The role of an expanded family of exported effector kinases in environmental sensing and regulation of virulence in human malaria.

Introduction

The most severe form of malaria in humans is caused by Plasmodium falciparum. Cytoadhesion of infected red blood cells (iRBCs) to host endothelium and iRBC rigidification are the major contributors to pathology.

Cytoadhesion Mechanism

Cytoadhesion is mediated by the transport of a protein called PfEMP1 onto the surface of the iRBC. It prevents clearance of iRBCs in the spleen and promotes parasite survival, but can cause the obstruction of blood vessels leading to pathology.

Balance of Survival and Pathology

Thus, the parasite has to strike a fine balance between preventing its own clearance through sufficiently strong cytoadhesion and control of rigidity, and killing the host. The paradigm in the field is that the strength of cytoadhesion is dominated by the expression of PfEMP1 variants with different affinities for host cell receptors.

Regulation of Cytoadhesive Properties

We now have strong evidence that the parasite can rapidly regulate its cytoadhesive properties using a family of atypical kinases (the FIKK kinases) it exports into the host cell. This gives the parasite a yet unrecognized ability to respond to conditions encountered in the host, such as fever or hypoxia in areas of high parasite sequestration, and influence disease outcome.

Importance of FIKK Kinases

This is important: Of the 6 human infecting Plasmodium species, only P. falciparum exports FIKK kinases into the host cell. As this species is responsible for ~95% of all fatal human malaria cases, it is paramount to understand FIKK function in pathogenesis.

Research Objectives

We will use cutting-edge approaches to:

1. Identify the function of FIKK kinases in controlling cytoadhesion and rigidity in conditions frequently encountered in the human host and determine RBC remodelling in samples from patients.
2. Identify the molecular underpinnings of FIKK function in controlling cytoadhesion.
3. Perform a thorough biochemical characterization of the atypical FIKK kinase family.

Conclusion

In summary, we aim to answer the paramount question about the functional role and the evolution of the FIKK kinases and the pathogenesis of P. falciparum malaria.