Changes in the microbiota cause genetically modified
            <i>Anopheles</i>
            to spread in a population

Pike, Andrew; Dong, Yuemei; Dizaji, Nahid Borhani; Gacita, Anthony; Mongodin, Emmanuel F.; Dimopoulos, George

doi:10.1126/science.aak9691

Cited by 57 publications

(67 citation statements)

References 22 publications

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“…Our work raises the possibility that genetically engineered mosquitoes could be used to block filarial worm transmission. Overexpression of Rel2, the IMD pathway-specific NF-κB transcription factor, in Anopheles stephensi using a blood meal-responsive and tissue-restricted promoter blocks development of malaria parasites without imposing significant fitness costs (50,51). To adopt this approach to block transmission of filariae, an appropriate promoter will need to be identified.…”

Section: Discussionmentioning

confidence: 99%

Activation of mosquito immunity blocks the development of transmission-stage filarial nematodes

Edgerton

Mccrea

Berry

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Mosquito-borne helminth infections are responsible for a significant worldwide disease burden in both humans and animals. Accordingly, development of novel strategies to reduce disease transmission by targeting these pathogens in the vector are of paramount importance. We found that a strain of Aedes aegypti that is refractory to infection by Dirofilaria immitis, the agent of canine heartworm disease, mounts a stronger immune response during infection than does a susceptible strain. Moreover, activation of the Toll immune signaling pathway in the susceptible strain arrests larval development of the parasite, thereby decreasing the number of transmission-stage larvae. Notably, this strategy also blocks transmission-stage Brugia malayi, an agent of human lymphatic filariasis. Our data show that mosquito immunity can play a pivotal role in restricting filarial nematode development and suggest that genetically engineering mosquitoes with enhanced immunity will help reduce pathogen transmission.

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Section: Discussionmentioning

confidence: 99%

Activation of mosquito immunity blocks the development of transmission-stage filarial nematodes

Edgerton

Mccrea

Berry

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…After mosGILT-gRNA female mosquitoes were crossed with Cas9 male mosquitoes, the offspring larvae were maintained according to a standard procedure with 400 larvae per tray (Pike et al, 2017). For pupation time measurement, pupae were collected and screened under the fluorescent microscope to record the number of mosGILT mutant pupae (GFP + /RFP + ) and their siblings (GFP + /RFP − ) on a daily basis.…”

Section: Fitness Measurements Of Adult Mosquitoesmentioning

confidence: 99%

Disruption of mosGILT in Anopheles gambiae impairs ovarian development and Plasmodium infection

Yang

Schleicher

Dong

et al. 2019

Journal of Experimental Medicine

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Plasmodium infection in Anopheles is influenced by mosquito-derived factors. We previously showed that a protein in saliva from infected Anopheles, mosquito gamma-interferon–inducible lysosomal thiol reductase (mosGILT), inhibits the ability of sporozoites to traverse cells and readily establish infection of the vertebrate host. To determine whether mosGILT influences Plasmodium within the mosquito, we generated Anopheles gambiae mosquitoes carrying mosaic mutations in the mosGILT gene using CRISPR/CRISPR associated protein 9 (Cas9). Here, we show that female mosaic mosGILT mutant mosquitoes display defects in ovarian development and refractoriness to Plasmodium. Following infection by either Plasmodium berghei or Plasmodium falciparum, mutant mosquitoes have significantly reduced oocyst numbers as a result of increased thioester-containing protein 1 (TEP1)–dependent parasite killing. Expression of vitellogenin (Vg), the major yolk protein that can reduce the parasite-killing efficiency of TEP1, is severely impaired in mutant mosquitoes. MosGILT is a mosquito factor that is essential for ovarian development and indirectly protects both human and rodent Plasmodium species from mosquito immunity.

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“…The mosquito midgut microbiota needs to be continuously controlled by the mosquito's innate immune system to avoid over proliferation that could result in a lethal infection [7]. Since both miR-14 and miR-305 could target multiple immunity genes, we assessed the effect of sponges-mediated miR-14 and miR-305 depletion on the midgut microbiota load.…”

Section: Sponges-mediated Depletion Of Aga-mir-14 and Aga-mir305 Enhamentioning

confidence: 99%

“…This bottleneck is to a significant degree imposed by the mosquito's innate immune system, which is largely guided by the immune deficiency (Imd), Toll, Janus kinase/signal transducers and activators of transcription (JAK/STAT), and c-Jun N-terminal kinase (JNK) pathways [4,5]. Overexpression of the Imd pathway transcription factor (Rel2) in midguts of transgenic Anopheles stephensi mosquitoes significantly reduces parasite oocyst numbers in the midgut [6], demonstrating that transgenic enhancement of mosquito immunity may provide an effective approach for controlling the spread of malaria [7].…”

Section: Introductionmentioning

confidence: 99%

Broad spectrum immunomodulatory effects of Anopheles gambiae microRNAs and their use for transgenic suppression of Plasmodium

Dong

et al. 2020

PLoS Pathog

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Malaria, caused by the protozoan parasite Plasmodium and transmitted by Anopheles mosquitoes, represents a major threat to human health. Plasmodium's infection cycle in the Anopheles vector is critical for transmission of the parasite between humans. The midgutstage bottleneck of infection is largely imposed by the mosquito's innate immune system. microRNAs (miRNAs, small noncoding RNAs that bind to target RNAs to regulate gene expression) are also involved in regulating immunity and the anti-Plasmodium defense in mosquitoes. Here, we characterized the mosquito's miRNA responses to Plasmodium infection using an improved crosslinking and immunoprecipitation (CLIP) method, termed covalent ligation of endogenous Argonaute-bound RNAs (CLEAR)-CLIP. Three candidate miRNAs' influence on P. falciparum infection and midgut microbiota was studied through transgenically expressed miRNA sponges (miR-SPs) in midgut and fat body tissues. MiR-SPs mediated conditional depletion of aga-miR-14 or aga-miR-305, but not aga-miR-8, increased mosquito resistance to both P. falciparum and P. berghei infection, and enhanced the mosquitoes' antibacterial defenses. Transcriptome analysis revealed that depletion of aga-miR-14 or aga-miR-305 resulted in an increased expression of multiple immunityrelated and anti-Plasmodium genes in mosquito midguts. The overall fitness cost of conditionally expressed miR-SPs was low, with only one of eight fitness parameters being adversely affected. Taken together, our results demonstrate that targeting mosquito miRNA by conditional expression of miR-SPs may have potential for the development of malaria control through genetically engineered mosquitoes.

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Changes in the microbiota cause genetically modified Anopheles to spread in a population

Cited by 57 publications

References 22 publications

Activation of mosquito immunity blocks the development of transmission-stage filarial nematodes

Activation of mosquito immunity blocks the development of transmission-stage filarial nematodes

Disruption of mosGILT in Anopheles gambiae impairs ovarian development and Plasmodium infection

Broad spectrum immunomodulatory effects of Anopheles gambiae microRNAs and their use for transgenic suppression of Plasmodium

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