Thursday, February 28, 2013

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. 

Wednesday, February 13, 2013

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. 

Thursday, February 7, 2013

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.