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. 

Modeling the Human Brain

The human brain is a highly complex organ that is responsible for remarkably sophisticated behavior.  In order to more fully elucidate the relationship between brain structure and function, investigators involved with attempting to understand the neuroscience of brain systems especially concerning  cognition are testing large-scale simulations of brain structure and function.  This is a particularly daunting challenge.

 

For example, there is the so-called, "Blue Brain Project" that involves the simulation of about one million neurons arranged in cortical columns.  The design of this model incorporates significant biological detail that reflects known spatial relationships and neuronal connectivity data.  Another example of a human brain-modeling project involving some 100 billion neurons has also been reported. 

 

A limitation to these approaches has been that although they seek to model the complexity of brain organization they do not address the relationship between brain structure and brain function, i.e. human behavior.  Dr. Chris Eliasmith and colleagues from the Centre for Theoretical Neuroscience from the University of Waterloo, Waterloo, Ontario in Canada has attempted examine this relationship.  To do so, they have created a neuron model of 2.5 million neurons that focuses on the relationship between neuronal structure in the brain and the resulting human behavior.

 

Within this model, the inputs are represented by images of handwritten or typed characters.  All the outputs are the movement of an "arm" that possesses appropriate physical properties such as mass, length and inertia.  The designers of this model refer to it as "Spaun" – an acronym for Semantic Pointer Architecture Unified Network.  Incorporated within Spaun are typical brain-related functions such as image recognition, serial working memory and learning.  Furthermore, the eight tasks that Spaun performs are:

·         Copy drawing

·         Image recognition

·         So-called three-armed bandit task in which it is required to determine which of the three possible choices results in the statistically greatest reward

·         Successful reproduction of a list of any length

·         Counting

·         Responding to questions

·         Ability to create variables

·         Simple reasoning.

 

The model is so structured that it represents the anatomical structure of the human brain as established by current brain research.  Although a more detailed examination of the theoretical basis for this model is beyond the scope of this report, this kind of intensive work indicates the degree to which the apparent enigmas associated with high-order brain function are being methodically unraveled.

The Immunological Mechanism Behind the Battle to Contain Chronic Viral Infection

The lifelong immunity to viral infection involves a multistep process:

·         The maintenance of so-called long-lived memory lymphocytes – lymphocytes are circulating white blood cells that play a critical role in the immune response

·         Upon reinfection, these memory lymphocytes then generate large numbers of short-lived cells that actively combat infection

·         Lastly, the pool of long-lived memory cells is replenished for use in future assaults.

 

There are a number of viral infections in which the virus following active infection can become quiescent and actually be incorporated in the host DNA and subsequently be reactivated under the appropriate conditions.  An example of a low-level virus of this type is cytomegalovirus (CMV) – a herpes virus that can reside within a host for a lifetime.  To combat such an infection, a balance is achieved between the maintenance of a pool of long-lived immunological memory cells and short-lived lymphocytes designed to fight the infection as described above.  A balance of these modalities confers lifelong immunity to the individual.

 

The issue becomes more problematic in the case of persistent infections with high viral loads such as the human immunodeficiency virus (HIV) that causes AIDS.  In such infections, the ability to maintain a consistent pool of long-term memory cells can be compromised on account of the necessity to maintain a persistently high level of short-term lymphocytes.  In the case of AIDS it is believed that a constantly elevated population of CD8+ lymphocytes (CD8 is a particular protein that resides on the cell surface of these cells) that are involved in combatting the HIV infections leads to a decreased pool of memory cells and eventually results in the collapse of immunity towards HIV.

 

What is not clear is the actual mechanism that is responsible for this immunological imbalance in regard to chronic viral infections.  In attempt to elucidate this issue, Dr. Michael A. Paley and his colleagues at the Department of Microbiology and Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania worked with chronically infected mice as the animal model for their studies.  From their work, they discovered two unique subsets of CD8+ lymphocytes in response to chronic viral infection – one subset involved in the renewal of the CD8+ population and the other in differentiation.  Furthermore, they found that elimination of either of these subsets resulted in the organism's inability to control chronic infection.  These findings seem to suggest that an imbalance in differentiation and renewal may be ultimately responsible for the collapse of immunity in human patients suffering from chronic infection.

 

The clarification of this mechanism may help in the ultimate development of targeted therapies for chronic viral infections in humans.  

The Role of inflammation in Colorectal Cancer

Chronic inflammation has been implicated as playing an essential role in a number of human cancers including colorectal cancer (CRC).  Chronic inflammation is a condition in which the body's immune system's inflammatory response is turned on.  When the inflammatory response is prevalent in the intestines, powerful factors are secreted including: Interleukin-6 (IL-6), tumor necrosis factor (TNF-α), IL-23 and reactive oxygen species.  All these may act in consort to create a microenvironment that can lead to accelerated DNA damage in the intestinal epithelia and thereby increase the likelihood of leading to CRC as is demonstrated by the discovery of a colitis-associated CRC.

 

Furthermore, within the lumen of the colon, literally trillions of bacteria coexist in an environment referred to as the "microbiota."  These bacteria live in close proximity to the epithelial cells that line the colon.  From this information, the question naturally arises, "Do these bacteria, under the right conditions participate in some way with the cancer-causing process – carcinogenesis?"

 

In attempt to determine the answer to his question, Janelle C. Arthur and her colleagues at the Department of Medicine at the University of North Carolina at Chapel Hill studied the association of the microbiota, chronic inflammation and the onset of colon cancer in mice with a genetic susceptibility to colitis.  Their findings can be summarized in the following way:

 

·       Monocolonization  of the experimental animal's gut with Escherichia coli (E. coli) NC101 promoted the development of CRC in azomethane treated animals – azomethane is a potent carcinogen

·         Deletion of the particular strain of E-coli – polyketide synthase (pks+) strain known to have a deleterious impact on host genes, genotoxic, decrease the amount of invasive tumors

·         Pks+ E. coli are found in a significant percentage of human patients with inflammatory bowel disease and CRC.

 

These data demonstrate that within the scope of the mouse model, colitis, as an example of chronic inflammation in the gut, can promote CRC by altering the microbial composition of the intestinal microbiota.  In addition, these findings may have direct application to the understanding of the development of human CRC.

Iron and Good Health

There are many so-called "micronutrients" that are required in the human diet.  Many of these are metals including Sodium, Potassium, Zinc, Cobalt and Iron.  Iron plays a special role since it is a member of the transition state elements and can assume a number of different charged states; this attribute has made it quite useful as an essential cofactor in the function of many enzymes and oxygen transport systems not only in humans but also in many diverse life forms across the entire spectrum of living things.

 

On account of these properties, iron has been shown to play an important role in host-pathogen interactions during infections.  As a matter of fact, it has been clearly shown that a host's iron status can directly impact the degree and intensity of infection.  In one particular study involving Somalis who were iron-deficient, these individuals had a five-fold increase in various infections including  reactivation of preexisting malaria in relation to those individuals that were given iron supplements.  A degree of caution needs to be stressed in regards to the ingestion of iron supplements in that excessive intake can prove toxic.

 

A hormone, Hepcidin, present in humans has been shown to play a key role in the absorption of iron consumed in the diet and its subsequent distribution to many tissues throughout the body.  In addition, Hepcidin, a peptide hormone (peptides are small protein molecules), has antimicrobial properties.

 

Dr. Hal Drakesmith and his colleagues from the Molecular Immunology Group and Medical Research Council Human Immunology Unit at the Weatherall Institute of Molecular Medicine at the University of Oxford in Oxford, UK, have shown that the synthesis of Hepcidin is regulated by not only the levels of iron present in the body but also immunological status i.e. the presence of infectious agents.

 

Another aspect of iron regulatory mechanisms relates to the presence of unbound iron or heme – that is often released during infections – in the circulation.  Unbound iron can have a number of deleterious side effects:

·         It can provide an essential nutrient to an ongoing infection

·         It can generate harmful free radicals and result in tissue damage.

For these reasons, there are proteins present that can safely bind the unbound iron.  These proteins include transferrin, lactoferrin and ferritin for iron; haptoglobin for hemoglobin – the essential component for delivering oxygen to the tissues- and hemopexin for heme.  The antimicrobial properties of these iron carriers is supported by the observation that they inhibit the growth of certain bacteria in the laboratory and by the fact that lactoferrin is found in abundance in breast milk and is released from neutrophils – immunological cells that are involved in the body's first line of defense against infection.

 

These data strongly implicate iron status in the body with good health and the natural defense against infection.