Biology subjects

Gamain, B.

Publications and source records attributed to Gamain, B..

4 recordsLinked to original sources

bioRxiv2026

FIKK1, a member of the FIKK kinase family, phosphorylates VAR2CSA and regulates adhesion of Plasmodium falciparum-infected erythrocytes to the placental receptor CSA

Plasmodium falciparum promotes the adhesion of infected erythrocytes (IEs) to host cells by extensively remodeling their surface. For this process, the parasite exports a large number of proteins to its host erythrocyte, including members of the P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1) adhesin family and members of the FIKK family. Several FIKK have been shown to play a role in P. falciparum virulence, notably affecting IES cell surface remodeling, rigidity and cytoadhesion. VAR2CSA, a member of the PfEMP1 adhesin family, is associated with IES sequestration in the placenta and has been shown to be phosphorylated. In view of the previously described importance of VAR2CSA phosphorylation, we investigated the role of FIKK1. We show that FIKK1 is capable of phosphorylating VAR2CSA in vitro, and that this phosphorylation increases the binding of recombinant VAR2CSA to the placental receptor chondroitin sulphate A (CSA). In an inducible transgenic cell line expressing HA-tagged FIKK1, immunofluorescence assays indicate that the kinase localizes to punctuated foci within Maurers Cleft, similarly to VAR2CSA. Rapamycin-induced knock out of FIKK1 reduces IEs cytoadhesion to CSA, even though levels of VAR2CSA are not affected. In vitro phosphorylation assays show that FIKK1 can phosphorylate recombinant DBL1-3 domains on several residues, including S429 and T934, previously implicated in in vitro binding and IES cytoadhesion to CSA. Taken together, these data support a model whereby FIKK1 contributes to placental malaria virulence through IEs sequestration mediated by VAR2CSA phosphorylation. Having no orthologs in mammals, this orphan kinase therefore represents an attractive target for the development of drugs against placental malaria. Author summarySequestration of Plasmodium falciparum infected erythrocytes (IEs) in the placenta is a hallmark of placental malaria and a major driver of adverse maternofetal outcomes. This process is mediated by VAR2CSA, a member of the P. falciparum Erythrocyte Membrane Protein (PfEMP1) family. VAR2CSA binds to chondroitin sulfate A (CSA) on the placental syncytium, facilitating IEs sequestration. In a previous study, we demonstrated that endogenous VAR2CSA is phosphorylated and identified specific phosphosites important for its cytoadhesive function. To elucidate the molecular mechanisms underlying these post-translational modifications, we examined the role of the P. falciparum FIKK1 kinase in VAR2CSA phosphorylation and its impact on IEs adhesion. Using a FIKK1::HA conditional knockout transgenic line, we found that FIKK1 deletion impairs IEs cytoadhesion, likely due to altered VAR2CSA phosphorylation. Importantly, both endogenous and recombinant FIKK1 interact with and phosphorylate the extracellular region of VAR2CSA. Furthermore, recombinant FIKK1 also enhances VAR2CSA binding to CSA in vitro and phosphorylates a residue previously identified as important for CSA binding and IEs adhesion. Collectively, these findings highlight a pivotal role for FIKK1 in placental adhesion and underscore the potential of targeting this kinase family for interventions against placental malaria.

biochemistry↗

bioRxiv2025

Taurine is a Natural Host Cytoadhesion Inhibitor in Asymptomatic Malaria Cases

The prolonged dry season in malaria-endemic regions of sub-Saharan Africa can be divided into periods of high and low transmission. The majority of symptomatic malaria cases are restricted to the short high transmission period that follows the rainy season. Shortly after, persistent asymptomatic malaria cases are more prevalent throughout the prolonged low transmission period. It is still unclear whether host metabolic alterations play a role in asymptomatic infections during seasonal malaria. In this study, we analyzed the blood plasma metabolome (n=199) of individuals in The Gambia, West Africa, capturing data from both high and low malaria transmission periods. Plasma samples from individuals (n=16) were collected monthly throughout the low transmission season, enabling a longitudinal analysis of metabolic alternations over six months. Our findings reveal that significant changes in host plasma metabolite composition are associated with seasonality and malaria pathogenicity. Notably, we observed elevated levels of taurine in asymptomatic malaria infections, especially during periods of low transmission. In vitro, this naturally occurring host molecule inhibits the cytoadhesion of malaria-infected red blood cells (iRBCs), which is key to malaria disease severity and mortality. Exogenous taurine can significantly reduce or reverse binding of iRBCs to the common adhesion receptor CD36 and the endothelial protein C receptor (EPCR), the later being associated with cerebral malaria. This study uncovers a mechanism by which elevated taurine plasma levels in asymptomatic infections could reduce cytoadhesion and lead to increased splenic clearance, thereby strengthening host resistance to symptomatic infections. In the absence of health strategies targeting dry season parasite reservoirs, our findings highlight taurine as a potential prophylactic or therapeutic agent to reduce symptomatic malaria in sub-Saharan Africa. One Sentence SummaryMetabolomics uncovers taurine as a natural host inhibitor of Plasmodium falciparum cytoadhesion in asymptomatic malaria carriers, offering new insights for disease control.

microbiology↗

bioRxiv2022

Aotus nancymaae model predicts human immune response to the placental malaria vaccine candidate VAR2CSA

Placental malaria vaccines (PMV) are being developed to prevent severe sequelae of placental malaria (PM) in pregnant women and their offspring. The leading candidate vaccine antigen VAR2CSA mediates parasite binding to placental receptor chondroitin sulfate A (CSA). Despite promising results in small animal studies, recent human trials of the first two PMV candidates (PAMVAC and PRIMVAC) generated limited cross-reactivity and cross-inhibitory activity to heterologous parasites. Here, we immunized Aotus nancymaae monkeys with three PMV candidates (PAMVAC, PRIMVAC and ID1-ID2a_M1010) adjuvanted with Alhydrogel(R), and exploited the model to investigate boosting of functional vaccine responses during PM episodes as well as with nanoparticle antigens. PMV candidates induced high levels of antigen-specific IgG with significant cross-reactivity across PMV antigens by ELISA. Conversely, PMV antibodies recognized native VAR2CSA and blocked CSA-adhesion of only homologous parasites and not heterologous parasites. PM episodes did not significantly boost VAR2CSA antibody levels or serum functional activity; nanoparticle and monomer antigens alike boosted serum reactivity but not functional activities. Overall, PMV candidates induced functional antibodies with limited heterologous activity in Aotus monkeys, similar to responses reported in humans. The Aotus model appears suitable for preclinical down-selection of PMV candidates and assessment of antibody boosting by PM episodes. Research in Context Evidence before this studyThe Plasmodium falciparum erythrocyte membrane protein VAR2CSA is the leading vaccine candidate antigen to protect pregnant women against placental malaria (PM), which causes serious adverse pregnancy outcomes particularly in first-time mothers living in malaria-endemic areas. Two VAR2CSA-based vaccines (PAMVAC and PRIMVAC) induced strong heterologous functional antibodies in small animals, but induced antibodies with limited cross-inhibitory functional activity in human clinical trials. These observations highlighted the need to establish new animal models that could better recapitulate human pathogenesis and immunity. In ongoing development of a nonhuman primate model for PM, we established an Aotus nancymaae model susceptible to P. falciparum infection during pregnancy that reproduces all the immunoparasitological and histological features of human PM. In this study, we explore the new Aotus model as a platform for evaluating PM vaccine (PMV) immunogenicity and for boosting of vaccine responses during PM episodes. Added value of this studyIn this manuscript, we demonstrate that PMV (including PAMVAC and PRIMVAC) are immunogenic in Aotus monkeys, inducing antibodies with mainly homologous and little heterologous functional activity, as seen in humans but contrary to preclinical reports on these vaccines in small animals. Implications of all the available evidenceOur findings suggest Aotus is a suitable model to assess immunogenicity of VAR2CSA-derived vaccines, in contrast to small animal models. PMV data from human trials and Aotus monkeys suggest that improvements to current VAR2CSA immunogens and/or adjuvants are needed to enhance protective antibody responses, as are studies that evaluate the potential for natural infection to boost vaccine antibody in pregnancy. Therefore, the Aotus PM model may be useful to assess second-generation PMVs seeking to increase strain-transcending activity and to prioritize these for further clinical development.

immunology↗

bioRxiv2018

Duffy Antigen Expression in Erythroid Bone Marrow Precursor Cells of Genotypically Duffy Negative Individuals

The gene encoding the Duffy blood group protein (Fy, CD234; additional designations Duffy Antigen Receptor of Chemokines [DARC] and Atypical Chemokine Receptor 1 [ACKR1]) is characterized by a SNP in a GATA-1 transcription factor binding site associated with the erythrocyte silent (ES) phenotype. FYES homozygous people are viewed to be highly resistant to blood stage infection with Plasmodium vivax. Increasingly, however, studies are reporting P. vivax infections in Fy-negative individuals across malarious African countries where FYES approaches genetic fixation. This suggests that P. vivax has evolved a Fy-independent RBC invasion pathway, or that the GATA-1 SNP does not abolish Fy expression. Here, we tested the second hypothesis through binding studies to erythroid lineage cells using recombinant P. vivax Duffy binding protein, the parasites invasion ligand and Fy6-specific antibodies. We first observed variable Fy expression on circulating RBCs, irrespective of FY genotype; FYES RBCs were periodically Fy-positive. Furthermore, during the in vitro erythroid differentiation of CD34+ cells and on ex vivo bone marrow samples, we observed Fy expression on erythroid precursor cells from FYES people. Finally, the Fy6-specific nanobody, CA111 was used to capture Fy from the surface of FYES RBCs. Our findings reveal that the GATA-1 SNP does not fully abolish Fy expression and provide insight on potential susceptibility of Fy-negative people to vivax malaria.\n\nSignificanceDuffy blood group negativity results from a single nucleotide polymorphism (SNP) in the gene promoter, and reaches genetic fixation in many African ethnicities. Because the Duffy protein (Fy) is an important contact point during Plasmodium vivax human red blood cell invasion, Fy-negativity is considered to confer resistance to P. vivax malaria. With recent studies in African countries reporting P. vivax infection in Fy-negative people, we studied Fy expression across erythroid development. Here we report that the FY promoter SNP does not abolish Fy protein expression in erythroid progenitors developing in the bone marrow. These results further emphasizes the importance of reticulocytes as targets for P. vivax blood stage infection and propose a mechanism for P. vivax infections in Fy-negative people.

genetics↗