The complex interplay between mosquito positive and negative regulators of Plasmodium development

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The malaria parasite, Plasmodium, requires sexual development in the mosquito before it can be transmitted to the vertebrate host. Mosquito genes are able to substantially modulate this process, which can result in major decreases in parasite numbers. Even in susceptible mosquitoes, haemolymph proteins implicated in systemic immune reactions, together with local epithelial responses, cause lysis of more than 80% of the ookinetes that cross the mosquito midgut. In a refractory mosquito strain, immune responses lead to melanisation of virtually all parasites. Conversely, certain mosquito genes have an opposite effect: they are used by the parasite to evade defence reactions. Detailed understanding of the interplay between positive and negative regulators of parasite development could lead to the generation of novel approaches for malaria control through the vector.

Introduction

Malaria is a leading infectious disease that is responsible for up to three million deaths annually, mainly among young children in Sub-Saharan Africa. It is caused by the protozoan parasite Plasmodium, which requires Anopheles mosquitoes for transmission as it is in these that the parasite undergoes sexual development. However, of the several hundred Anopheline species only around 70 can transmit human malaria, and of these only half are significant vectors [1]. For example, in the Anopheles funestus species complex only two of the nine recognized species are important vectors. Vectorial capacity can also vary widely between and within different populations or strains of the same mosquito species [2, 3], which suggests the existence of genetic refractory mechanisms that might help to design new strategies for malaria control.

Anopheles gambiae is the main vector of human malaria in Africa. This has become a workable model through the development of an important toolkit that includes: genetic and chromosome maps [4, 5], transgenic technology [6], a method for reverse genetic analysis by double-stranded RNA-mediated RNAi in cell lines and in adult mosquitoes [7, 8], a set of cultured cell lines [9], an extensive collection of cDNAs and expressed sequence tag sequences [10, 11], DNA microarrays [12, 13], and recently — and most importantly — a full genome sequence [14] and the related bioinformatics resources [15, 16]. These tools, in combination with the development of molecular markers and recent advances in image analysis, have been vital for deciphering the cellular and molecular mechanisms that underlie vector–parasite interactions.

Below, we review the current understanding of mosquito genes that affect and, in many cases, that determine Plasmodium development in the vector. A key concept that emerged from recent studies is the existence of a fine balance between mosquito factors that negatively or positively affect the development of the parasite [17, 18••]. To date, such factors have been shown to act during penetration of the mosquito midgut by Plasmodium (Figure 1). This step is the strongest bottleneck of the malaria transmission cycle in the vector, and has been studied extensively. Furthermore, other genetically selected strains have revealed that refractory mechanisms operate during or immediately after midgut invasion [2, 19]. For these reasons, the subsequent sections of the review are organised relative to the invasion process.

Section snippets

Vector–parasite interactions before midgut invasion

The first step towards malaria transmission is the ingestion of Plasmodium gametocytes by female mosquitoes during a bloodmeal. In the midgut lumen, gametocytes rapidly differentiate into male and female gametes, which then fuse to produce zygotes (Figure 1). In some mosquito species, male gametogenesis (a process known as exflagellation) has never been recorded, which suggests either the absence of activators or the presence of inhibitors. An important factor that is required for induction of

Vector–parasite interactions during midgut invasion

The great majority of parasites are lost during midgut invasion — the most crucial step in the sexual development of a parasite [23]. However, the presence of just a few surviving ookinetes is sufficient to establish successful transmission: soon after invasion they transform into oocysts that undergo serial mitotic divisions, with each one producing several thousand sporozoites. It remains unknown whether or not midgut invasion is receptor-mediated. Recently, annexins (which are strongly

Vector–parasite interactions after midgut invasion

Surviving ookinetes transform into oocysts after they emerge at the basal subepithelial space of the midgut (Figure 1). At least two components of the midgut basal lamina — laminin and collagen — are implicated in this transition [23]. Several ookinete surface and secreted proteins, including P28, P25, CTRP and SOAP, are known to bind to these two molecules [49, 50, 51], however, the role of these interactions remains unknown. To date, the minimal set of components from both the vector and the

Conclusions

Our understanding of the molecular basis of vector–parasite interactions, especially of the model P. berghei–A. gambiae system, has greatly advanced during the past five years. It is now well-established that the mosquito immune system is activated during infection, and that immune genes and reactions account for substantial parasite losses, especially during invasion of the mosquito midgut (even though the immune system often allows immune escape and parasite transmission). Additional classes

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank GK Christophides for fruitful discussions and T Schlegelmilch for helping in manuscript presentation. The work of our laboratory discussed in this review was supported by a National Institute of Allergy and Infectious Diseases–National Institutes of Health Programme Project grant 2PO1AI044220-06A1, a European Commission Research Training Network grant HPRN-CT-2000-00080, a European Commission Network of Excellence grant (BioMalPar) and the European Molecular Biology Laboratory (EMBL).

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    Current address: Department of Biological Sciences, Imperial College London, SW7 2AZ, London, UK

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