Infection Intensity-Dependent Responses of Anopheles gambiae to the African Malaria Parasite Plasmodium falciparum

Abstract

Malaria remains a devastating disease despite efforts at control and prevention. Extensive studies using mostly rodent infection models reveal that successful Plasmodium parasite transmission by the African mosquito vector Anopheles gambiae depends on finely tuned vector-parasite interactions. Here we investigate the transcriptional response of A. gambiae to geographically related Plasmodium falciparum populations at various infection intensities and different infection stages. These responses are compared with those of mosquitoes infected with the rodent parasite Plasmodium berghei. We demonstrate that mosquito responses are largely dependent on the intensity of infection. A major transcriptional suppression of genes involved in the regulation of midgut homeostasis is detected in low-intensity P. falciparum infections, the most common type of infection in Africa. Importantly, genes transcriptionally induced during these infections tend to be phylogenetically unique to A. gambiae. These data suggest that coadaptation between vectors and parasites may act to minimize the impact of infection on mosquito fitness by selectively suppressing specific functional classes of genes. RNA interference (RNAi)-mediated gene silencing provides initial evidence for important roles of the mosquito G protein-coupled receptors (GPCRs) in controlling infection intensity-dependent antiparasitic responses.Malaria is a devastating parasitic disease that remains an enormous public health burden, especially in sub-Saharan Africa, where the deadliest of the malaria parasites, Plasmodium falciparum, is transmitted mainly by Anopheles gambiae mosquitoes. Extensive laboratory studies of mosquito-parasite interactions have exploited genomics and postgenomics technologies for gene expression profiling and functional characterization to generate new knowledge. It has been established that parasite development in the mosquito midgut is the most vulnerable stage of the entire transmission cycle. This appears to be due largely to robust mosquito responses that effectively reduce the number of parasites able to invade the midgut and establish infections in the hemolymph (8,22,30). Therefore, detailed understanding of the vector-parasite interactions could lead to novel strategies that can supplement current control methods.Recent studies have identified mosquito genes that affect P. falciparum and the rodent malaria parasite, Plasmodium berghei, which is often used as a laboratory model, similarly; however, such conserved responses can only partly explain the vector-parasite interactions in natural settings (6,8,11,20,21). In fact, A. gambiae is not a natural vector of P. berghei, and the intensities of P. berghei infection are much higher than those commonly observed in nature with P. falciparum (2). Differences in P. falciparum infection levels have been associated with several genomic loci and have been shown to depend on vector-parasite genotype-by-genotype interactions (12,16,29).Evidence is now accumulating that input parasite densities affe...

Regulation of Anti-Plasmodium Immunity by a LITAF-like Transcription Factor in the Malaria Vector Anopheles gambiae

“…These results are consistent with previous gene expression analysis for LL3 [19], and are remarkably similar to the patterns of SRPN6 expression identified in previous experiments [9] and in this report. Consistent with these results, immunolocalization experiments imply that LL3 expression occurs in cells of the midgut epithelium in close proximity to invading ookinetes.…”

The Peptidoglycan Recognition Proteins PGRPLA and PGRPLB Regulate Anopheles Immunity to Bacteria and Affect Infection by Plasmodium

“…Indeed, P. falciparum and P. berghei infection of the mosquito midgut occur with different timing and at different temperatures. In that respect, published data suggest that PGRPLA1 and PGRPLA2 expression differs between mosquito strains and Plasmodium infection stages [21][22][23][24] , and we found that PGRPLA2 expression is 14 and 10 times lower than that of PGRPLA1 in the midguts of sugar-and blood-fed mosquitoes of our colony, respectively. Moreover, as mentioned in the results, the observed phenotypic difference may arise from PGRPLA1 dsRNA having a higher silencing efficiency and being less isoform specific than PGRPLA2 dsRNA.…”

The JNK Pathway Is a Key Mediator of Anopheles gambiae Antiplasmodial Immunity

“…Only a modest increase was observed in one of the replicates at 12 hpi but, in another, the expression was lower after infection than in the uninfected control. Although activation of the JNK pathway involves a cascade of post-translational phosphorylation events, transcription of JNK pathway members has been reported to increase upon Plasmodium infection in Anopheles and transcriptional activation of JNK at the mRNA and protein level has also been observed in Drosophila midguts in response to bacterial challenge [26]–[28]. JNK protein expression was also induced in the mosquito midgut in response to Plasmodium infection (Figure S1).…”