How the Influenza A Virus Enters the Host Cell

Influenza A Virus (IAV) has, of course, major implications in regards to public health.  Given the possibility of an influenza pandemic, it is vitally important to understand the mechanism of infection for this virus, since all viruses are unique in this regard. 

IAV is a single-stranded RNA virus that is subdivided into eight RNA molecules.  Each of these is precisely packaged into helical ribonucleoproteins (vRNPs).   These vRNPs carry a copy of a viral polymerase enzyme complex and the nucleoprotein (NP).   Within the structure of the virus, these vRNPs are arranged into a capsid-like complex that forms a shell around the vRNPs.   This is the state of the virus prior to its entry into the host cell.

As IAV gains entry into the host cell, it begins a process of uncoating initiated by the acidic conditions within the endosome – a membrane-bound structure providing transport within eukaryotic cells.  In the later stages of the process, the protein hemagglutunin (HA) – native to the virus – is activated and the IAV finally is transferred to the cell cytosol – cytoplasm .  Ultimately, the vRNPs gain access to the nucleus through the nuclear membrane.  It is at this final stage that the viral genome begins to co-opt the host cellular machinery to make more copies of the virus leading to the death of the host cell and the release of many more infectious agents into the surrounding tissue.

Dr. Indranil Banerjee and his colleagues at the Institute of Biochemistry, Eidgenossische Technische Hochschule in Zurich, Switzerland studied the process of capsid disassembly in detail, since it plays such a crucial role in IAV entry into the host cell.  They found that the virus exploits the host cell’s aggresome formation and disassembly mechanisms.  An aggresome is a cellular complex that is created in response to cell stress characterized by misfolded or unfolded proteins .

By helping to elucidate the underlying mechanisms responsible for host cell entry of IAV, this knowledge creates opportunities for the application of novel therapeutic approaches to combat infection.    

Ocean Acidification Disrupts Chemical Signaling In Marine Organisms

The relationship between the apparently inexorable increase in atmospheric carbon dioxide (CO2) as a direct result of human activity and the increasing acidity in the world’s oceans has been well documented. The current projected estimate is that at the current rate of atmospheric CO2 buildup, the pH in the oceans will drop from the current and historic range of 8.15 – 8.25 to ~ 7.8 or below by the end of the 21st century.

In addition to the disastrous impact of acidification upon the calcification that impedes coral and shell formation in the affected organisms, there is an additional side effect of this acidification that is worthy of attention. Many of the waterborne biologically-significant chemical signals, such as pheromones, that play essential roles in marine biology are disrupted by changes in the pH of the local marine environment. These signaling processes play a crucial role in important biological activities associated with mating, foraging, recruitment and alarm mechanisms.

The impact of this chemical disruption resides on two distinct levels. Increased acidity can affect the signaling compounds directly, and, secondly, impact their required interaction with specific receptor proteins designed to bind with the signaling molecule. This specific interaction between a signaling compound and its unique receptor represents the essential first step in producing the desired effect. This kind of interaction is found throughout metazoan biology.

The mechanism of this disruption caused by increased acidity within the marine environment can be attributed to changes in hydrogen bonding, electrostatic potential and hydrophilic and hydrophobic interactions that affect both ligands and their specific receptors. The types of organic compounds that are so affected include pheromones, nucleosides, thiols (sulfur-based compounds) organic acids and others.

The critical behavioral patterns that suffer from continued acidification of the oceans include sexual reproduction, recognition of the presence of predators, fertilization, larval settlement and many others. Unfortunately, the rate of acidification exceeds the ability of evolutionary mechanisms to respond to the kinds of changes described. This kind of impact of the increase of greenhouse gases within the natural environment needs further study, for the implications can prove to be devastating.

Epigenetics

Epigenetics is the study of the changes in phenotype brought about by modification of genetic expression rather than through changes in the actual structural information found within the DNA i.e. genetic mutations.

Although the individual organisms within a species share the same essential blueprint imbedded within the DNA, they express individual phenotypes.  In addition, complex traits and diseases cannot be fully explained via differences in genotype.  This suggests that developmental and environmental factors that are unique to the individual play an important role in determining the terminal phenotype.

The kinds of chemical modifications that are associated with epigenetics are DNA methylation and histone modification.  Histones are the family proteins that are intimately associated with DNA and play an important role in genetic expression.  Other factors that have been implicated in epigenetics are nonocoding RNAs and nucleosome location.

Since much current genetic research is focused on the role of epigenetics in determining phenotypic characteristics, there has been considerable confusion as to what constitutes epigenetics.  An epigenetic system needs to meet the following criteria:

• Heritable
• Self-perpetuating
• Reversible.

Prions – infectious proteins – meet these criteria since they perpetuate themselves through altered protein folding states and may, in fact, serve as indicators of environmental stressors.  Prions certainly alter phenotype as exemplified by the diseases they produce – Creutzfeldt-Jakob disease (CJD) being an example.

Some metazoans – metazoans encompass all animals advanced enough to have differentiated tissue - undergo genome-wide reprogramming of DNA methylation and histone modifications during gametogenesis and embryogenesis as a way of clearing those epigenetic changes that were introduced by environmental factors during the life of the individual.  Furthermore, there is evidence that small noncoding RNAs may serve as tags for marking deleterious sequences within the DNA. This Reprogramming may play a critical role in cell differentiation, and has been linked to pluripotency in both gametes and zygotes.

The field of epigenetics is undergoing rapid expansion; the implication of the critical role epigenetic processes play in the development of the individual is just beginning to be understood.

Implications of the Continually Growing Accumulation of Microplastics in the World’s Oceans

In an article appearing in the journal Science, authored by Kara Lavender Law of the Department of Oceanography at Woods Hole, Massachusetts and Richard C. Thompson of the School of Marine Science and Engineering at Plymouth University UK, attention is drawn to microplastics in the world's oceans. 

Although the focus of the pollution of the marine environment with plastics is usually on the unsightly appearance of this detritus, there is now growing concern among the scientific community of the presence of so-called, “microplastics” – particles of plastic so small as to be essentially undetectable by the eye.  Microplastics have been used to describe particles smaller than 5 mm in diameter (where 5 mm = .197 inches).  This particular population of marine pollutants is ever-growing due to the ineluctable degradation of plastic pollutants to microplastic-sized particles. 

One of the chief environmentally-based concerns is focused on the fact that particles of this size are readily ingested by organisms as small as zooplankton – organisms that play a crucial role in the marine food chain. The sources for microplastics in the marine ecosystem are manifold including –

·         Degradation of larger items entering rivers through runoff, tides, wind and catastrophic events such as tsunamis, hurricanes and earthquakes

·         Cargo lost at sea and other debris originating from on board ocean vessels

·         Microplastic-size particles such as cosmetic beads and clothing fibers that on account of their size can readily pass through waste water treatment facilities.

Once in the oceans these particles are passively transported by many and diverse factors.  They are found ubiquitously in coastal sediments around the world and, as stated previously, are readily ingested by many types of marine organisms including mussels that can retain these particles long after ingestion.  The impact of the presence of these particles on the biology of the organisms that ingest them is not clearly understood.

One of the more disturbing properties of microplastics is their propensity to adsorb environmentally harmful chemicals such as dichlorodiphenyl-trichloromethane (DDT) and polychlorinated biphenyls (PCBs) on their surface and consequently passively concentrate these dangerous substances.

Although the real risk of the presence of microplastics upon the health of the marine ecosystem is exceedingly difficult to ascertain, it is certainly worthy of further study.

A Possible Relationship Between Preeclampsia and Proteins

Approximately 5% to 10% of pregnant women worldwide suffer from preeclampsia.   This is a condition in which there is a sudden and precipitous rise in the pregnant woman’s blood pressure.   In many cases, if the baby isn’t delivered immediately, the mother may die, for the full-blown development of eclampsia can lead to seizures and severe hemorrhaging.  This is especially problematic In low-resource countries that do not have access to the sophisticated equipment required to sustain the life of premature infants.  In fact, the death toll from this condition worldwide is estimated to be 76,000.

The etiology of this disease remains an enigma.  Some of the suggested causes include abnormalities in the immune system’s tolerance of the presence of the fetus, abnormalities in the development of the placenta or dietary factors. 

In spite of the apparent mysterious nature of this syndrome, there is a revealing aspect to its presentation.  It has recently been shown that preeclampsia is marked by the appearance of misfolded and clumped proteins.  Interestingly, among the proteins implicated is amyloid precursor protein – the same protein that is implicated in Alzheimer’s disease.   There is to date not enough evidence to unambiguously describe preeclampsia as a “misfolding” disease - It is also possible that the presence of misfolded proteins is a symptom rather than the cause.

Taking these data into account, Dr. Irina Buhimschi, an investigator from Nationwide Children’s Hospital and Ohio State University, decided to look for a diagnostic tool that would be a better predictor for this condition in pregnant women.   In a study involving 600 pregnant women, urine samples were taken and subsequently analyzed for the presence of misfolded proteins.   From this study, a simple test was devised using the dye Congo Red.  It was found that Congo Red binds to clumped and misfolded proteins producing a distinctive red color.  It was shown that this test has an accuracy of 80% or higher in indicating the presence of preeclampsia.

This is a very important discovery especially in regards to its worldwide application, for it is a very inexpensive and simple procedure that has the potential to save countless lives especially in low-resource environments.

In Search of New Classes of Antibiotics

Over the history of medicine, the development of antibiotics (1930 – 1980) to combat virulent and dangerous infections has saved countless lives and helped avoid the onset of dangerous pandemics.  The use of these antibiotics has been of immense value in increasing the longevity of human populations.

Antibiotics currently fit into five classes as described in the following table –

Class	Mode of Action	Example
Β-lactam	Inhibits bacterial cell wall biosynthesis	Penicillin
Aminoglycoside	Inhibits protein synthesis in Gram-negative bacteria  such as Streptomyces griseus	Neomycin
Macrolide	Inhibits protein synthesis in Gram-positive bacteria such as Streptococcus pneumoniae by preferentially binding to the  50S component of the bacterial ribosome	Erythromycin
Tetracycline	Inhbits protein synthesis by preferentially binding to the  30S component of the bacterial ribosome	Tetracycline
Fluoroquinolone	Irreversibly binds to and inactivates key enzymes that maintain bacterial DNA	Norfloxacin

Note: Antibiotics are of no use in treating viral infections since the biology of the virus is markedly different than that of bacterial agents.

However, no new classes of antibiotics have been developed since 1980 and the overuse of the standard antibiotics has led to the insidious development of antibiotic –resistant strains of disease like tuberculosis (TB) and gonorrhea.  From a public health perspective, it is of enormous importance to encourage the development of new classes of antibiotics with unique modes of action.

Nature of the Resistance of Flavivirus Infection to Host Cell Defenses

Flaviviruses (FVs) represent a family of viral pathogens responsible for human life-threatening diseases such as Dengue Fever, West Nile, Yellow Fever and Japanese Encephalitis.   The infectious agent within this family of viruses is single-stranded RNA.  During the process of infection (through arthropod vectors), the viral genome (gRNA) is successfully replicated and  subgenomic flaviviral  RNAs (sfRNAs) are also produced.  In animal studies, it has been demonstrated that these sfRNAs are an integral part of the disease process.  It is interesting to note that these sfRNAs are produced as a result of the incomplete degradation of gRNA by the host-derived exonuclease Xm1 – an enzyme that is a part of the host cell defense against infection.  In this scenario, host cell defenses inadvertently play a crucial role in producing disease.

This resistance to complete degradation of gRNA by Xm1 has been shown to be due to specific RNA sequences that are referred to as Xm1-resistant RNAs (xrRNAs).  It is therefore of interest to more fully understand the molecular structure of xrRNAs and, therefore, elucidate the nature of the resistance to the action of Xm1.

Dr. Erich G. Chapman and his colleagues at the Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado at Denver focused their research efforts on establishing the unique and precise structural aspects of xrRNAs  that make them impervious  to Xm1-mediated degradation.

As a result of their extensive analysis they were able to show that the three-dimensional structure of xrRNAs consist of a “ringlike” conformation that prevents Xm1 from breaking down sfRNAs.  In addition, the investigators purposefully disrupted this structure and effectively prevented the formation of sfRNAs during infection.  This is an important finding; for, it helps clarify the mechanism of FV infections that impact many individuals throughout the world.