Vector Signals

Briefing Document: Engineered Symbionts for Concurrent Malaria and Arbovirus Transmission Control

Citation: Hu, W., Gao, H., Cui, C. et al. Harnessing engineered symbionts to combat concurrent malaria and arboviruses transmission. Nat Commun 16, 2104 (2025). https://doi.org/10.1038/s41467-025-57343-2
Dates: Received - 27 July 2024 | Accepted - 19 February 2025 | Published - 01 March 2025
Prepared for: Saleh Lab

Executive Summary:
This research presents a novel paratransgenesis strategy utilizing engineered symbiotic bacteria (Serratia AS1) in mosquitoes to simultaneously combat the transmission of malaria parasites (transmitted by Anopheles mosquitoes) and arboviruses like dengue and Zika (transmitted by Aedes mosquitoes). The study demonstrates the successful engineering of Serratia AS1 to express anti-Plasmodium and anti-arbovirus effector proteins under the control of a blood-induced promoter. Both laboratory and semi-natural field-cage experiments show that these engineered bacteria effectively spread through mosquito populations and significantly inhibit pathogen infections in both Anopheles and Aedes mosquitoes, including reducing co-infection rates of dengue and Zika viruses. This work lays the groundwork for a promising tool to address the growing challenge of concurrent mosquito-borne disease outbreaks.
Main Themes and Important Ideas/Facts:
  1. The Growing Threat of Concurrent Mosquito-Borne Diseases:
  • More than half of the global population lives in areas at risk of contracting two or more major mosquito-borne diseases.
  • The geographic distributions of Anopheles (malaria) and Aedes (arboviruses) mosquitoes are increasingly overlapping, leading to co-existence and potential co-infection scenarios.
  • Co-infections of malaria and arboviruses (dengue, Zika, chikungunya) have been reported in various regions.
  • Co-circulation and simultaneous co-infection of multiple arboviruses are also prevalent.
  • These concurrent infections pose complex challenges for disease surveillance, diagnosis, and treatment.
  • "The overlapping distributions highlight the inevitable co-existence and potential co-infection of malaria and arboviruses, or multiple arboviruses, in single host. Such scenarios pose complex and multifaceted public health challenges."
  1. Limitations of Current Mosquito Control Strategies:
  • Reliance on mosquito management is hampered by widespread insecticide resistance.
  • Behavioral changes in Anopheles mosquitoes (e.g., outdoor biting) and antimalarial drug resistance have stalled progress in malaria control.
  • Current global outbreaks highlight the inadequacies of existing control tools.
  • "This situation underscores the urgent need for innovative intervention strategies to tackle the concurrent transmission of malaria and arbovirus diseases."
  1. Paratransgenesis as a Promising Innovative Strategy:
  • Paratransgenesis, utilizing genetically manipulated symbionts to inhibit pathogens, is an attractive approach.
  • While promising for malaria, its effectiveness against arboviruses and its potential to simultaneously target both requires further exploration.
  • "Here, we explore the potential of parastransgenesis strategy to concurrently inhibit the transmission of Plasmodium and arboviruses by Anopheles and Aedes mosquitoes, respectively."
  1. Identification and Engineering of Serratia AS1 as a Multifunctional Symbiont:
  • The symbiotic bacterium Serratia AS1 efficiently spreads through both Anopheles and Aedes mosquito populations (horizontally and vertically).
  • Laboratory cage experiments confirmed efficient spread in An. stephensi and Ae. aegypti.
  • Serratia AS1 proliferates in the mosquito midgut after a blood meal without significant fitness costs to the mosquitoes.
  • Wild-type Serratia AS1 did not significantly affect dengue virus infection in Ae. aegypti, making it a suitable chassis for engineering.
  • "...indicating that Serratia AS1 can efficiently spread throughout these two mosquito populations."
  • "...without causing obvious negative impact on fitness costs in both the mosquito species..."
  1. Development of Engineered Serratia AS1 Strains Expressing Anti-Pathogen Effectors:
  • The study engineered Serratia AS1 to co-express anti-Plasmodium peptides (Shiva1, scorpine) and anti-arbovirus peptides (DN59, Z2) using the efficient HlyA secretion system.
  • The initial construct (AS1-DK) with constitutive expression (using pnptII promoter) showed strong inhibition of P. berghei in Anopheles and DENV2 in Aedes.
  • "We found that AS1-DK strongly inhibited P. berghei ANKA (Pb ANKA) development in An. stephensi mosquitoes...and DENV2 infection in Ae. aegypti mosquitoes."
  1. Importance and Identification of a Blood-Induced Promoter (LipA):
  • Constitutive expression of effectors can impose fitness burdens on bacteria and potentially affect mosquitoes or lead to resistance.
  • Blood-inducible promoters are advantageous as effector expression is activated only upon blood meal ingestion, coinciding with pathogen entry.
  • A comprehensive analysis of Serratia transcriptional and proteomic data identified several blood-induced promoters.
  • The LipA promoter demonstrated the strongest inducible activity and the highest stringency for blood-induced expression.
  • "Notably, the LipA promoter showed the strongest activity, coupled with the highest stringency for blood-induced expression."
  1. Enhanced Pathogen Inhibition with LipA-Controlled Effector Expression (AS1-TK):
  • An engineered strain (AS1-TK) utilizing the LipA promoter to drive the expression of scorpine, Shiva1, DN59 (two copies), and Z2 (two copies) was developed.
  • AS1-TK strongly inhibited P. falciparum and P. berghei infection in Anopheles.
  • AS1-TK effectively inhibited both DENV2 and Zika virus infections in Ae. aegypti.
  • AS1-TK did not impose obvious fitness costs in either mosquito species.
  • "The recombinant strain AS1-TK strongly inhibit development of the human malaria parasite P. falciparum NF54 infection...and rodent malaria parasite P. berghei ANKA...in An. stephensi mosquitoes. Moreover, AS1-TK effectively inhibit both DENV2...and Zika virus infections...in Ae. aegypti mosquitoes..."
  1. Efficacy of AS1-TK in Semi-Natural Field-Cage Conditions:
  • Outdoor field-cage experiments demonstrated that AS1-TK efficiently colonized both An. stephensi and Ae. aegypti mosquitoes under semi-natural conditions.
  • Colonized female mosquitoes showed strong inhibition of P. berghei infection.
  • AS1-TK effectively inhibited all four serotypes of dengue viruses and Zika virus infection in Ae. aegypti in the field-cage setting.
  • "The outdoor field-cage experiments showed that the recombinant AS1-TK strain efficiently colonized both An. stephensi and Ae. aegypti mosquitoes..."
  • "Recombinant AS1-TK strain strongly inhibited P. berghei ANKA infection in An. stephensi mosquitoes."
  • "...the recombinant AS1-TK strain effectively inhibited the infection of all four serotypes of dengue viruses in Ae. aegypti mosquitoes...Moreover, AS1-TK dramatically inhibited Zika virus infection in Ae. aegypti mosquitoes."
  1. Blocking Concurrent Dengue and Zika Virus Transmission:
  • AS1-TK significantly reduced viral RNA levels of DENV2 and ZIKV in Aedes mosquitoes co-infected with both viruses in field-cage experiments.
  • The proportion of mosquitoes carrying both viruses (co-infected) was significantly reduced.
  • "The recombinant Serratia strain AS1-TK markedly inhibited the viral RNA levels of DENV2 and ZIKV in Aedes mosquitoes...Moreover, the proportion of mosquitoes carrying both viruses (co-infected) was significantly reduced..."
  1. Discussion and Future Directions:
  • The study highlights the potential of engineered multifunctional Serratia AS1 strains for simultaneously targeting malaria and arboviruses.
  • The blood-inducible system minimizes potential adverse effects on non-target organisms.
  • The robust inhibitory efficiency and broad-spectrum pathogen inhibition demonstrate the potential of paratransgenesis.
  • Key challenges remain in overcoming regulatory, ethical, and social issues related to the release of genetically modified organisms.
  • "By combining the adaptable mosquito symbiotic Serratia AS1 with various anti-pathogen effectors, our findings provide a highly efficient strategy to weaponized the mosquito gut symbiotic bacteria to combat the concurrent transmission of malaria and arboviruses."
Conclusion:
This research provides compelling evidence for the potential of engineered symbiotic bacteria, specifically Serratia AS1 expressing anti-pathogen effectors under blood-induced control, as a powerful tool to combat the concurrent transmission of malaria and arbovirus diseases. The successful results in both laboratory and contained field settings warrant further investigation and development of this strategy for future public health interventions.
Potential Implications:
  • Development of a novel, cost-effective, and potentially sustainable approach to control multiple mosquito-borne diseases simultaneously.
  • Mitigation of synergistic outbreaks of malaria and arboviruses.
  • A tool to combat insecticide resistance and drug resistance.
  • Potential for adaptation to target other mosquito-borne diseases.
Next Steps:
  • Further optimization of effector protein expression and delivery.
  • Comprehensive risk assessment and addressing regulatory and ethical considerations for potential field deployment.
  • Exploration of strategies for sustainable establishment and maintenance of engineered symbionts in wild mosquito populations.
  • Evaluation of the long-term impact on mosquito populations and the broader ecosystem.

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