11 May Red Blood Cell Surface Molecule May Be Target For New Malaria Vaccine and Treatment
MedicalResearch.com Interview with:
Manoj Duraisingh Ph.D.
John LaPorte Given Professor of Immunology and Infectious Diseases
Harvard T.H. Chan School of Public Health
Department of Immunology and Infectious Diseases
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Duraisingh: The malaria parasite P. falciparum is one of the most important pathogens of humans, with enormous mortality resulting from blood-stage infections, when parasites replicate exponentially in red blood cells. Although anti-Plasmodial drugs are in clinical use, widespread and increasing parasite drug-resistance has contributed to an ongoing public health crisis, and we urgently need to find novel approaches to prevent and treat disease.
Targeting host red blood cell molecules presents an unexploited alternative. However, the highly differentiated and enucleated red blood cell poses a significant technical hurdle for genetic experimentation, due to the lack of a nucleus.
Here we have developed a novel, forward genetic screen to identify critical factors of malaria infection of red blood cells in an unbiased fashion. Our screen takes advantage of recent advances in human stem cell biology that enable the ex vivo culture of red blood cells from nucleated hematopoietic precursors which are amenable to in vitro genetics.
We have now identified a surface molecule CD55 (alias Decay-Accelerating Factor, DAF) as an essential host factor required for the invasion of red blood cells by P. falciparum. We demonstrate that this protein is required by all P. falciparum strains tested (laboratory and field) for invasion. Furthermore, we demonstrate that CD55 acts at the initial stage of invasion when the P. falciparum parasite attaches to the surface of the red blood cell.
Collectively, our findings indicate that CD55 is an ideal target for the development of new host-directed and vaccine therapeutics for malaria.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Duraisingh: Parasites have evolved to use multiple surface protein receptors to enter red blood cells. Targeting specific receptors was previously thought to be problematic as the notion was that the parasite would simply invade using alternative receptors. Here we have identified an essential surface protein, CD55, required by all P. falciparum parasites for entry into the cell.
Blocking this interaction between CD55 and the parasite should be a very powerful approach in the development of blood-stage therapeutics. This could be either through the development of a drug-like molecule in the form of a CD55-mimetic, or through the identification of the parasite molecule that binds to the CD55 protein, which would immediately become a top vaccine candidate.
Our unbiased screening approach can also be used to identify novel host molecules that the parasite needs for growth in the red blood cell. Targeting host molecules by drugs instead of the parasite would have the advantage that host molecules in the fully differentiated and enucleated red blood cell cannot change to become resistant to drugs. The evolution of drug-resistance in parasitic targets remains one of the greatest challenges of malaria control.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Duraisingh: In the future, we would very much like to explore the exploitation of CD55 for the development of host-targeted therapeutics, as is used in HIV. In addition, CD55 provides a starting point for the search of a parasite ligand that binds to it. As the interaction is essential, the putative CD55-binding protein could be pursued for vaccine development. Finally, CD55 is a blood group protein, and there are a few polymorphisms in this molecule that are at high prevalence in African populations that bear the brunt of malaria, and may confer protection against malaria. It would of great interest to study the effect of these CD55 polymorphisms on human selection by the malaria parasite.
MedicalResearch.com Interview with:, & Manoj Duraisingh Ph.D. (2015). Red Blood Cell Surface Molecule May Be Target For New Malaria Vaccine and Treatment