Plasmodium falciparum-Derived Uric Acid Precipitates Induce Maturation of Dendritic Cells

Abstract

Malaria is characterized by cyclical fevers and high levels of inflammation, and while an early inflammatory response contributes to parasite clearance, excessive and persistent inflammation can lead to severe forms of the disease. Here, we show that Plasmodium falciparum-infected erythrocytes contain uric acid precipitates in the cytoplasm of the parasitophorous vacuole, which are released when erythrocytes rupture. Uric acid precipitates are highly inflammatory molecules that are considered a danger signal for innate immunity and are the causative agent in gout. We determined that P. falciparum-derived uric acid precipitates induce maturation of human dendritic cells, increasing the expression of cell surface co-stimulatory molecules such as CD80 and CD86, while decreasing human leukocyte antigen-DR expression. In accordance with this, uric acid accounts for a significant proportion of the total stimulatory activity induced by parasite-infected erythrocytes. Moreover, the identification of uric acid precipitates in P. falciparum- and P. vivax-infected erythrocytes obtained directly from malaria patients underscores the in vivo and clinical relevance of our findings. Altogether, our data implicate uric acid precipitates as a potentially important contributor to the innate immune response to Plasmodium infection and may provide a novel target for adjunct therapies.

Dual Engagement of the NLRP3 and AIM2 Inflammasomes by Plasmodium-Derived Hemozoin and DNA during Malaria

“…A number of studies have demonstrated a role for uric acid in the immune response to malaria (Guermonprez et al, 2013; Lopera-Mesa et al, 2012; Orengo et al, 2008; Orengo et al, 2009; van de Hoef et al, 2013) and released urate has been suggested as the cause of Hz-induced inflammasome activation in vivo (Griffith et al, 2009). To determine if sHz is activating NLRP3 via the release of uric acid, we pretreated macrophages with uricase before adding sHz/CpG.…”

High numerical aperture Fourier ptychography: principle, implementation and characterization

“…We prepare a sample slide containing malaria-infected blood cells by first maintaining erythrocyte asexual stage cultures of the P. falciparum strain 3D7 in culture medium, following the protocol described in [31]. Then, we smear these cultures on glass slide, fix them with methanol and stain them with a Hema 3 stain set (a modified Wright-Giemsa stain).…”

The immunological balance between host and parasite in malaria

“…In vitro, uric acid, together with ROS released during the conversion of (hypo)xanthine, stimulates pyrogenic cytokine secretion, e.g. TNF and IL-6, by murine DCs and human PBMCs, and induces maturation of human DCs by increasing costimulatory expression (Orengo et al 2008(Orengo et al , 2009Van de Hoef et al 2013). Uric acid precipitates also promote DC expansion and CD8 + T cell activation by triggering the release of Flt3L by mast cells (Guermonprez et al 2013).…”

“…It is indicative of a poor prognosis and may manifest itself as diffuse intravascular coagulation (DIC), ring-form hemorrhages in the brain during CM (thereby defining the CM2 subgroup of patients), microhemorrhages in lungs or other forms of bleedings ( Van den Steen et al 2013;Angchaisuksiri 2014). A generalized procoagulant state results in consumption and exhaustion of platelets and coagulation factors, which, combined with endothelial damage, results in an increased sensitivity to hemorrhages.…”

“…Extensive non-cardiogenic pulmonary edema is well established in both mice and patients with MA-ALI and in its more severe form MA-ARDS (reviewed in Van den Steen et al 2013). VEGF may increase vascular permeability by dissociation of vascular endothelial (VE)-cadherin from its cytoskeletal anchoring protein β-catenin (Weis et al 2004) and by redistribution of actin, occludin and zona occludens-1 (ZO-1) (Pedram, Razandi and Levin 2002).…”