Browsing by Author "Doumbo, Ogobara K."

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    Extent and Dynamics of Polymorphism in the Malaria Vaccine Candidate Plasmodium falciparum Reticulocyte-Binding Protein Homologue-5 in Kalifabougou, Mali
    (The American Society of Tropical Medicine and Hygiene, 2018-07) Ouattara, Amed; Tran, Tuan M.; Doumbo, Safiatou; Matthew, Adams; Agrawal, Sonia; Niangaly, Amadou; Nelson-Owens, Sara; Doumtabé, Didier; Tolo, Youssouf; Ongoiba, Aissata; Takala-Harrison, Shannon; Traoré, Boubacar; Silva, Joana C.; Crompton, Peter D.; Doumbo, Ogobara K.; Plowe, Christopher V.; Medicine, School of Medicine
    Reticulocyte-binding homologues (RH) are a ligand family that mediates merozoite invasion of erythrocytes in Plasmodium falciparum. Among the five members of this family identified so far, only P. falciparum reticulocyte-binding homologue-5 (PfRH5) has been found to be essential for parasite survival across strains that differ in virulence and route of host-cell invasion. Based on its essential role in invasion and early evidence of sequence conservation, PfRH5 has been prioritized for development as a vaccine candidate. However, little is known about the extent of genetic variability of RH5 in the field and the potential impact of such diversity on clinical outcomes or on vaccine evasion. Samples collected during a prospective cohort study of malaria incidence conducted in Kalifabougou, in southwestern Mali, were used to estimate genetic diversity, measure haplotype prevalence, and assess the within-host dynamics of PfRH5 variants over time and in relation to clinical malaria. A total of 10 nonsynonymous polymorphic sites were identified in the Pfrh5 gene, resulting in 13 haplotypes encoding unique protein variants. Four of these variants have not been previously observed. Plasmodium falciparum reticulocyte-binding homologue-5 had low amino acid haplotype (h = 0.58) and nucleotide (π = 0.00061) diversity. By contrast to other leading blood-stage malaria vaccine candidate antigens, amino acid differences were not associated with changes in the risk of febrile malaria in consecutive infections. Conserved B- and T-cell epitopes were identified. These results support the prioritization of PfRH5 for possible inclusion in a broadly cross-protective vaccine.
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    A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation
    (Elsevier, 2019-10-15) Tran, Tuan M.; Guha, Rajan; Portugal, Silvia; Skinner, Jeff; Ongoiba, Aissata; Bhardwaj, Jyoti; Jones, Marcus; Moebius, Jacqueline; Venepally, Pratap; Doumbo, Safiatou; DeRiso, Elizabeth A.; Li, Shanping; Vijayan, Kamalakannan; Anzick, Sarah L.; Hart, Geoffrey T.; O’Connell, Elise M.; Doumbo, Ogobara K.; Kaushansky, Alexis; Alter, Galit; Felgner, Phillip L.; Lorenzi, Hernan; Kayentao, Kassoum; Traore, Boubacar; Kirkness, Ewen F.; Crompton, Peter D.; Medicine, School of Medicine
    Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment; upregulation of T-helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses; and p53 activation associated with control of malarial fever and coordinated with Pf-specific IgG and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.
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    Public antibodies to malaria antigens generated by two LAIR1 insertion modalities
    (Springer Nature, 2017-08-31) Pieper, Kathrin; Tan, Joshua; Piccoli, Luca; Foglierini, Mathilde; Barbieri, Sonia; Chen, Yiwei; Silacci-Fregn, Chiara; Wolf, Tobias; Jarrossay, David; Anderle, Marica; Abdi, Abdirahman; Ndungu, Francis M.; Doumbo, Ogobara K.; Traore, Boubacar; Tran, Tuan M.; Jongo, Said; Zenklusen, Isabelle; Crompton, Peter D.; Daubenberger, Claudia; Bull, Peter C.; Sallusto, Federica; Lanzavecchia, Antonio; Medicine, School of Medicine
    In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.
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    Synergistic malaria vaccine combinations identified by systematic antigen screening
    (National Academy of Sciences, 2017-11-07) Bustamante, Leyla Y.; Powell, Gareth T.; Lin, Yen-Chun; Macklin, Michael D.; Cross, Nadia; Kemp, Alison; Cawkill, Paula; Sanderson, Theo; Crosnier, Cecile; Muller-Sienerth, Nicole; Doumbo, Ogobara K.; Traore, Boubacar; Crompton, Peter D.; Cicuta, Pietro; Tran, Tuan M.; Wright, Gavin J.; Rayner, Julian C.; Medicine, School of Medicine
    Malaria still kills hundreds of thousands of children each year. Malaria vaccine development is complicated by high levels of parasite genetic diversity, which makes single target vaccines vulnerable to the development of variant-specific immunity. To overcome this hurdle, we systematically screened a panel of 29 blood-stage antigens from the most deadly human malaria parasite, Plasmodium falciparum. We identified several targets that were able to inhibit erythrocyte invasion in two genetically diverse strains. Testing these targets in combination identified several pairs that blocked invasion more effectively in combination than in isolation. Video microscopy and studies of natural immune responses to malaria in patients suggest that targeting multiple steps in invasion is more likely to produce a synergistic vaccine response., A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.
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    Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria
    (SpringerNature, 2016-08-10) Tran, Tuan M.; Jones, Marcus B.; Ongoiba, Aissata; Bijker, Else M.; Schats, Remko; Venepally, Pratap; Skinner, Jeff; Doumbo, Safiatou; Quinten, Edwin; Visser, Leo G.; Whalen, Elizabeth; Presnell, Scott; O’Connell, Elise M.; Kayentao, Kassoum; Doumbo, Ogobara K.; Chaussabel, Damien; Lorenzi, Hernan; Nutman, Thomas B.; Ottenhoff, Tom H. M.; Haks, Mariëlle C.; Traore, Boubacar; Kirkness, Ewen F.; Sauerwein, Robert W.; Crompton, Peter D.; Department of Medicine, IU School of Medicine
    Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.
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    Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection
    (Oxford, 2017-03) Portugal, Silvia; Tran, Tuan M.; Ongoiba, Aissata; Bathily, Abroudramane; Li, Shanping; Doumbo, Safiatou; Skinner, Jeff; Doumtabe, Didier; Kone, Younoussou; Sangala, Jules; Jain, Aarti; Davies, D. Huw; Hung, Christopher; Liang, Li; Ricklefs, Stacy; Homann, Manijeh Vafa; Felgner, Philip L.; Porcella, Stephen F.; Färnert, Anna; Doumbo, Ogobara K.; Kayentao, Kassoum; Greenwood, Brian M.; Traore, Boubacar; Crompton, Peter D.; Medicine, School of Medicine
    Background. Chronic asymptomatic Plasmodium falciparum infections are common in endemic areas and are thought to contribute to the maintenance of malaria immunity. Whether treatment of these infections increases the subsequent risk of clinical episodes of malaria is unclear. Methods. In a 3-year study in Mali, asymptomatic individuals with or without P. falciparum infection at the end of the 6-month dry season were identified by polymerase chain reaction (PCR), and clinical malaria risk was compared during the ensuing 6-month malaria transmission season. At the end of the second dry season, 3 groups of asymptomatic children were identified: (1) children infected with P. falciparum as detected by rapid diagnostic testing (RDT) who were treated with antimalarials (n = 104), (2) RDT-negative children whose untreated P. falciparum infections were detected retrospectively by PCR (n = 55), and (3) uninfected children (RDT/PCR negative) (n = 434). Clinical malaria risk during 2 subsequent malaria seasons was compared. Plasmodium falciparum–specific antibody kinetics during the dry season were compared in children who did or did not harbor asymptomatic P. falciparum infections. Results. Chronic asymptomatic P. falciparum infection predicted decreased clinical malaria risk during the subsequent malaria season(s); treatment of these infections did not alter this reduced risk. Plasmodium falciparum–specific antibodies declined similarly in children who did or did not harbor chronic asymptomatic P. falciparum infection during the dry season. Conclusions. These findings challenge the notion that chronic asymptomatic P. falciparum infection maintains malaria immunity and suggest that mass drug administration during the dry season should not increase the subsequent risk of clinical malaria.