TY - JOUR
T1 - The exception that proves the rule
T2 - Virulence gene expression at the onset of Plasmodium falciparum blood stage infections
AU - Wichers-Misterek, Jan Stephan
AU - Krumkamp, Ralf
AU - Held, Jana
AU - von Thien, Heidrun
AU - Wittmann, Irene
AU - Höppner, Yannick Daniel
AU - Ruge, Julia M.
AU - Moser, Kara
AU - Dara, Antoine
AU - Strauss, Jan
AU - Esen, Meral
AU - Fendel, Rolf
AU - Sulyok, Zita
AU - Jeninga, Myriam D.
AU - Kremsner, Peter G.
AU - Sim, B. Kim Lee
AU - Hoffman, Stephen L.
AU - Duffy, Michael F.
AU - Otto, Thomas D.
AU - Gilberger, Tim Wolf
AU - Silva, Joana C.
AU - Mordmüller, Benjamin
AU - Petter, Michaela
AU - Bachmann, Anna
N1 - Funding Information:
JH, ME, RF, ZS, PGK, BM and AB received funding for the clinical trial and the var gene expression analysis by the Federal Ministry of Education and Research in the framework of the German Centre for Infection Research (DZIF) (TTU 03.702 Clinical Trial Platform and TTU 03.703 Clinical Research Group), and the MAVACHE study was supported by the DZIF grant TTU 03.902. RK also received DZIF funding through his research group "Mathematical Models and Biostatistics (TTU 03.708) (http://www.dzif.de/). AB and MP received the DFG grants BA 5213/6-1 and PE 1618/4-1 (project #433302244), respectively, as part of the DFG Sequencing call 2019. JSWM and AB were funded by the German Research Foundation (DFG) grants BA 5213/3-1 (project #323759012). Manufacture of the Sanaria PfSPZ vaccine, PfSPZ challenge (NF54), and PfSPZ challenge (7G8) was funded in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under SLH's SBIR award numbers SLH 5R44AI058375 and 5R44AI055229. JCS, KAM and AD were funded by awards U19 AI110820 and R01 AI141900, from the National Institute for Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank all volunteers who participated in the trials at the Institute of Tropical Medicine in Tübingen, Germany, and the entire study team. We thank Sanaria Inc. for providing the 7G8 working cell bank parasites and the PfSPZ Challenge (7G8) used in the CHMI trials and Balázs Horváth for his help with data analysis, mapping and variant calling. The following reagents were obtained through BEI Resources, NIAID, NIH: Plasmodium falciparum, Strain 7G8, MRA-152, contributed by David Walliker, MRA-154, contributed by Dennis E. Kyle and MRA-926, contributed by Karen Hayton and Tom Wellems.
Publisher Copyright:
Copyright: © 2023 Wichers-Misterek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/6
Y1 - 2023/6
N2 - Controlled human malaria infections (CHMI) are a valuable tool to study parasite gene expression in vivo under defined conditions. In previous studies, virulence gene expression was analyzed in samples from volunteers infected with the Plasmodium falciparum (Pf) NF54 isolate, which is of African origin. Here, we provide an in-depth investigation of parasite virulence gene expression in malaria-naïve European volunteers undergoing CHMI with the genetically distinct Pf 7G8 clone, originating in Brazil. Differential expression of var genes, encoding major virulence factors of Pf, PfEMP1s, was assessed in ex vivo parasite samples as well as in parasites from the in vitro cell bank culture that was used to generate the sporozoites (SPZ) for CHMI (Sanaria PfSPZ Challenge (7G8)). We report broad activation of mainly B-type subtelomeric located var genes at the onset of a 7G8 blood stage infection in naïve volunteers, mirroring the NF54 expression study and suggesting that the expression of virulence-associated genes is generally reset during transmission from the mosquito to the human host. However, in 7G8 parasites, we additionally detected a continuously expressed single C-type variant, Pf7G8_040025600, that was most highly expressed in both pre-mosquito cell bank and volunteer samples, suggesting that 7G8, unlike NF54, maintains expression of some previously expressed var variants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission. Trial registration: ClinicalTrials.gov NCT02704533; 2018-004523-36.
AB - Controlled human malaria infections (CHMI) are a valuable tool to study parasite gene expression in vivo under defined conditions. In previous studies, virulence gene expression was analyzed in samples from volunteers infected with the Plasmodium falciparum (Pf) NF54 isolate, which is of African origin. Here, we provide an in-depth investigation of parasite virulence gene expression in malaria-naïve European volunteers undergoing CHMI with the genetically distinct Pf 7G8 clone, originating in Brazil. Differential expression of var genes, encoding major virulence factors of Pf, PfEMP1s, was assessed in ex vivo parasite samples as well as in parasites from the in vitro cell bank culture that was used to generate the sporozoites (SPZ) for CHMI (Sanaria PfSPZ Challenge (7G8)). We report broad activation of mainly B-type subtelomeric located var genes at the onset of a 7G8 blood stage infection in naïve volunteers, mirroring the NF54 expression study and suggesting that the expression of virulence-associated genes is generally reset during transmission from the mosquito to the human host. However, in 7G8 parasites, we additionally detected a continuously expressed single C-type variant, Pf7G8_040025600, that was most highly expressed in both pre-mosquito cell bank and volunteer samples, suggesting that 7G8, unlike NF54, maintains expression of some previously expressed var variants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission. Trial registration: ClinicalTrials.gov NCT02704533; 2018-004523-36.
UR - http://www.scopus.com/inward/record.url?scp=85164601172&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1011468
DO - 10.1371/journal.ppat.1011468
M3 - Article
C2 - 37384799
AN - SCOPUS:85164601172
SN - 1553-7366
VL - 19
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 6
M1 - e1011468
ER -
