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  • 1
    Online Resource
    Online Resource
    Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s
    American Society for Microbiology ; 2023
    In:  mSphere
    Details
    In: mSphere, American Society for Microbiology
    Abstract: Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an “adult-like” response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This “adult-like” response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant.
    Type of Medium: Online Resource
    ISSN: 2379-5042
    URL: Article
    DOI: 10.1128/msphere.00451-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2844248-9
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  • 2
    Online Resource
    Online Resource
    Antibodies to Peptides in Semiconserved Domains of RIFINs and STEVORs Correlate with Malaria Exposure
    American Society for Microbiology ; 2019
    In:  mSphere Vol. 4, No. 2 ( 2019-04-24)
    Details
    In: mSphere, American Society for Microbiology, Vol. 4, No. 2 ( 2019-04-24)
    Abstract: The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria. IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum , causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malaria. Potential vaccines for severe malaria should include consideration of peptides within the semiconserved domains of RIFINs and STEVORs.
    Type of Medium: Online Resource
    ISSN: 2379-5042
    URL: Article
    DOI: 10.1128/mSphere.00097-19
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 2844248-9
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  • 3
    Online Resource
    Online Resource
    HLA-A2 Supertype-Restricted Cell-Mediated Immunity by Peripheral Blood Mononuclear Cells Derived from Malian Children with Severe or Uncomplicated Plasmodium falciparum Malaria and Healthy Controls
    American Society for Microbiology ; 2005
    In:  Infection and Immunity Vol. 73, No. 9 ( 2005-09), p. 5799-5808
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 73, No. 9 ( 2005-09), p. 5799-5808
    Abstract: Understanding HLA-restricted adaptive host immunity to defined epitopes of malarial antigens may be required for the development of successful malaria vaccines. Fourteen epitopes of preerythrocytic malarial antigens known to mediate cytotoxic T-lymphocyte responses against target cells expressing HLA-A2-restricted epitopes were synthesized and pooled based on antigen: thrombospondin-related anonymous protein (TRAP), circumsporozoite protein (CSP), and export protein 1 (Exp-1) peptides. HLA-A2 supertype (*0201, *0202, *0205, *6802) peripheral blood mononuclear cells collected from 774 Malian children, aged 3 months to 14 years, with severe Plasmodium falciparum malaria matched to uncomplicated malaria or healthy controls were stimulated with the HLA-A2-restricted peptide pools. Significant gamma interferon production, determined by enzyme-linked immunospot assay to at least one of the three peptide pools, was observed in 24/58 (41%) of the severe malaria cases, 24/57 (42%) of the uncomplicated malaria cases, and 34/51 (67%) of the healthy controls. Significant lymphoproliferation to these peptides was observed in 12/44 (27%) of the severe malaria cases, 13/55 (24%) of the uncomplicated malaria cases, and 18/50 (36%) of the healthy controls. Responses to individual peptide pools were limited. These studies confirm the presence of adaptive cell-mediated immunity to preerythrocytic malaria antigens in volunteers from Mali and demonstrate that suballeles of the HLA-A2 supertype can effectively present antigenic epitopes. However, whether these immune responses to TRAP, CSP, and Exp-1 malarial proteins play a substantial role in protection remains a matter of controversy.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.73.9.5799-5808.2005
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2005
    detail.hit.zdb_id: 1483247-1
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  • 4
    Online Resource
    Online Resource
    Host and Parasite Transcriptomic Changes upon Successive Plasmodium falciparum Infections in Early Childhood
    American Society for Microbiology ; 2020
    In:  mSystems Vol. 5, No. 4 ( 2020-08-25)
    Details
    In: mSystems, American Society for Microbiology, Vol. 5, No. 4 ( 2020-08-25)
    Abstract: Children are highly susceptible to clinical malaria, and in regions where malaria is endemic, their immune systems must face successive encounters with Plasmodium falciparum parasites before they develop immunity, first against severe disease and later against uncomplicated malaria. Understanding cellular and molecular interactions between host and parasites during an infection could provide insights into the processes underlying this gradual acquisition of immunity, as well as to how parasites adapt to infect hosts that are successively more malaria experienced. Here, we describe methods to analyze the host and parasite gene expression profiles generated simultaneously from blood samples collected from five consecutive symptomatic P. falciparum infections in three Malian children. We show that the data generated enable statistical assessment of the proportions of (i) each white blood cell subset and (ii) the parasite developmental stages, as well as investigations of host-parasite gene coexpression. We also use the sequences generated to analyze allelic variations in transcribed regions and determine the complexity of each infection. While limited by the modest sample size, our analyses suggest that host gene expression profiles primarily clustered by individual, while the parasite gene expression profiles seemed to differentiate early from late infections. Overall, this study provides a solid framework to examine the mechanisms underlying acquisition of immunity to malaria infections using whole-blood transcriptome sequencing (RNA-seq). IMPORTANCE We show that dual RNA-seq from patient blood samples allows characterization of host/parasite interactions during malaria infections and can provide a solid framework to study the acquisition of antimalarial immunity, as well as the adaptations of P. falciparum to malaria-experienced hosts.
    Type of Medium: Online Resource
    ISSN: 2379-5077
    URL: Article
    DOI: 10.1128/mSystems.00116-20
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 2844333-0
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  • 5
    Online Resource
    Online Resource
    Effects of Concomitant Schistosoma haematobium Infection on the Serum Cytokine Levels Elicited by Acute Plasmodium falciparum Malaria Infection in Malian Children
    American Society for Microbiology ; 2006
    In:  Infection and Immunity Vol. 74, No. 10 ( 2006-10), p. 5718-5724
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 74, No. 10 ( 2006-10), p. 5718-5724
    Abstract: Polyparasitism is common in the developing world, and interactions that alter disease severity may occur. We previously demonstrated that infection with Schistosoma hematobium was associated with protection against Plasmodium falciparum infection in children who were 4 to 8 years old. In this study, we determined whether underlying helminth infections affected the cytokine responses to acute falciparum malaria. A total of 338 schistosomiasis-positive [Sch(+)] children who were 4 to 14 years old were matched by age, residence, and sex with 338 schistosomiasis-negative [Sch(−)] children and monitored for a malaria transmission season (25 weeks). Serologic cytokine levels were measured at the time of the first clinical malaria episode and in children who did not contract malaria. Elevated background levels of interleukin-6 (IL-6) (37.1 pg/ml versus 10.9 pg/ml [ P = 0.04]), IL-4 (27.7 pg/ml versus 6.9 pg/ml [ P = 0.02]), IL-10 (18.2 pg/ml versus 7.2 pg/ml [ P 〈 0.001]), and gamma interferon (18.2 pg/ml versus 4.7 pg/ml [ P = 0.006]) were noted in Sch(+) children compared to Sch(−) children without malaria. IL-6 and IL-10 levels were elevated in association with acute malaria, but the levels appeared to be blunted in Sch(+) children compared to Sch(−) children who were 4 to 8 years old (for IL-6, 96.2 pg/ml versus 137.2 pg/ml [ P = 0.08]; for IL-10, 195.9 pg/ml versus 282.2 pg/ml [ P = 0.06]). The level of IL-10 was similarly lower in Sch(+) children than in Sch(−) children who were 9 to 14 years old (91.2 pg/ml versus 141.2 pg/ml [ P = 0.03]). IL-4 levels were inversely correlated with the time until the first malaria infection in both the Sch(+) children ( P 〈 0.001) and the Sch(−) children ( P 〈 0.001) who were 4 to 8 years old. We postulate that the Th2-enriched environment induced by schistosomiasis protects against malaria and alters the cytokine milieu during an actual infection.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.01822-05
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2006
    detail.hit.zdb_id: 1483247-1
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