Medical Biology - Research Publications

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Author: Duffy, Michael × Author: Papenfuss, Anthony × End date: 2019 × Start date: 2016 × Type: Journal Article ×

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    The &ITPlasmodium falciparum &ITtranscriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen-encoding &ITvar &ITgenes
    Tonkin-Hill, GQ ; Trianty, L ; Noviyanti, R ; Nguyen, HHT ; Sebayang, BF ; Lampah, DA ; Marfurt, J ; Cobbold, SA ; Rambhatla, JS ; McConville, MJ ; Rogerson, SJ ; Brown, G ; Day, KP ; Price, RN ; Anstey, NM ; Papenfuss, AT ; Duffy, MF ; Schneider, D (PUBLIC LIBRARY SCIENCE, 2018-03)
    Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to-or is selected by-this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to-or are selected by-the host environment in severe malaria.
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    Differences in PfEMP1s recognized by antibodies from patients with uncomplicated or severe malaria
    Duffy, MF ; Noviyanti, R ; Tsuboi, T ; Feng, Z-P ; Trianty, L ; Sebayang, BF ; Takashima, E ; Sumardy, F ; Lampah, DA ; Turner, L ; Lavstsen, T ; Fowkes, FJI ; Siba, P ; Rogerson, SJ ; Theander, TG ; Marfurt, J ; Price, RN ; Anstey, NM ; Brown, GV ; Papenfuss, AT (BIOMED CENTRAL LTD, 2016-05-05)
    BACKGROUND: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by var genes and mediate pathogenic cytoadhesion and antigenic variation in malaria. PfEMP1s can be broadly divided into three principal groups (A, B and C) and they contain conserved arrangements of functional domains called domain cassettes. Despite their tremendous diversity there is compelling evidence that a restricted subset of PfEMP1s is expressed in severe disease. In this study antibodies from patients with severe and uncomplicated malaria were compared for differences in reactivity with a range of PfEMP1s to determine whether antibodies to particular PfEMP1 domains were associated with severe or uncomplicated malaria. METHODS: Parts of expressed var genes in a severe malaria patient were identified by RNAseq and several of these partial PfEMP1 domains were expressed together with others from laboratory isolates. Antibodies from Papuan patients to these parts of multiple PfEMP1 proteins were measured. RESULTS: Patients with uncomplicated malaria were more likely to have antibodies that recognized PfEMP1 of Group C type and recognized a broader repertoire of group A and B PfEMP1s than patients with severe malaria. CONCLUSION: These data suggest that exposure to a broad range of group A and B PfEMP1s is associated with protection from severe disease in Papua, Indonesia.