Tuesday, April 23, 2013

The Role of Platelets in Defense against Malaria

Platelets are normal constituents of the blood.  They play a fundamental role in blood clotting, but have been shown to play other more diverse functions.  For example, it has been well established that platelets impede the growth of the malaria parasite, Plasmodium falciparum.  The malaria parasite enters the bloodstream following the bite of its carrier, the female anopheles mosquito.  Once circulating in the bloodstream, the parasite preferentially invades circulating red blood cells.  Platelets bind to parasitized cells and kill the parasites within.  This has been amply demonstrated in studies with mice – normally resistant to infection – that have been purposefully depleted of platelets.  These mice invariably die of infection.  It has also been shown, that this property of platelets is independent of species – platelets derived from mice or humans exert the same effect in either host.  In addition, platelets seemed to bind to both infected and non-infected cells, but have a marked preference for infected red cells. 

Although this capability of platelets has been well established, the actual molecular mechanism underlying this function has not been fully demonstrated.  Dr. Brendan J. McMorran and his colleagues from the Australian School of Advanced Medicine in Macquarie University, Sydney Australia and the Menzies Research Institute Tasmania University, Hobart, Australia have made a significant contribution to the understanding of the mechanism involved.

From their work, they have shown that platelet factor 4 (PF4) together with the Duffy-antigen receptor (Fy) are necessary for the platelet-mediated eradication of the Plasmodium falciparum parasite.  Furthermore, they have shown that upon the binding of platelets to the parasitized red blood cell, PF4 is released and that it is this protein that is responsible for the killing of the parasites residing within the infected red blood cells.  In order for PF4 to exert its effect, Fy needs to be present; it is Fy that selectively binds to PF4.  It has also been shown that those individuals that have a genetic anomaly that undermines the expression of Fy are devoid of the protection against the parasite provided by platelets.

These findings help to elucidate the role that platelets play in the defense against parasitic infections.  Uncovering the underlying mechanism for such a defense may prove to be invaluable in combating malaria - a disease that has a devastating impact on a significant portion of the world’s population.    

Friday, April 5, 2013

DNA Supercoils

The structure of DNA is ordinarily represented as a double helix.  In fact, functional DNA found within cells has an additional level of complexity – the double helix also twists upon itself resulting in “extended intertwined loops” called plectonemes.  Since it is well established that there is close and necessary relationship between structure and function in the biological realm, it is of immense scientific interest to understand the dynamics of this supercoiling property.

DNA, of course, possesses the blueprint upon which life is based – it contains the information that is used to construct the structural and enzymatic proteins that are essential for life.  In order to fulfill its role successfully, the genomic processes depend upon exquisite and precise mechanisms to control the expression of genes.  Furthermore, since the complex structure of DNA involving supercoils plays a pivotal role in these control mechanisms, it would be of interest to understand the dynamics of the individual plectonemes.

Current understanding of supercoiling suggests that this phenomenon is caused by the movement of proteins along the path of the DNA molecule.  This movement produces perturbations in the DNA structure causing the DNA to twist or writhe- the coiling of the DNA around itself.  The overall impact of these conformational changes induces both local and global effects.

A locally-derived distortion or destabilization of the DNA can alter transcription – the process by which the information contained in genes is transcribed to messenger RNA (m-RNA) – or induce binding to the DNA.  A global change in the overall conformation of DNA can bring distant sections of the DNA together resulting in genetic recombination.

Heretofore, it has proved to be an immense technological problem to study the actual dynamics of supercoiling since analysis has relied, almost exclusively, upon static imaging.  Dr. M.T.J. van Loenhout and his colleagues from the Delft University of Technology, Department of Bionanoscience, Kavti Institute of Nanoscience in Delft Netherlands have overcome this obstacle by designing what they refer to as, “single-molecule magnetic tweezers.”  With this new analytical tool, they have been able to study the real-time dynamics of individual plectonemes.

Van Loenhout and his co-workers have found that plectonemes move along the DNA by simple diffusion or what they refer to as, “fast hopping” that enables long range plectoneme displacement.  These conclusions as to the nature of the supercoiling of DNA are extremely important for they help elucidate the dynamics of a process that is fundamental to the nature of DNA within living cells.