Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission-intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G-the transcription factor that initiates reproduction-increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1-two histone deacetylases that epigenetically regulate the parasite's replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite's adaptive regulatory architecture has identified new potential molecular targets for malaria control.

BackgroundMultiparameter flow cytometry has revealed extensive phenotypic and functional heterogeneity of CD4 T cell responses in mice and humans, emphasizing the importance of assessing multiple aspects of the immune response in correlation with infection or vaccination outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully.Methodology/Principal FindingsWe developed polychromatic flow cytometry antibody panels for immunophenotyping the major CD4 T cell subsets as well as broadly characterizing the functional profiles of the CD4 T cells in peripheral blood. We then validated these assays by conducting a pilot study comparing CD4 T cell responses in distinct populations of healthy adults living in either rural or urban Kenya. This study revealed that the expression profile of CD4 T cell activation and memory markers differed significantly between African and European donors but was similar amongst African individuals from either rural or urban areas. Adults from rural Kenya had, however, higher frequencies and greater polyfunctionality among cytokine producing CD4 T cells compared to both urban populations, particularly for “Th1” type of response. Finally, endemic exposure to malaria in rural Kenya may have influenced the expansion of few discrete CD4 T cell populations with specific functional signatures.Conclusion/SignificanceThese findings suggest that environmentally driven T cell activation does not drive the dysfunction of CD4 T cells but is rather associated with greater magnitude and quality of CD4 T cell response, indicating that the level or type of microbial exposure and antigenic experience may influence and shape the functionality of CD4 T cell compartment. Our data confirm that it is possible and mandatory to assess multiple functional attributes of CD4 T cell response in the context of infection.

BackgroundGene copy number variants (CNVs), which consist of deletions and amplifications of single or sets of contiguous genes, contribute to the great diversity in the Plasmodium falciparum genome. In vitro studies in the laboratory have revealed their important role in parasite fitness phenotypes such as red cell invasion, transmissibility and cytoadherence. Studies of natural parasite populations indicate that CNVs are also common in the field and thus may facilitate adaptation of the parasite to its local environment.ResultsIn a survey of 183 fresh field isolates from three populations in Eastern Africa with different malaria transmission intensities, we identified 94 CNV loci using microarrays. All CNVs had low population frequencies (minor allele frequency < 5%) but each parasite isolate carried an average of 8 CNVs. Nine CNVs showed high levels of population differentiation (FST > 0.3) and nine exhibited significant clines in population frequency across a gradient in transmission intensity. The clearest example of this was a large deletion on chromosome 9 previously reported only in laboratory-adapted isolates. This deletion was present in 33% of isolates from a population with low and highly seasonal malaria transmission, and in < 9% of isolates from populations with higher transmission. Subsets of CNVs were strongly correlated in their population frequencies, implying co-selection.ConclusionsThese results support the hypothesis that CNVs are the target of selection in natural populations of P. falciparum. Their environment-specific patterns observed here imply an important role for them in conferring adaptability to the parasite thus enabling it to persist in its highly diverse ecological environment.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4689-7) contains supplementary material, which is available to authorized users.

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