Long Term Effects of Measles Infection on the Immune System

It is a well-established that contraction of measles has a lasting impact on the immune system predisposing the individuals affected to opportunistic infections.  The period of vulnerability was thought to last for months.  In fact, it has recently been shown that this deleterious impact on the host’s immune system can persist for over 2 to 3 years.  This is of particular concern to public health professionals especially in those parts of the world where the measles immunization regimen is poorly administered or in those regions where there is a complete lack of infrastructure for the delivery of health care.  Public health data shows that wherever mass measles immunizations are employed childhood mortality is lowered by 30 to 50% in so-called resource-poor countries and up to 90% for impoverished populations.

It has been of interest to determine the mechanistic explanation for this apparent lost in immune-competency in individuals infected by the measles virus.  The suspicion has been that measles infection results in the loss of the host’s immune system memory-cell population – a condition referred to as “immune amnesia.”

Dr. Michael J. Mina and his colleagues at the Department of Ecology and Evolutionary Biology at Princeton University, Princeton NJ were able to confirm through epidemiological data that, in fact, measles infection leads to the ablation of those T and B lymphocytes responsible for immunological memory thereby leaving patients susceptible to opportunistic infections.  Children in this group are particularly prone to increased mortality in this setting.

In addition, the data also unambiguously demonstrated the efficacy of measles vaccination in preventing potentially lethal opportunistic infections that would otherwise spread through susceptible populations impacted by uncontrolled measles infections.  These finding are of particular interest in terms of improving public health on a global basis.

Dermal Adipocytes Involved in the Immune Response against Staphylococcus Infections

There has been some evidence in the scientific literature that adipocytes – cells whose specialized function is the storage of fat – play an immunological role.  Since microbial infection immediately results in the rapid growth of the infectious agent, it is essential that the host tissue mount an immediate immunological defense.  Part of this innate defense involves the mobilization of host cells from the local environment such as epidermal cells, mast cells and locally resident leukocytes – white cells found in the peripheral blood circulation.  This line of defense is especially important during the lag phase before the recruitment of neutrophils and monocytes.  The production of antimicrobial peptides (AMPs) by locally available cells and leukocytes is critical during the initial stage of infection.

In an effort to further elucidate the mechanism of early immunological responses to infection, Dr. Ling-Juan Zhang and fellow researchers from the Division of Dermatology at the University of California in San Diego, examined in detail the initial stages of infection by Staphylococcus aureus - a microorganism responsible for serious skin and soft tissue infections that often results in systemic as well as local disease.  From these studies, they discovered some interesting findings.

What these investigators discovered, using the mouse animal model, was that increased cellular expansion of the subcutaneous adipose layer consisting of adipocytes accompanied infection with Staphylococcus aureus.   Furthermore, these adipocytes were responsible for the production of a potent AMP referred to as cathelicidin.  As further evidence that adipocytes had an immunological role in defending against infection, mice that possessed adipocytes that lacked the ability to produce cathelicidin were unable to inhibit bacterial infection.   Finally, it was also demonstrated that human adipocytes also were responsible for the production of cathelicidin.

Clarifying the role of adipocytes in the initial immunological response to infection is of great interest.  A full understanding of this mechanism may prove to be of immense therapeutic value in the treatment of infection by Staphylococcus aureus. 

The Role of Telomerase Activity in Urothelial Cancer

Telomerase is an enzyme whose activity within a cell leads to cell immortality due to repeated cell divisions.   The telomerase enzyme is highly active in embryonic cells and in stem cells where uninterrupted cell divisions are requisite for the role of these cells in the growth and development of the individual organism.    In addition, telomerase activity is a significant factor in cancer – its activity has been shown to be up-regulated in over 85% of cancers.  However, there is no detectable telomerase activity in most somatic – body – cells.  This lack of activity is due to the suppressed production of telomerase reverse transcriptase (TERT).  It has been suggested that mutations associated with TERT reactivation may be the, “most prevalent of all noncoding mutations in cancer.”

The question, of course, arises as to what is the cellular event that turns on telomerase activity in cancerous cells.  Due to exhaustive genetic analysis, there is evidence of point mutations in the TERT gene promoter in many cancer types including urothelial cancer (UC) – UC ranks five in the number of cancer cases reported in the Western world.  However, it remained unclear as to whether any of these mutations actually results in the reactivation of telomerase.

Dr. Sumit Borah from Howard Hughes Medical Institute at the University of Colorado BioFrontiers Institute in Boulder Colorado and collaborators from other institutions have done genetic studies on cell lines from 23 different UC patients.  They have clearly shown a correlation between these mutations and higher levels of TERT messenger – mRNA -, TERT protein and, most importantly, telomerase enzymatic activity.   Furthermore this group of investigators has established that elevated levels of TERT m-RNA expression is strongly associated with reduced survival in two independent UC patient studies.

These findings are highly significant; because they further elucidate the underlying genetic mechanisms that can transform a normal cell into a cancerous one. 

How the Ebola Virus Gains Entry into its Target Cell

Many viruses that have been studied require a specific cell surface receptor in order to gain entry to their target cell(s).  To this date, no specific cell surface receptor has been identified for the Ebola virus.   The Ebola virus is responsible for a highly infectious disease referred to as hemorrhagic fever in humans.  However, important strides have been made in understanding the mechanism of Ebola virus infection.

Once the Ebola virus successfully binds specifically to its host cell, it is engulfed by a process known as micropinocytosis that encapsulates the virus in a cell organelle referred to as endosome – a membrane-bound vesicle.  While within this environment, the virus’ surface glycoproteins are cleaved through the action of a protease (an enzyme that degrades proteins).

The process by which the virus is ultimately released from the endosome into the intracellular environment remains to be completely characterized.  However Dr. Yasuteru Sakurai and his colleagues from the Texas Biomedical Research Institute in San Antonio Texas have elucidated an important step in this process.  Through exhaustive and painstaking studies they have shown that endosomal calcium channels – two-pore channels (TPCs) are necessary for the release of the Ebola virus from the endosome that holds it.

More importantly, from a therapeutic standpoint, the investigators used a number of research techniques to disrupt TPC function including gene knockout – where the gene responsible for the production of TPC protein is rendered dysfunctional  - and were able to effectively disrupt virus trafficking and, thereby, prevent infection.  Finally the use of Tetrandrine -  a calcium channel blocker possessing anti-inflammatory, immunologic and antiallergenic effects - inhibited infection of human macrophages; these cells have been shown to be the primary target of the Ebola virus in an in-vitro setting.

These are important findings for a number of reasons.  They demonstrate that TPC-related proteins play an essential role in the Ebola virus infection process.  In addition, their preliminary results using Tetrandrine illustrate how this information may be used to develop effective strategies against hemorrhagic fever. 

Revolutionary Advances in Genomic Engineering

The area of study encompassed by genomic engineering has made so many technological advances that the modification of genomes – including the human genome – has rapidly come within the reach of those adequately trained in the techniques and methodologies of molecular biology.

There have been two extraordinary technological advances in the field of molecular biology that have made the ability to modify specific genes a reality.  First of all, the complete sequencing of the human genome in 2003 has made it possible to identify the genes implicated in many cellular and disease processes.  Secondly, the use of cluster regularly interspaced short palindromic repeats (CRISPRs) together with Cas9 has made it possible to specifically engineer the modification of literally any targeted gene.   Cas genes code for proteins that are directly related to CRISPR activity.

The CRISPR-Cas9 system was discovered in prokaryotic cells, bacteria for example.  It has been shown that this system provides protection from foreign genetic elements such as plasmids and phages- phages are viruses that target prokaryotic cells - that often attack prokaryotic cells.  This system has been likened to acquired immunity found in more complex organisms such as human.

CRISPRs are found in approximately 40% of sequenced bacteria genomes.  CRISPRs are, in fact, composed of segments of prokaryotic DNA made up of short repetitions of base sequences followed by segments of so-called, "spacer DNA."   These spacer segments seem to result from the cell’s previous exposure to an invading organism and serve as a template for the production of RNA transcription products that interact with Cas gene – related proteins in a system designed to inactivate invading phages or plasmids.

Since 2013, the CRISPR-Cas9 system has been adapted for use in the specific editing of genes.  When a specifically engineered CRISPR-Cas9 system is introduced into a host mammalian cell such as human it can alter a target gene in a very specific way.  This was amply demonstrated when researches at MIT effectively used this approach to effectively cure mice of a rare genetic liver disorder.   

This is such a powerful technique carrying with it such profound implications for the future of genetic engineering that in January of 2015 a group of those scientists intimately associated with these studies met in Napa, California at the Innovative Genomics Initiative (IGI) Forum on Bioethics to discuss the scientific, medical, legal and ethical implications of their work.

A Possible New Treatment Option for Patients with Acute Myeloid Leukemia (AML)

AML is the most common form of adult leukemia accounting for some twenty-five percent of adult patients with leukemia.  The standard protocol for treatment involves a shot-gun approach using non- selective chemotherapy to induce successful remission.   Although this clinical methodology has shown to be effective for most patients, other avenues of treatment are needed for those who prove refractory to the standard approach and to those patients who cannot endure high dose chemotherapy.

The biology of cancer cells has progressed dramatically since the complete sequencing of the human genome.  As a result, it has been clearly established that cancer is the result of genetic mutations that involve either/or those genes referred to as proto-oncogenes involved in normal cell division and tumor suppressor genes involved in the normal suppression of cell division The new era of cancer treatment involves the development of methodologies to specifically target these mutations either by developing specialized drugs to target these changes or mobilizing the immune system through targeted immunotherapy.

Dr. Anuradha Illendula and his colleagues from the Department of Molecular Physiology and Biological Physics at the University of Virginia in Charlottesville, using the mouse animal model,  have developed a small molecule referred to as AI-10-49 that effectively binds to a transcription factor subunit referred to as core bind factor β (CBFβ).

Molecular Structure of AI-10-49 -

  

   

These investigators were able to show that the use of A!-10-49 not only prolonged the survival of mice transplanted with leukemic cells without any observable toxic effects but was also able to inhibit the proliferation of a sub-type of human AML cells grown in culture.  These findings are of particular importance for this approach may serves as a model for development of drugs specifically targeting "uninhibited cell division resulting from genetically altered transcription factor function."

Extreme Winter Weather in the Lower Latitudes and Warming of the Arctic Ocean

For the past two winters, the continental United States has experienced harsh weather conditions with unusual amounts of precipitation in the form of snow.  Meteorologists have established that arctic-born weather has been directed to the Northeastern, Midwestern and even Southeastern continental United States as a result of a shift in the direction, depth and pattern of the jet stream described as “wavy.”

Dr. Jennifer Francis, a climatologist, and her colleagues at Rutgers University in collaboration with Dr. Steven Vavrus from the University of Wisconsin at Madison have published data establishing a connection between warming in the Arctic Ocean and the extreme winter weather in the lower latitudes. 

  

Ordinarily sea ice exerts an influence on global temperature by its ability to reflect back solar radiation into space on account of its whiteness through what is referred to as the albedo effect.  However, as a result of the gradual warming of the planet due to the accumulation of greenhouse gases, the temperature in the Arctic has increased at twice the rate as the rest of the earth.   This increased temperature is accelerating the melting of Artic sea ice.  As this sea ice melts, it reduces the albedo effect and results in increased warming and therefore the further melting of sea ice.  This cycle of increased warming is referred to as negative feedback.

 

It seems that this warming trend in the Arctic has disrupted normal climate conditions in the following way - cold air that is usually contained within the Arctic region by so-called “polar vortex winds” has moved southward into the mid-latitudes as a result of the high pressure that is a direct consequence of the enhanced melting of the sea ice.   Accordingly, the lower latitudes have experienced unusually extreme winter weather.

If this explanation is proven to be correct for seasonal aberrations in weather in the lower latitudes, then these changes would suggest a permanent alteration in weather patterns for the regions impacted.