Expression Patterns of Plasmodium falciparum Clonally Variant Genes at the Onset of a Blood Infection in Malaria-Naive Humans.

Anastasia K Pickford,Pedro L Alonso,Florian Dupuy,Catherine Lavazec,Alfred Cortés,Alfredo Mayor,Lucas Michel-Todó

doi:10.1128/mbio.01636-21

Abstract

ABSTRACTClonally variant genes (CVGs) play fundamental roles in the adaptation of Plasmodium falciparum to fluctuating conditions of the human host. However, their expression patterns under the natural conditions of the blood circulation have been characterized in detail for only a few specific gene families. Here, we provide a detailed characterization of the complete P. falciparum transcriptome across the full intraerythrocytic development cycle (IDC) at the onset of a blood infection in malaria-naive human volunteers. We found that the vast majority of transcriptional differences between parasites obtained from the volunteers and the parental parasite line maintained in culture occurred in CVGs. In particular, we observed a major increase in the transcript levels of most genes of the pfmc-2tm and gbp families and of specific genes of other families, such as phist, hyp10, rif, or stevor, in addition to previously reported changes in var and clag3 gene expression. Increased transcript levels of individual pfmc-2tm, rif, and stevor genes involved activation in small subsets of parasites. Large transcriptional differences correlated with changes in the distribution of heterochromatin, confirming their epigenetic nature. Furthermore, the similar expression of several CVGs between parasites collected at different time points along the blood infection suggests that the epigenetic memory for multiple CVG families is lost during transmission stages, resulting in a reset of their transcriptional state. Finally, the CVG expression patterns observed in a volunteer likely infected by a single sporozoite suggest that new epigenetic patterns are established during liver stages.

Highlights

Variant genes (CVGs) play fundamental roles in the adaptation of Plasmodium falciparum to fluctuating conditions of the human host
In P. falciparum, the most virulent human malaria parasite species, Clonally variant genes (CVGs) include gene families such as var, rif, stevor, pfmc-2tm, hyp1 to hyp17, phist, and surfin linked to pathogenesis, antigenic variation, and host cell remodeling; mspdbl2, eba140, and pfrh4 genes linked to erythrocyte invasion; clag genes involved in solute transport; acs and acbp families linked to acyl-CoA metabolism; and pfap2-g, the master regulator of sexual conversion [9–12], among others
Here, we provide the first genome-wide transcriptional characterization across the full intraerythrocytic development cycle (IDC) of P. falciparum parasites obtained during the initial days of a blood infection in malaria-naive humans and compare it with the transcriptome of parasites with the same genome but maintained under in vitro culture conditions

Summary

Introduction

Variant genes (CVGs) play fundamental roles in the adaptation of Plasmodium falciparum to fluctuating conditions of the human host. In addition to environmental diversity associated with life cycle progression, malaria parasites have to confront fluctuating conditions within the same niche These fluctuations, which can occur between individual hosts of the same species or even within the course of a single blood infection, may derive, for instance, from changes in the host’s physiological or immunological state or from the effects of antimalarial treatment [6, 7]. While in malaria parasites genetic changes play a major role in species evolution and long-term adaptation to new conditions, as in any other organism, rapid adaptation to conditions that fluctuate frequently requires reversible, dynamic mechanisms that provide phenotypic plasticity (i.e., alternative phenotypes from the same genome) [8] One such mechanism is clonally variant gene (CVG) expression, which refers to genes that can be found in a different state (active or silent) in different individual parasites with identical genomes and at the same stage of life cycle progression. Specific adaptive roles have been demonstrated for changes in the expression of var [16–18] and clag3 [19–24] genes

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