The exception that proves the rule: Virulence gene expression at the onset ofPlasmodium falciparumblood stage infections

AbstractControlled human malaria infections (CHMI) are a valuable tool to study parasite gene expressionin vivounder defined conditions. In previous studies, virulence gene expression was analyzed in samples from volunteers infected with thePlasmodium 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 ofvargenes, encoding major virulence factors of Pf, PfEMP1s, was assessed inex vivoparasite samples as well as in parasites from thein vitrocell 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 locatedvargenes 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 expressedvarvariants during transmission. This suggests that in a new host, the parasite may preferentially express the variants that previously allowed successful infection and transmission.