By Justine Rouge

Malaria is one of the deadliest human parasitic diseases with negative impacts that continue to spread. In 2016, malaria affected around 216 million individuals and was responsible for the death of 445,000 people [1]. Malaria is caused by Plasmodium parasites that invade red blood cells whose Plasmodium falciparum (Welch, 1897) is the most widespread species infecting humans throughout the world. This parasite is transmitted by the bite of an infected female mosquito (Anopheles genus) during a blood meal [2] which will allow the feeding of their eggs.

The mechanism of parasitic invasion in the mosquito is complex. Within Anopheles gambiae mosquito midgut, the main human malaria vector, the parasite undergoes an infectious cycle comprising different steps allowing or not to attain the mosquito salivary glands. This infectious cycle is dependant on the several mosquito proteins whose fibrinogen proteins (FBN/FREP) (1). Among these immunity proteins, some are implied in the mosquito immunity defense and are antagonist to the parasitic development (FBN9 and FBN30) [3], [4] while others such as the protein FREP1 favors the Plasmodium parasite survival in the midgut of Anopheles gambiae, allowing an optimal development in order to attain the mosquito salivary glands [5] and to be injected to the host at the sporozoite (2) stage.

To prevent malaria, there are several vector control methods. Currently, the use of genetic tools and the use of “gene-drive” method are on the rise to try to control vector-borne disease and vectors. It’s the case of the CRISPR/Cas9 (3) technology, a collection of molecule editing DNA which are implied in the bacterial mechanism for defence against viruses.

Recently, scientists tried to adapt this gene-editing technology to genetically modify mosquitoes responsible causing infectious disease [6]–[10]. That is what the team of George Dimopoulos from the Johns Hopkins Malaria Research Institute, have used to study the effect of inactivating the fibrinogen-related protein (FREP1) gene on the Anopheles gambiae mosquito’s susceptibility to Plasmodium and on mosquito fitness (4). Results were recently published in the review Plos Pathogen [11].

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They generated mutant mosquitoes (knock-out mosquitoes (KO)) for the FREP1 gene and showed that the deletion of the FREP1 gene significantly reduced the mosquitoes sensitivity to the Plasmodium infection whatever the infection rate, brightening the light of resistance to the infection for these KO mosquitoes. Moreover, after deletion of FREP1, the number of parasites at sporozoite stage significantly reduced in salivary glands of KO-mosquitoes, suggesting a reduction of the possibilities of malaria transmission by these mutant mosquitoes if these could later replace wild mosquitoes in nature.

However, researchers observed an important fitness-cost adaptation for the FREP1 KO-mosquitoes. Indeed, they showed a reduction of their feeding ability, a slower larval development, and decreased fecundity with an egg hatch rate significantly lower than wild mosquitoes. Moreover, taking a blood meal failed to improve their longevity contrary to their wild counterparts. These results raise questions regarding the sustainability of these mutants mosquitoes and their ability to compete with wild mosquitoes population if they were to be used in large-scale field trials to fight malaria. Further studies are necessary.

However, this study shows that the use of CRISPR/Cas9 gene editing technique is improving knowledge about the biological features of mosquitoes and their ability to influence the transmission of malaria.

Thanks for reading. Don’t forget: Fight Malaria!

Notes:

(1) FBN: fibrinogen domain immunolectin / FREP: fibrinogen-related protein family.

(2) Sporozoïte: 1st infectious parasitic stage penetrating the bloodstream after the bite by an infected female mosquito.

(3) CRISPRS/Cas9: Clustered Regular Interspaced Short Palindromic Repeats associated with the protein Cas9

(4) Fitness: Relative ability of an individual or population to survive, reproduce and propagate genes in an environment.

Bibliography:

[1] World Health Organisation (WHO), World Malaria Report 2017. 2017.

[2] A. Trampuz, M. Jereb, I. Muzlovic, and R. M. Prabhu, “Clinical review: Severe malaria.,” Crit. Care, vol. 7, no. 4, pp. 315–23, Aug. 2003.

[3] Y. Dong, R. Aguilar, Z. Xi, E. Warr, E. Mongin, and G. Dimopoulos, “Anopheles gambiae immune responses to human and rodent Plasmodium parasite species,” PLoS Pathog., vol. 2, no. 6, pp. 0513–0525, 2006.

[4] Y. Dong and G. Dimopoulos, “Anopheles fibrinogen-related proteins provide expanded pattern recognition capacity against bacteria and malaria parasites,” J. Biol. Chem., vol. 284, no. 15, pp. 9835–9844, 2009.

[5] G. Zhang, G. Niu, C. M. Franca, Y. Dong, X. Wang, N. S. Butler, G. Dimopoulos, and J. Li, “Anopheles midgut FREP1 mediates plasmodium invasion,” J. Biol. Chem., vol. 290, no. 27, pp. 16490–16501, 2015.

[6] S. Dong, J. Lin, N. L. Held, R. J. Clem, A. L. Passarelli, and A. W. E. Franz, “Heritable CRISPR/Cas9-mediated genome editing in the yellow fever mosquito, Aedes aegypti,” PLoS One, vol. 10, no. 3, pp. 1–13, 2015.

[7] A. B. Hall, S. Basu, X. Jiang, Y. Qi, A. Vladimir, J. K. Biedler, M. V Sharakhova, R. Elahi, A. Michelle, E. Anderson, X. Chen, I. V Sharakhov, and Z. N. Adelman, “HHS Public Access,” vol. 348, no. 6240, pp. 1268–1270, 2016.

[8] L. Grigoraki, A. Puggioli, K. Mavridis, V. Douris, M. Montanari, R. Bellini, and J. Vontas, “Striking diflubenzuron resistance in Culex pipiens, the prime vector of West Nile Virus,” Sci. Rep., vol. 7, no. 1, pp. 1–8, 2017.

[9] S. Basu, A. Aryan, J. M. Overcash, G. H. Samuel, M. A. E. Anderson, T. J. Dahlem, K. M. Myles, and Z. N. Adelman, “Silencing of end-joining repair for efficient site-specific gene insertion after TALEN/CRISPR mutagenesis in Aedes aegypti,” Proc. Natl. Acad. Sci., vol. 112, no. 13, pp. 4038–4043, 2015.

[10] K. E. Kistler, L. B. Vosshall, and B. J. Matthews, “HHS Public Access,” vol. 11, no. 1, pp. 51–60, 2016.

[11] Y. Dong, M. L. Simões, E. Marois, G. Dimopoulos, and W. H. Feinstone, “CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection,” vol. 1, pp. 1–16, 2018.

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