Fighting malaria with engineered symbiotic bacteria from vector mosquitoes.
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.
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Sibao
S
Wang
Anil K
AK
Ghosh
Nicholas
N
Bongio
Kevin A
KA
Stebbings
David J
DJ
Lampe
Marcelo
M
Jacobs-Lorena
D000818:Animals; D000852:Anopheles / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology; D000962:Antimalarials / Q000378:metabolism*; D058947:Bacterial Secretion Systems / Q000235:genetics; D029968:Escherichia coli Proteins / Q000096:biosynthesis* / Q000235:genetics; D006460:Hemolysin Proteins / Q000096:biosynthesis* / Q000235:genetics; D007303:Insect Vectors / Q000276:immunology / Q000469:parasitology; D016778:Malaria, Falciparum / Q000378:metabolism / Q000517:prevention & control*; D020636:Pantoea / Q000235:genetics / Q000378:metabolism*; D010962:Plasmodium berghei; D010963:Plasmodium falciparum; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013559:Symbiosis
D000962:Antimalarials; D058947:Bacterial Secretion Systems; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; D011994:Recombinant Proteins