Plasmodium liver stage schizogony: high replication and genetic diversity

Introduction

A world free of malaria is certainly a desirable goal. However, in spite of the significant incidence reduction achieved globally between 2000-2015, malaria still kills a child every minute. The limited understanding of Plasmodium's biology hampers the development of novel intervention strategies.

Plasmodium Infection Process

Upon transmission by Anopheles mosquitos, Plasmodium parasites must reach the liver and infect hepatocytes. Inside a hepatocyte, each parasite replicates into thousands of new erythrocyte-infectious forms, which lead to disease.

Replication and Malaria Severity

The parasite biomass generated during the liver stage (LS) of infection is directly associated with malaria severity. However, how the parasite achieves such a high replication rate, and the consequences of that, remain utterly unexplored. Notably, Plasmodium replication is unusual.

1. The parasite divides by schizogony, with divisions occurring without cytokinesis.
2. It cannot salvage pyrimidines from the environment, relying solely on nucleotides synthesized de novo.

Research Findings

Using a Plasmodium transgenic line specifically designed to study DNA replication throughout parasite development, I unveiled for the first time the temporal dynamics of DNA replication throughout parasite LS. I show that Plasmodium's LS high replication rate is accompanied by DNA damage.

Hypothesis

Thus, I hypothesize that DNA damage accumulation during LS schizogony is a generator of genetic variability prior to intra-erythrocytic infection.

Proposed Research

By using a combination of molecular, cell biology, and genetic approaches, I now propose to:

1. Characterize the mechanisms.
2. Define the molecular players.
3. Reveal the causes and consequences of such a high replication rate in the outcome of infection and progression of disease.

This will expose the consequences for parasite genetic diversity and virulence.

Significance

Connecting LS schizogony with parasite genetic diversity and virulence for the first time will be conceptually transformative and will certainly provide valuable targets and tools for the combat against malaria.