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.

Delftia tsuruhatensis TC1 symbiont suppresses malaria transmission by anopheline mosquitoes

“…S1). The capacity of mosquitoes carrying D. tsuruhatensis TC1 to transmit P. berghei from infected to naïve mice ( 13 ) was also assessed (Fig. 1C).…”

Assessing Survival of Transgenic Bacteria, Serratia AS1 and Enterobacter cloacae, in Sugar Bait, White Saxaul Plant (Haloxylon persicum) and Rodent Barrow’s Soil, A Contained-Field Study for Paratransgenesis Approach

“…Our previous laboratory and field studies revealed that two genetically engineered bacteria, Serratia AS1, and Enterobacter cloacae, are suitable candidates for paratransgenic control of leishmaniasis (14,(24)(25)(26)(27). These bacteria were found in sand flies (12,(28)(29)(30)(31) and genetically manipulated to produce effector molecules that interfered with Leishmania development in the sand fly gut and consequently reduced the chance of parasite transmission (13,14,25,32). Also, these two bacteria were used successfully in the paratransgenesis strategy for combating malaria in laboratory conditions (15,26,33,34).…”