The exception that proves the rule: Virulence gene expression at the onset of Plasmodium falciparum blood stage infections

Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

JH, ME, 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) (http://www.dzif.de/). This work was supported by the DFG Research Infrastructure NGS_CC (project #1016) as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the production site WGGC-Bonn. 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, YDH and AB were funded by the German Research Foundation (DFG) grants BA 5213/3-1 (project #323759012) and BA 5213/6-1 (project #433302244). Manufacture of 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 SBIR award numbers 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.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee of the University Clinic and the Medical Faculty of the University of Tuebingen approved both studies, MAVACHE and CVac-Tue3, of which samples were examines in this work, and the U.S. Food and Drug Administration Agency (FDA) provided regulatory oversight.

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