Transcriptional Regulation and Epigenetic Mechanisms Underlying Host-Parasite Interactions in Human Malaria

Abstract

Human malaria is one of the most important infectious diseases and a major cause of death and poverty worldwide. It is caused by protozoan parasites of the genus Plasmodium that are transmitted by the bites of mosquitoes of the genus Anopheles. The parasites Plasmodium falciparum and the mosquitoes Anopheles gambiae are the leading figures of this global burden, which disproportionally affects Africa and children under the age of five. To fulfill development and to achieve adaptation to changing environments in the human and mosquito hosts, Plasmodium parasites are capable of drastic transcriptional switches. The Anopheles mosquitoes are the main vectors for human malaria, and they can display phenotypic variability in life history traits, including vector competence or responses against Plasmodium. Yet, the transcriptional regulation underlying host parasite interactions in human malaria, particularly based on epigenetic mechanisms and regarding the life cycle in the mosquito, remain almost completely unknown. In this doctoral thesis, we have applied multi-omic approaches and bioinformatic analyses to investigate the regulatory genome of both P. falciparum and A. gambiae mosquitoes, associated with the Plasmodium development and interactions within hosts, and with the responses of Anopheles mosquitoes to the parasitic infection. We have integrated genomic, epigenomic and transcriptomic approach to unveil relevant cis-regulatory elements and to assay the relationship between gene expression levels and chromatin-related mechanisms, such as histone marks or chromatin accessibility levels. We applied different techniques to these organisms, integrating RNA-seq, ChIP-seq and ATAC-seq for the first time. We reported the positive correlation between transcription and chromatin accessibility by ATAC-seq or active histone marks by ChIP-seq. We also identified thousands of active regulatory sequences, including enhancer candidates, that appeared to be linked to Plasmodium developmental transitions or clonally variant gene expression within humans, or that in the case of mosquitoes seemed to be specific to tissues or Plasmodium infection status. Ultimately, these allowed us to predict cognate transcription factors. Altogether, we provide evidence for genome-wide mechanisms and regulatory regions that may be involved in the dynamic transcriptional regulation underlying host-parasite interactions between malaria parasites and the human and mosquito hosts. This is much required in the context of current efforts against malaria, to inform existing and new mosquito-control and anti-malaria strategies.