Fighting malaria with engineered symbiotic bacteria from vector mosquitoes

Abstract

The most vulnerable stages of Plasmodium development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. Here, we describe a strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes refractory to malaria infection. The Escherichia coli hemolysin A secretion system was used to promote the secretion of a variety of anti-Plasmodium effector proteins by Pantoea agglomerans, a common mosquito symbiotic bacterium. These engineered P. agglomerans strains inhibited development of the human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98%. Significantly, the proportion of mosquitoes carrying parasites (prevalence) decreased by up to 84% for two of the effector molecules, scorpine, a potent antiplasmodial peptide and (EPIP) 4 , four copies of Plasmodium enolase-plasminogen interaction peptide that prevents plasminogen binding to the ookinete surface. We demonstrate the use of an engineered symbiotic bacterium to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria.Anopheles gambiae | malaria control | paratransgenesis | transmission blocking

Bacterial Biodiversity in Midguts of Anopheles Mosquitoes, Malaria Vectors in Southeast Asia

“…Recent studies reported the presence of symbiotic bacteria, such as Pantoea agglomerans or Asaia in midgut lumen with anti-Plasmodium effector proteins that render host mosquitoes refractory to malaria infection [6,10,13]. Engineered P. agglomerans strains were able to inhibit Plasmodium falciparum development by 98% [13]. Other studies showed that insects with an important microbiota seem more resistant to infections and certain bacteria, such as Enterobacter sp.…”

“…Then, there is a growing interest on bacterial biodiversity in Anopheles mosquitoes and particularly those based on the identification of bacteria to be used for malaria transmission blocking based on bacterial genetic changes to deliver antiparasite molecules or paratransgenic approach [5][6][7][8][9][10][11][12][13]. Recent studies reported the presence of symbiotic bacteria, such as Pantoea agglomerans or Asaia in midgut lumen with anti-Plasmodium effector proteins that render host mosquitoes refractory to malaria infection [6,10,13]. Engineered P. agglomerans strains were able to inhibit Plasmodium falciparum development by 98% [13].…”

Interwoven Biology of the Tsetse Holobiont

“…For example, Wolbachia has been shown to inhibit the replication of multiple arboviruses and filarial nematodes within Aedes mosquitoes (27)(28)(29)(30), as well as to shorten the host life span, not permitting cyclical pathogen development and transmission (31). Additionally, symbionts within the guts of mosquitoes and triatome bugs are being genetically modified to produce antiparasitic molecules, in efforts to block transmission of malaria (32) and Chagas disease (33), respectively. Knowledge of tsetse fly symbiosis not only stands to provide basic insight into how microbial partners adapt and respond to changes in ecological factors and parasite infections but may also be of applied value to generate novel modes of pest biocontrol (26).…”

Developing the Arsenal Against Pest and Vector Dipterans: Inputs of Transgenic and Paratransgenic Biotechnologies

“…gambiae and An. stephensi and successfully suppressed transmission of Plasmodium falciparum and P. berghei, respectively [68].…”