-depth assessment of transgenesis and paratransgenesis and evaluate the combination of the two approaches. Using the Q-system to drive gene expression, we engineered mosquitoes to produce and secrete two effectors - scorpine and the MP2 peptide - into the mosquito gut and salivary glands. We also engineered Serratia, a commensal bacterium capable of spreading through mosquito populations to secrete effectors into the mosquito gut. Whereas both mosquito-based and bacteria-based approaches strongly reduced the oocyst and sporozoite intensity, a substantially stronger reduction of Plasmodium falciparum development was achieved when transgenesis and paratransgenesis were combined. Most importantly, transmission of Plasmodium berghei from infected to naïve mice was maximally inhibited by the combination of the two approaches. Combining these two strategies promises to become a powerful approach to combat malaria.

SUBMITTER: Huang W

PROVIDER: S-EPMC9596157 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Combining transgenesis with paratransgenesis to fight malaria.

Huang Wei W Vega-Rodriguez Joel J Kizito Chritopher C Cha Sung-Jae SJ Jacobs-Lorena Marcelo M

eLife 20221025

Malaria is among the deadliest infectious diseases, and <i>Plasmodium</i>, the causative agent, needs to complete a complex development cycle in its vector mosquito for transmission to occur. Two promising strategies to curb transmission are transgenesis, consisting of genetically engineering mosquitoes to express antimalarial effector molecules, and paratransgenesis, consisting of introducing into the mosquito commensal bacteria engineered to express antimalarial effector molecules. Although bo ...[more]

PMID: 36281969

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Project description:BackgroundTsetse flies (Diptera: Glossinidae) are the cyclical vectors of the causative agents of African Trypanosomosis, which has been identified as a neglected tropical disease in both humans and animals in many regions of sub-Saharan Africa. The sterile insect technique (SIT) has shown to be a powerful method to manage tsetse fly populations when used in the frame of an area-wide integrated pest management (AW-IPM) program. To date, the release of sterile males to manage tsetse fly populations has only been implemented in areas to reduce transmission of animal African Trypanosomosis (AAT). The implementation of the SIT in areas with Human African Trypanosomosis (HAT) would require additional measures to eliminate the potential risk associated with the release of sterile males that require blood meals to survive and hence, might contribute to disease transmission. Paratransgenesis offers the potential to develop tsetse flies that are refractory to trypanosome infection by modifying their associated bacteria (Sodalis glossinidius) here after referred to as Sodalis. Here we assessed the feasibility of combining the paratransgenesis approach with SIT by analyzing the impact of ionizing radiation on the copy number of Sodalis and the vectorial capacity of sterilized tsetse males.ResultsAdult Glossina morsitans morsitans that emerged from puparia irradiated on day 22 post larviposition did not show a significant decline in Sodalis copy number as compared with non-irradiated flies. Conversely, the Sodalis copy number was significantly reduced in adults that emerged from puparia irradiated on day 29 post larviposition and in adults irradiated on day 7 post emergence. Moreover, irradiating 22-day old puparia reduced the copy number of Wolbachia and Wigglesworthia in emerged adults as compared with non-irradiated controls, but the radiation treatment had no significant impact on the vectorial competence of the flies.ConclusionAlthough the radiation treatment significantly reduced the copy number of some tsetse fly symbionts, the copy number of Sodalis recovered with time in flies irradiated as 22-day old puparia. This recovery offers the opportunity to combine a paratransgenesis approach - using modified Sodalis to produce males refractory to trypanosome infection - with the release of sterile males to minimize the risk of disease transmission, especially in HAT endemic areas. Moreover, irradiation did not increase the vector competence of the flies for trypanosomes.

Project description:Human African trypanosomiasis (HAT), transmitted by tsetse flies, has historically infected hundreds of thousands of individuals annually in sub-Saharan Africa. Over the last decade, concerted control efforts have reduced reported cases to below 10,000 annually, bringing complete elimination within reach. A potential technology to eliminate HAT involves rendering the flies resistant to trypanosome infection. This approach can be achieved through the introduction of transgenic Sodalis symbiotic bacteria that have been modified to produce a trypanocide, and propagated via Wolbachia symbionts, which confer a reproductive advantage to the paratransgenic tsetse. However, the population dynamics of these symbionts within tsetse flies have not yet been evaluated. Specifically, the key factors that determine the effectiveness of paratransgenesis have yet to be quantified. To identify the impact of these determinants on T.b. gambiense and T.b. rhodesiense transmission, we developed a mathematical model of trypanosome transmission that incorporates tsetse and symbiont population dynamics. We found that fecundity and mortality penalties associated with Wolbachia or recombinant Sodalis colonization, probabilities of vertical transmission, and tsetse migration rates are fundamental to the feasibility of HAT elimination. For example, we determined that HAT elimination could be sustained over 25 years when Wolbachia colonization minimally impacted fecundity or mortality, and when the probability of recombinant Sodalis vertical transmission exceeded 99.9%. We also found that for a narrow range of recombinant Sodalis vertical transmission probability (99.9-90.6% for T.b. gambiense and 99.9-85.8% for T.b. rhodesiense), cumulative HAT incidence was reduced between 30% and 1% for T.b. gambiense and between 21% and 3% for T.b. rhodesiense, although elimination was not predicted. Our findings indicate that fitness and mortality penalties associated with paratransgenic symbionts, as well as tsetse migration rates, are instrumental to HAT elimination, and should be a key focus in the development of paratransgenic symbionts.

Project description:This study investigated malaria epidemiology in Edo-North, Nigeria; a region within the equatorial rainforest belt that has lacked prior research on malaria prevalence. This research sought to investigate the prevalence of malaria and identify potential risk factors in Edo-North, Nigeria. Additionally, the study aimed to analyze trends in malaria cases to inform the development of effective malaria control measures. A cross-sectional study was conducted in six local government areas of Edo-North, Nigeria, between June and August 2023. Using systematic sampling, study zones, local governments, towns, villages, and households were selected. Data on sociodemographics and environmental risk factors were collected from 605 participants through questionnaires and blood samples. Blood smears were microscopically examined, binary and multivariate logistic regression was used for data analysis. Malaria disease rate trends were also analyzed from health records. Statistical analyses were performed using R software, with p-values less than 0.05 considered statistically significant. The overall malaria prevalence in the study area was 15.54%, with males more likely to be infected than females. Prevalence varied across localities, with Akoko-Edo having the highest rate. Children had the highest prevalence. Rural residents were more likely to have malaria than urban residents. Binary logistic regression identified several risk factors, including age, location, local government area, education, occupation, marital status, housing type, household size, water source, sanitation, surrounding environment, window net use, ceiling type, water storage, and parasite density. The multivariate logistic regression analysis identified several significant risk factors for malaria in the study population. Children, residents of Owan-East, individuals using pit latrines, and those not sleeping under LLINs were at significantly increased risk. Environmental factors such as proximity to bushes, streams/rivers, and storing water in open containers were also associated with higher malaria prevalence. History of malaria treatment at pharmacies and use of Chloroquine/Quinine medication were linked to recurrent infections. The study found a high average parasite density (5,146 parasites/μL) and low consistent LLIN use despite widespread ownership. Trend analysis from malaria records revealed a decline in malaria prevalence from 2020 to 2023. The study identified several demographic, environmental and behavioural factors associated with malaria risk in Edo North. Males, children, urban dwellers, those living in mud houses and those in large households, proximity to natural features such as bushes, rivers and streams and low LLIN were more likely to contract malaria. These findings highlight the importance of implementing targeted interventions to address these risk factors and reduce the burden of malaria.

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Combining transgenesis with paratransgenesis to fight malaria.

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Combining transgenesis with paratransgenesis to fight malaria.

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