May 1, 2014

A gene that protects malarial parasites from mosquito defences

Despite a relatively low mortality rate, there are hundreds of millions of malaria cases worldwide per year, making the parasitic disease responsible for a massive annual death toll [1,2]. The definitive hosts of the apicomplexan parasites that cause malaria (Plasmodium spp) are anopheline mosquitoes, and various attempts have been made in endemic areas to control mosquito populations as a means of limiting or interrupting transmission [3]. Malaria’s pantropical distribution – therefore, prevalence mostly in developing countries – means that even controlling vector transmission is met by a suite of social, economical, and political obstacles. The same combination of issues added to the parasite’s complex life cycle, have hinder widespread treatment or the development of effective vaccines.

One of the many aspects of malaria control currently being researched is mosquito immunity to the parasite. Within the last decade, work on disease transmission in Africa has revealed Anopheles gambiae’s ability to combat Plasmodium [4–6]. Nevertheless, African P. falciparum, appears to evade the mosquito’s immune system, thus avoiding activating the nitration reactions that promote lysis and melanisation of the parasite, which then become enveloped in a coat of melanin [7].

Pfs47 enables the parasite to survive within its anopheline host, unbeknownst to the insect’s immune system. Pinpointing this gene involved a combination of multiple genetic approaches. Firstly, Molina-Cruz et al. [8] crossed an immunity-evading P. falciparum strain from Ghana (GB4) and immunity-susceptible strain from Brazil (7G8). Amongst the cloned descendent lines, there was a distinct separation between those parasites which were melanised and expulsed by mosquito’s immune system (7G8 phenotype) and those which escaped detection (GB4 phenotype). Logarithm of odds (LOD) analysis of quantitative trait loci (QTL) mapping of the melanised parasites identified one significant linkage peak, in chromosome 13 (Chr13). By infecting refractory and susceptible strains of A. gambiae with the 7G8, GB4, and recombinant parasite progeny obtained from the genetic cross, Molina-Cruz et al. [8] found that the same region identified of Chr13, by QTL analysis, exerts negative selective pressure against the 7G8 genotype in the refractory mosquito strain, yet exerts none in the susceptible strain.

Molina-Cruz et al. [8] analysed gene expression within the identified region of Chr13 in surviving strains, to identify potential candidates responsible for parasite survival. They then produced knockout lines of the most likely genes. Pfs47 knockout parasites were capable of infecting A. gambiae but were successfully melanised in the host. However, this outcome could be reversed by inhibiting the expression of the mosquito protein thought to be involved in Plasmodium modification: this indicates that Pfs47 affects the mosquito’s immune system. Reintroducing Pfs47 alleles from immune-evading strains could also reverse melanisation in resistant mosquitoes, whereas alleles from strains such as the Brazilian 7G8 could not.

Enabling the anopheline complement-like immune system to interrupt the Plasmodium life cycle could play a crucial role in reducing malaria transmission to humans. Thus, Molina-Cruz et al. [8] findings suggest Pfs47 activity could be a promising target for malaria disease control.

Cited literature
[1] Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I. (2005). The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature, 434(7030), 214-217.
[2] Murray, C. J. L., Rosenfeld, L. C., Lim, S. S., Andrews, K. G., Foreman, K. J., Haring, D., Fullman, N., Naghavi, M., Lozano, R. & Lopez, A. D. (2012). Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet, 379(9814), 413-431.
[3] Alonso PL, Brown G, Arevalo-Herrera M, Binka F, Chitnis C, et al. (2011) A Research Agenda to Underpin Malaria Eradication. PLoS Med 8(1): e1000406.
[4] Kumar, S., Gupta, L., Han, Y. S. & Barillas-Mury, C. (2004) Inducible Peroxidases mediate nitration of Anopheles midgut cells undergoing apoptosis in response to Plasmodium invasion. Journal of Biological Chemistry, 279(51), 53475-53482.
[5] Oliveira Gde A, Lieberman J, Barillas-Mury C (2012) Epithelial nitration by a peroxidase/NOX5 system mediates mosquito antiplasmodial immunity. Science 335:856-9.
[6] Mitri C, Jacques J-C, Thiery I, Riehle MM, Xu J, et al. (2009) Fine Pathogen Discrimination within the APL1 Gene Family Protects Anopheles gambiae against Human and Rodent Malaria Species. PLoS Pathog 5(9): e1000576. doi:10.1371/journal.ppat.1000576
[7] Molina-Cruz, A., DeJong, R. J., Ortega, C., Haile, A., Abban, E., Rodrigues, J., Jaramillo-Gutierrez, G. & Barillas-Mury, C. (2012) Some strains of Plasmodium falciparum, a human malaria parasite, evade the complement-like system of Anopheles gambiae mosquitoes. Proceedings of the National Academy of Sciences, 109(28), E1957-E1962.

[8] Molina-Cruz, A., Garver, L. S., Alabaster, A., Bangiolo, L., Haile, A., Winikor, J., Ortega, C., van Schaijk, B. L., Sauerwein, R. W., Taylor-Salmon, E. & Barillas-Mury, C. (2013). The Human Malaria Parasite Pfs47 Gene Mediates Evasion of the Mosquito Immune System. Science, 340(6135), 984-987.

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