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.    

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. 

Chronic Myeloid Leukemia (CML) and a Remarkable Drug to Treat It.

Chronic Myeloid Leukemia impacts approximately 5000 people a year.  It is characterized by the uncontrolled growth of a subset of circulating white blood cells (WBC).  The onset of this disease correlates with a particular genetic abnormality that has been well categorized.  The change in the genetic material is demonstrated by the appearance of the so-called “Philadelphia” chromosome.  This chromosome results from the anomalous exchange of genes between chromosome 9 and chromosome 22 – the human genome possesses 23 pairs of chromosomes one pair of which contains the genes that determine human gender XX (female) and XY (male).  This genetic rearrangement results in the juxtaposition of two genes namely, BCR and ABL.  The resulting gene combination, BCR-ABL is responsible for the production of a novel gene product that contributes to uncontrolled cell growth i.e. CML.

The realization of this mechanism opened the possibility that if the activity of the deleterious protein product could be curtailed, a cure of CML could be envisioned.  This particular approach is known as molecular targeting, for it targets a particular molecular substance known to play a critical role in the development of disease – in this case, CML.

When it became clear that the “offending” protein was a member of a class of proteins referred to as kinase enzymes, Drs. Zimmerman and Buchdunger tested a plethora of possible drug candidates to see what compound could precisely target this enzyme without adversely affecting any other cellular processes.  Their work proved rewarding; they ultimately discovered the efficacy of a drug given the name, Gleevec (imatinib).

The results have been very impressive.  As reported in the Journal of the National Cancer Institute (JNCI), CML patients who have been treated with Gleevec have gone into complete remission after two years of treatment and have been shown to have survival rates similar to the general population.  According to a statement released by the journal, “This study offers the first evidence that a disseminated cancer, not amenable to surgery, can be controlled to the point of giving patients a normal life expectancy.”

These results are extraordinary, yet they point to the efficacy of the molecular targeting approach.  This methodology may prove applicable to other heretofore treatment-resistant diseases. 

Stimulants, Opiates and the Human Brain

Chemical stimulants such as cocaine and opiates such as morphine profoundly influence behavior through their interaction with and alteration of brain chemistry.  Members of the opiate family of compounds are known to markedly reduce the experience of pain.  Of particular interest in this regard is the neurotrophic factor, BDNF – a direct product of brain chemistry.  BDNF plays a very important role in maintaining so-called “neural plasticity.”  This plasticity represents an intrinsic ability of the human brain to alter neuronal pathways and synapses – the junctions between nerve cells that allow the passage of electrical signals through the nervous system – in response to changes in behavior and the environment especially in regard to bodily injury.  This is a highly adaptive function of the brain that is often seen in the victims of stroke – allowing individuals to compensate for brain damage.

BDNF has been shown to play a key role in the kind of neural and behavioral plasticity that is induced by the use of cocaine and other stimulants.  Furthermore, it has been demonstrated that the mode of action of BDNF in this regard is intimately connected with the mesolimbic dopamine (DA) system that represents a key reward circuit in the brain.  Dopamine is one of major neurotransmitters in the brain that is involved in many diverse brain functions.  It is the irreversible loss of dopamine-producing cells that results in the symptoms associated with Parkinson’s disease.  The net result of the interaction of BDNF with DA system is the promotion of further actions of stimulant drugs.

Dr. Ja Wook Koo and his colleagues at the Fishberg Department of Neuroscience and Friedman Brain Institute at the Mount Sinai School of Medicine in New York have implicated BDNF in the mode of action of the opiate drug, morphine and have helped elucidate the mechanism through which it works.  In contrast to stimulants, opiates exert their effect on the brain through the promotion of DA signaling by the inhibition of ϒ-aminobutyric acid (GABA) – an important neurotransmitter in the brain that plays a role in regulating neuronal excitability through an inhibitory pathway.  The investigators have clearly shown that BDNF is, in fact, a negative modulator of morphine action.

This is an important finding in that is helps elucidate the mechanisms involved  with  brain-associated adaptations within the reward circuitry that occur with the use of morphine – a drug that is widely used to treat severe chronic pain especially at the end of life. 

How the Paramyxovirus Evades Human Innate Immunity

Paramyxoviruses represent a class of single-stranded RNA viruses that include the measles, parainfluenza, Sendai and Nipah viruses.  The resulting infections associated with these viruses involve respiratory ailments, and ubiquitous childhood diseases.   Paramyxoviruses – associated diseases represent a significant public health concern especially among children and the elderly.   The major route for disease transmission is via respiration.   Although measles has decreased dramatically in the developed world due mainly to extensive vaccination programs, it continues to be problematic in Africa and Central and South America.

The human immune system is equipped with two tiers of defense against viral infections – the innate and adaptive systems.  The innate system represents the first line of defense.  Within this line of defense, the retinoic acid – inducible gene 1 (RIG -1) – like melanoma differentiation – associated protein 5 (MDA5) senses a broad spectrum of viruses in the form of their cytoplasmic viral RNAs and subsequently activates antiviral innate immunity.

 

Through the process of biological evolution, viruses have developed diverse mechanisms to evade the innate immune system.  It has been shown that Paramyxovirus, manages to effectively subvert this immunological defense mechanism.  How this is accomplished is poorly understood.  Dr. Carina Motz and colleagues at the Department of Biochemistry and Gene Center at Ludwig – Maximilians University in Munich, Germany have labored painstakingly to elucidate the mechanism of this evasion.

They were able to demonstrate that this class of viruses elaborates a protein product – Paramyxovirus V Protein – that is able to alter the configuration of the host MDA5 protein in such a way as to effectively inhibit its antiviral signaling function.  The end result of this interaction is a compromised first line of defense.

Such studies add significantly to the body of information that helps explain how certain types of virus infections lead to disease in spite of host defense mechanisms.  This information may prove to be invaluable in regards to potential cures and treatments of intractable ailments. 

How Did the Earth Get its Moon?

We, as inhabitants of planet Earth, take the presence of the Moon in the night sky for granted.  Yet, the evidence tells us that at one time in the Earth's 4 and ½ billion year history there was no satellite in Earth orbit.  The generally accepted explanation among astronomers and cosmologists is that at a time early in the Earth's history there was a collision between Earth and another large planet resulting in the ejection of massive amounts of material into Earth orbit forming a disk of debris.  It is further postulated that from this disk, the Moon was formed in a process not unlike the formation of the planets of our solar system around the sun.  This is referred to as the giant impact theory.

According to this paradigm, a low-velocity impact of a planetary body (impactor) roughly the size of Mars could produce an iron-poor debris disk with sufficient total mass and energy in the form of angular momentum – a measure of the rotation of a body that is the product of its inertia and angular velocity - to produce an iron-poor Moon.  In addition, this model also predicts that the debris disk would contain material primarily from the impactor's mantle.   This data is where the inconsistency lies; for, the Earth and Moon, in fact, share many similarities in regards to composition, including the isotopes of oxygen, chromium and titanium.  It is unlikely that any postulated impactor would share these similarities.

Dr. Robin M Canup from the Planetary Science Directorate at the Southwest Research Institute in Boulder, Colorado has proposed a solution to this apparent dilemma.  Canup has postulated through the use of sophisticated and computer-assisted simulations that if a larger-sized impactor than the one proposed in the giant impact theory was involved, then the resulting collision with Earth would produce a disk with the same composition as the Earth's mantle.  The actual size of the impactor used in these simulations was comparable in mass to the Earth.

This proposed scenario demonstrates just how chaotic and disruptive the environment of our solar system was during the early stages of its evolution.  The cosmos is, in fact, ever-changing in its past, its present and for the foreseeable future. 

Insights into the Mode of Action of the Human Cytomegalovirus

There is form of the human cytomegalovirus that is responsible for herpes – this virus is referred to as the herpesvirus human cytomegalovirus (HCMV).  This virus can have severe repercussions for infants and those individuals who are immune-compromised such as AIDS patients.  The entire HCMV genome was completely sequenced twenty years ago.  In spite of this accomplishment, the understanding of the complete array of proteins that are produced by this virus has not been fully elucidated.  This is because of the fact that although the genome is quite small – 240 kilobases (kb) – it has been estimated that there are between 165 and 252 open reading frames (ORFs).  An ORF is the part of a reading frame in the genome that contains no stop codons – stop codons terminate transcription.

A gene is defined as that part of the genome (DNA) that contains the information for the production of a protein product.  Transcription is the first step in the process that converts the information contained within the reading frame into what is referred to as messenger RNA (m-RNA).  It is the m-RNA that migrates to the highly specialized cell organelles, the ribosomes, where proteins are ultimately produced.  This phase is called translation.  It seems that the translation products of HCMV are far more complex than previously believed.

To help unravel this apparent mystery, Dr. Noam Stern-Ginossar and colleagues at the Department of Cellular and Molecular Pharmacology at Howard Hughes Medical Institute of California at San Francisco infected human foreskin fibroblasts (HFFs) with a clinical strain of HCMV.  They subsequently harvested cells 5, 24 and 72 hours post infection and analyzed the full range of translation protein products. 

As a result of this very intensive analysis, they were able to identify 751 translated ORFs - hundreds of which had not been identified before.  The explanation that best fits the results is that transcription involves the use of alternative start sites with the net effect being the production of multiple and distinct protein products.  This result was not anticipated by the investigators and demonstrates a level of complexity that far exceeded expectations.

This kind of work is significant in that it provides important insights into the full scope of the functional and antigenic – a measure of the capacity to produce an immune response – potential of HCMV.