Malaria transmission depends on the competence of some Anopheles mosquitoes to sustain Plasmodium development (susceptibility). A genetically selected refractory strain of Anopheles gambiae blocks Plasmodium development, melanizing, and encapsulating the parasite in a reaction that begins with tyrosine oxidation, and involves three quantitative trait loci. Morphological and microarray mRNA expression analysis suggest that the refractory and susceptible strains have broad physiological differences, which are related to the production and detoxification of reactive oxygen species. Physiological studies corroborate that the refractory strain is in a chronic state of oxidative stress, which is exacerbated by blood feeding, resulting in increased steady-state levels of reactive oxygen species, which favor melanization of parasites as well as Sephadex beads.T he natural transmission cycle of the malaria parasite, Plasmodium, requires completion of a complex developmental cycle in the midgut and salivary glands of the Anopheles mosquito vector (1). However, after its entry with the blood meal, the parasite encounters the innate immune responses of the mosquito, which are often robust and coincide with major parasite losses (2-4). At the extreme, the vector is refractory and completely blocks transmission of the parasite. Genetically selected susceptible and refractory strains (4A r͞r and L3-5; henceforth S and R, respectively) have been described in the African mosquito, Anopheles gambiae. The R strain blocks parasite development in the midgut, oxidatively converting tyrosine to melanin, which crosslinks proteins into a capsule assembled around the parasite (5, 6). Melanotic encapsulation largely depends on three quantitative trait mosquito loci; the Plasmodium encapsulation genes Pen1, Pen2, and Pen3 that have been mapped (7), although not yet identified with particular sequences. The major locus, Pen1, has also been associated with the ability of the R strain to melanize CM-Sephadex beads (8).When the malaria ookinete passes the refractory mosquito midgut, the melanotic capsule first appears, and is significantly thicker, on the ookinete's apical end facing the hemolymph (6). This observation indicates that key components of the melanization reaction derive from the hemolymph. In a histological and ultrastructural survey of the R and S strains, we noted pronounced differences in their pericardial cells. These are scavenging nephrocytes, which are present alongside the dorsal vessel and that harbor numerous peroxisomes, catalase-rich organelles that are active in detoxification and neutralization of reactive oxygen species (ROS). The pericardial cells of S mosquitoes contain numerous peroxisomes, including some very large ones (Fig. 1A), whereas the cells of the R strain possess significantly fewer and smaller peroxisomes (Fig. 1B). These morphological differences suggested that the refractory phenotype may result from a systemic deficiency in ROS detoxification.We have previously used cDNA microarrays to explore the ...
SummaryInvasion of the Anopheles mosquito midgut by the Plasmodium ookinete is a critical step in the malaria transmission cycle. We have generated a fluorescent P. berghei transgenic line that expresses GFP in the ookinete and oocyst stages, and used it to perform the first real-time analysis of midgut invasion in the living mosquito as well as in explanted intact midguts whose basolateral plasma membranes were vitally stained. These studies permitted detailed analysis of parasite motile behaviour in the midgut and cell biological analysis of the invasion process. Throughout its journey, the ookinete displays distinct modes of motility: stationary rotation, translocational spiralling and straight-segment motility. Spiralling is based on rotational motility combined with translocation steps and changes in direction, which are achieved by transient attachments of the ookinete's trailing end. As it moves from the apical to the basal side of the midgut epithelium, the ookinete uses a predominant intracellular route and appears to glide on the membrane in foldings of the basolateral domain. However, it traverses serially the cytoplasm of several midgut cells before entering and migrating through the basolateral intercellular space to access the basal lamina. The invaded cells commit apoptosis, and their expulsion from the epithelium invokes wound repair mechanisms including extensive lamellipodia crawling. A 'hood' of lamellipodial origin, provided by the invaded cell, covers the ookinete during its egress from the epithelium. The flexible ookinete undergoes shape changes and temporary constrictions associated with passage through the plasma membranes. Similar observations were made in both A. gambiae and A. stephensi, demonstrating the conservation of P. berghei interactions with these vectors.
Hemocytes limit the capacity of mosquitoes to transmit human pathogens. Here we profile the transcriptomes of 8506 hemocytes of Anopheles gambiae and Aedes aegypti mosquito vectors. Our data reveal the functional diversity of hemocytes, with different subtypes of granulocytes expressing distinct and evolutionarily conserved subsets of effector genes. A previously unidentified cell type in An. gambiae, which we term “megacyte,” is defined by a specific transmembrane protein marker (TM7318) and high expression of lipopolysaccharide-induced tumor necrosis factor–α transcription factor 3 (LL3). Knockdown experiments indicate that LL3 mediates hemocyte differentiation during immune priming. We identify and validate two main hemocyte lineages and find evidence of proliferating granulocyte populations. This atlas of medically relevant invertebrate immune cells at single-cell resolution identifies cellular events that underpin mosquito immunity to malaria infection.
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