Browsing by Author "Lavstsen, Thomas"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria
    (Nature Publishing Group, 2016-06-03) Shabani, Estela; Opoka, Robert O.; Bangirana, Paul; Park, Gregory S.; Vercellotti, Gregory M.; Guan, Weihua; Hodges, James S.; Lavstsen, Thomas; John, Chandy C.; Department of Pediatrics, IU School of Medicine
    The endothelial protein C receptor (EPCR) appears to play an important role in Plasmodium falciparum endothelial cell binding in severe malaria (SM). Despite consistent findings of elevated soluble EPCR (sEPCR) in other infectious diseases, field studies to date have provided conflicting data about the role of EPCR in SM. To better define this role, we performed genotyping for the rs867186-G variant, associated with increased sEPCR levels, and measured sEPCR levels in two prospective studies of Ugandan children designed to understand immunologic and genetic factors associated with neurocognitive deficits in SM including 551 SM children, 71 uncomplicated malaria (UM) and 172 healthy community children (CC). The rs867186-GG genotype was more frequent in CC (4.1%) than SM (0.6%, P = 0.002). The rs867186-G variant was associated with increased sEPCR levels and sEPCR was lower in children with SM than CC (P < 0.001). Among SM children, those who had a second SM episode showed a trend toward lower plasma sEPCR both at initial admission and at 6-month follow-up compared to those without repeated SM (P = 0.06 for both). The study findings support a role for sEPCR in severe malaria pathogenesis and emphasize a distinct role of sEPCR in malaria as compared to other infectious diseases.
  • Thumbnail Image
    Item
    Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season
    (Nature, 2020-12) Andrade, Carolina M.; Fleckenstein, Hannah; Thomson-Luque, Richard; Doumbo, Safiatou; Lima, Nathalia F.; Anderson, Carrie; Hibbert, Julia; Hopp, Christine S.; Tran, Tuan M.; Li, Shanping; Niangaly, Moussa; Cisse, Hamidou; Doumtabe, Didier; Skinner, Jeff; Sturdevant, Dan; Ricklefs, Stacy; Virtaneva, Kimmo; Asghar, Muhammad; Vafa Homann, Manijeh; Turner, Louise; Martins, Joana; Allman, Erik L.; N'Dri, Marie-Esther; Winkler, Volker; Llinás, Manuel; Lavazec, Catherine; Martens, Craig; Farnert, Anna; Kayentao, Kassoum; Ongoiba, Aissata; Lavstsen, Thomas; Osório, Nuno S.; Otto, Thomas D.; Recker, Mario; Traore, Boubacar; Crompton, Peter D.; Portugal, Silvia; Medicine, School of Medicine
    The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence.
  • Thumbnail Image
    Item
    Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection
    (American Society for Clinical Investigation, 2020-05-19) Obeng-Adjei, Nyamekye; Larremore, Daniel B.; Turner, Louise; Ongoiba, Aissata; Li, Shanping; Doumbo, Safiatou; Yazew, Takele B.; Kayentao, Kassoum; Miller, Louis H.; Traore, Boubacar; Pierce, Susan K.; Buckee, Caroline O.; Lavstsen, Thomas; Crompton, Peter D.; Tran, Tuan M.; Medicine, School of Medicine
    BACKGROUND Malaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum–infected erythrocytes to the microvasculature mediated via specific interactions between P. falciparum erythrocyte membrane protein (PfEMP1) variant domains and host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria. METHODS We evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variants to determine the rate and order of variant-specific antibody acquisition and their association with protection against febrile malaria in a prospective cohort study conducted in an area of intense, seasonal malaria transmission. RESULTS Using longitudinal data, we found that IgG antibodies against the pathogenic domain variants CIDRα1.7 and CIDRα1.8 were acquired the earliest. Furthermore, IgG antibodies against CIDRγ3 were associated with reduced prospective risk of febrile malaria and recurrent malaria episodes. CONCLUSION This study provides evidence that acquisition of IgG antibodies against PfEMP1 variants is ordered and demonstrates that antibodies against CIDRα1 domains are acquired the earliest in children residing in an area of intense, seasonal malaria transmission. Future studies will need to validate these findings in other transmission settings and determine the functional activity of these naturally acquired CIDR variant–specific antibodies. TRIAL REGISTRATION ClinicalTrials.gov NCT01322581.