The origin of Plasmodium falciparum in South America is controversial. Some studies suggest a recent introduction during the European colonizations and the transatlantic slave trade. Other evidence—archeological and genetic—suggests a much older origin. We collected and analyzed P. falciparum isolates from different regions of the world, encompassing the distribution range of the parasite, including populations from sub-Saharan Africa, the Middle East, Southeast Asia, and South America. Analyses of microsatellite and SNP polymorphisms show that the populations of P. falciparum in South America are subdivided in two main genetic clusters (northern and southern). Phylogenetic analyses, as well as Approximate Bayesian Computation methods suggest independent introductions of the two clusters from African sources. Our estimates of divergence time between the South American populations and their likely sources favor a likely introduction from Africa during the transatlantic slave trade.

CD36 is the major receptor mediating nonopsonic phagocytosis of Plasmodium falciparum-parasitized erythrocytes by macrophages. Its expression on macrophages is mainly controlled by the nuclear receptor PPARγ. Here, we demonstrate that inflammatory processes negatively regulate CD36 expression on human and murine macrophages, and hence decrease Plasmodium clearance directly favoring the worsening of malaria infection. This CD36 downregulation in inflammatory conditions is associated with a failure in the expression and activation of PPARγ. Interestingly, using siRNA mediating knock down of Nrf2 in macrophages or Nrf2- and PPARγ-deficient macrophages, we establish that in inflammatory conditions, the Nrf2 transcription factor controls CD36 expression independently of PPARγ. In these conditions, Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and CD36-mediated Plasmodium phagocytosis. These results were confirmed in human macrophages and in vivo where only Nrf2 activators improve the outcome of severe malaria. Collectively, this report highlights that the Nrf2 transcription factor could be an alternative target to PPARγ in the control of severe malaria through parasite clearance. Severe and fatal malaria is still increasing both in incidence and in its resistance to antimalarial agents. The improved understanding of immune mechanisms mediating Plasmodium elimination might therefore offer a complementary way to conventional therapeutic interventions. The main host innate immune defense mechanism against Plasmodium falciparum is the engulfment by macrophages through CD36, the macrophage receptor recognizing infected erythrocytes. The up-regulation of CD36 on macrophages therefore represents an alternative way to favor parasite clearance during infection. Severe malaria infection is associated with an excessive production of proinflammatory markers and an inability to control parasite proliferation. We demonstrate here that malaria-induced inflammation down regulates CD36 expression on macrophages and favors the worsening of malaria infection. The conventional way to promote CD36 expression through PPARγ nuclear receptor is inefficient under malaria inflammatory processes. Interestingly, we establish that the Nrf2 transcription factor may substitute PPARγ to promote CD36 expression and its associated functions in inflammatory conditions. As a consequence, only Nrf2 but not PPARγ activators improve the outcome of severe malaria in vivo. This paper which highlights a new area of application for Nrf2 activators in infectious diseases, heralds the emergence of a new therapeutic strategy against severe malaria.

Objectives: To assess the activity of a new organometallic chloroquine analogue, ferroquine, against numerous Plasmodium falciparum isolates from Gabon. Methods: The in vitro susceptibility of 116 P. falciparum isolates to chloroquine and ferroquine was assessed using the isotopic microtest. All isolates were from outpatients in the Franceville and Bakoumba medical centres in the province of Haut-Ogooué, south-east Gabon. Results: The in vitro resistance to chloroquine was 51.8% in Franceville and 96.7% in Bakoumba. The IC₅₀ geometric mean (95% CI) of ferroquine against isolates in Franceville was 16.0 (14.4–17.8) nM, with individual values ranging from 1.0 to 47.0 nM; in Bakoumba it was 27.9 (23.4–33.2) nM, with individual values ranging from 1.0 to 62.0 nM. Compared with chloroquine, ferroquine was 5.3 times more active on isolates susceptible to chloroquine, and 13.3 times more active on isolates resistant to chloroquine. A weak positive correlation was observed between responses of these two drugs, but too low to demonstrate cross-resistance. Conclusions: Ferroquine may be useful as an alternative drug for treating chloroquine-resistant malaria.

Plasmodium falciparum antigenic diversity and polymorphism confuses the issue of antimalarial vaccine development. Merozoite surface protein (MSP)-1 and -2 are two highly polymorphic vaccine candidates. Characterisation of their precise polymorphism in endemic regions may facilitate the design of an effective vaccine. Isolates obtained in 52 Gabonese children presenting with uncomplicated malaria were genotyped by nested-PCR of msp-1 block 2, and msp-2 block 3, to analyze both parasite population polymorphism and clone fluctuations. Twenty-five and 19 different alleles were respectively obtained for msp-1 and msp-2 loci, the RO33 family of msp-1 being poorly polymorphic. Four cases of non-random distribution of alleles were reported of the FC27, and/or 3D7 families of msp-2. All but two isolates were composed of more than one genotype, and the multiplicity of infection (MOI) was 4.0. Neither parasite density nor age was related to MOI. Clone fluctuations were studied for ten subjects who were sampled again at reappearance of parasites in blood. Disappearance and reappearance of alleles were observed following treatment, suggesting difficulties in assessing polymorphism and in distinguishing reinfection from recrudescence. P. falciparum polymorphism is extensive in Southeast Gabon, and most of infections are composed of multiple clones. The fluctuation of clones contributes to parasite diversity.

Background. Usefulness of sulfadoxine-pyrimethamine as first-line therapy for uncomplicated Plasmodium falciparum malaria and intermittent preventive

Colonic macrophages are considered to be major effectors of inflammatory bowel diseases (IBDs) and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis, the loss of dectin-1 on myeloid cells prevents intestinal inflammation, while the lack of mannose receptor (MR) exacerbates it. A marked increase in dectin-1 expression in dextran sulfate sodium (DSS)-exposed MR-deficient mice supports the critical contribution of dectin-1 to colitis outcome. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent interleukin-1β (IL-1β) secretion through leukotriene B4 production. Interestingly, colonic inflammation is associated with a concomitant overexpression of dectin-1/CCL2/LTA4H and downregulation of MR on macrophages from IBD patients. Thus, MR and dectin-1 on macrophages are important mucosal inflammatory regulators that contribute to the intestinal inflammation.