In areas endemic for malaria, pregnant women frequently present with a placenta that has been parasitized by Plasmodium falciparum, an infection associated with a reduction in the birth weight of the offspring. However, the impact of placental infection on malaria-related morbidity during the infant's first years of life has not been investigated. Between 1993 and 1995, 197 children in southern Cameroon were followed weekly clinically and monthly parasitologically. The dates of first positive blood smear and the evolution of the parasite prevalence rates were compared between infants born to mothers presenting with (n = 42) and without (n = 155) P. falciparum infection of the placenta. Infants born to placenta-infected mothers were more likely to develop a malaria infection between 4 and 6 months of age; then the difference progressively disappeared. Similarly, parasite prevalence rates were higher in placenta-infected infants from 5 to 8 months of age. Thus, malarial infection of the placenta seems to result in a higher susceptibility of infants to the parasite. This was not related to maternally transmitted antibodies, as specific antibody levels were similar in both groups of infants. A better understanding of the involved mechanisms may have important implications for the development of malaria control strategies.

Deciphering molecular interactions between the malaria parasite and its mosquito vector is an emerging area of research that will be greatly facilitated by the recent sequencing of the genomes of Anopheles gambiae mosquito and of various Plasmodium species. So far, most such studies have focused on Plasmodium berghei, a parasite species that infects rodents and is more amenable to studies. Here, we analysed the expression pattern of nine An.gambiae genes involved in immune surveillance during development of the human malaria parasite P.falciparum in mosquitoes fed on parasite-containing blood from patients in Cameroon. We found that P.falciparum ingestion triggers a midgut-associated, as well as a systemic, response in the mosquito, with three genes, NOS, defensin and GNBP, being regulated by ingestion of gametocytes, the infectious stage of the parasite. Surprisingly, we found a different pattern of expression of these genes in the An.gambiae-P.berghei model. Therefore, differences in mosquito reaction against various Plasmodium species may exist, which stresses the need to validate the main conclusions suggested by the P.berghei-An.gambiae model in the P.falciparum-An.gambiae system.

Anopheles gambiae is the major African vector of Plasmodium falciparum, the most deadly species of human malaria parasite and the most prevalent in Africa. Several strategies are being developed to limit the global impact of malaria via reducing transmission rates, among which are transmission-blocking vaccines (TBVs), which induce in the vertebrate host the production of antibodies that inhibit parasite development in the mosquito midgut. So far, the most promising components of a TBV are parasite-derived antigens, although targeting critical mosquito components might also successfully block development of the parasite in its vector. We previously identified A. gambiae genes whose expression was modified in P. falciparum-infected mosquitoes, including one midgut carboxypeptidase gene, cpbAg1. Here we show that P. falciparum up-regulates the expression of cpbAg1 and of a second midgut carboxypeptidase gene, cpbAg2, and that this up-regulation correlates with an increased carboxypeptidase B (CPB) activity at a time when parasites establish infection in the mosquito midgut. The addition of antibodies directed against CPBAg1 to a P. falciparum-containing blood meal inhibited CPB activity and blocked parasite development in the mosquito midgut. Furthermore, the development of the rodent parasite Plasmodium berghei was significantly reduced in mosquitoes fed on infected mice that had been immunized with recombinant CPBAg1. Lastly, mosquitoes fed on anti-CPBAg1 antibodies exhibited reduced reproductive capacity, a secondary effect of a CPB-based TBV that could likely contribute to reducing Plasmodium transmission. These results indicate that A. gambiae CPBs could constitute targets for a TBV that is based upon mosquito molecules.Malaria remains a leading cause of morbidity and mortality in human populations, with over 3 billion people living in areas at risk for malaria transmission and an estimated 350 to 500 million clinical episodes occurring annually (29). Plasmodium falciparum malaria causes more than a million deaths each year, mainly in young children in sub-Saharan Africa. Moreover, the malaria burden has increased over the last 10 to 15 years, and this situation has been associated in part with parasite resistance to commonly used antimalarial drugs and resistance of mosquito vectors to insecticides (29). Several strategies are being developed which target either the disease or its transmission. Owing to the complexity of the parasite life cycle, with both human stages that result in disease and mosquito stages that ensure transmission, an effective vaccine might combine pre-erythrocytic (sporozoite and liver stage), asexual erythrocytic, and transmission-blocking components. Although modeling of vaccine effects on malaria transmission dynamics indicates that a transmission-blocking vaccine (TBV) will be most effective in regions where the initial basic reproductive rate of malaria (R 0 ) is low (3,4,8,9), a TBV offers the advantage of blocking the spread of escape mutants that are resistant to asexual-stage ...