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Archive - Oct 23, 2015

Deadly Fish Virus Still Present in Wisconsin’s Lake Winnebago, UW-Madison-Led Study Shows; New Antibody Test Permits Rapid ID of Currently or Previously Infected Fish

In May 2007, hundreds of freshwater drum -- also known as sheepshead -- turned up dead in Lake Winnebago and nearby Little Lake Butte des Morts, both inland lakes near Oshkosh, Wisconsin. The fish were splotched with red and their eyes were swollen and bulging. The Wisconsin Department of Natural Resources (DNR) launched a quick response and, working with the Wisconsin Veterinary Diagnostic Laboratory (WVDL), quickly learned that a deadly virus was responsible: viral hemorrhagic septicemia virus (VHSv) (image). First detected in the U.S. among freshwater fish in 2005 -- including muskellunge, perch, and walleye -- VHSv had already caused mass fish die-offs in the Great Lakes and several regional waterways connected to them. The DNR subsequently encouraged anglers and boaters to adopt practices that have helped slow the spread of VHSv into other inland lakes in Wisconsin, but a new study led by Dr. Tony Goldberg, Professor of Epidemiology and Pathobiological Sciences at the University of Wisconsin-Madison (UW-Madison) School of Veterinary Medicine (SVM), shows that the virus is still circulating in Lake Winnebago. It also shows that some fish actually survive VHSv infection, but could be sources of future infections. The new study was published in an open-access article in the September 2015 issue of the Journal of Clinical Microbiology. The article is titled “Temporal Variation in Viral Hemorrhagic Septicemia Virus Antibodies in Freshwater Drum (Aplodinotus grunniens) Indicates Cyclic Transmission in Lake Winnebago, Wisconsin. "It's still possible to transmit the virus to fish in other lakes," says WVDL Virology Section Head Dr. Kathy Toohey-Kurth, a member of the research team and a clinical professor at the SVM.

Newly Discovered Component of Interferon Signaling Pathway (PARP9-DTX3L Complex) Interacts with STAT1 and Also Has E3 Ubiquitin Ligase Activity to Both Boost Interferon-Stimulated Gene Expression & Degrade Viral 3C Proteases with One-Two Punch

Many viral infections, such as the common cold, cause mild illnesses that the body's immune system eventually defeats. But when viruses cause severe disease, doctors have few options for effective treatment. Studying mice with a variety of viral infections, scientists at the Washington University School of Medicine in St. Louis (WUSL School of Medicine) have demonstrated a way to dial up the body's innate immune defenses, while simultaneously attacking a protein that many viruses rely on to replicate. The findings, published online on October 19, 2015 in Nature Immunology, reveal previously unknown weapons in the body's antiviral immune arsenal and provide guidelines for designing drugs that could be effective against a broad range of viruses. The new article is titled “PARP9-DTX3L Ubiquitin Ligase Targets Host Histone H2BJ and Viral 3C Protease to Enhance Interferon Signaling and Control Viral Infection.” The strategy involves enhancing the body's interferon signaling system, long understood to be a vital part of antiviral defenses. "We've discovered a new component of the interferon system," said senior author Michael J. Holtzman, M.D., the Selma and Herman Seldin Professor of Medicine. "It does something that other components don't do, and it works on both sides of the fence: It dials up the body's internal genes that fight viruses, and it attacks viral proteins directly." Dr. Holtzman and lead author Yong Zhang, Ph.D., an Instructor in Pulmonary Medicine WUSL School of Medicine, suspect that this one-two punch against the virus may explain the large difference in survival rates between control mice and mice genetically engineered to have increased signaling in their interferon systems.

GONE TODAY, HAIR TOMORROW: Topical Application of JAK Inhibitors Awakens Resting Hair Follicles; Treatment May Prove Effective in Restoring Hair Growth in Multiple Forms of Hair Loss, But Not Yet Shown

Inhibiting a family of enzymes inside hair follicles that are suspended in a resting state restores hair growth, a new study from researchers at Columbia University Medical Center (CUMC) has found. The research was published online on October 23, 2015 in an open-access article in Science Advances. The article is titled “Pharmacologic Inhibition of JAK-STAT Signaling Promotes Hair Growth.” In experiments carried out with mouse and human hair follicles, Angela M. Christiano (photo), Ph.D., and CUMC colleagues found that drugs that inhibit the Janus kinase (JAK) family of enzymes promote rapid and robust hair growth when applied direcly to the skin. [Note that the press release, for which a link is provided below, includes a video of Dr. Christiano explaining her group's new findings.] The study raises the possibility that drugs known as JAK inhibitors could be used to restore hair growth in multiple forms of hair loss such as that induced by male-pattern baldness, and additional types that occur when hair follicles are trapped in a resting state. Two JAK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for other indications. One is approved for the treatment of blood diseases (ruxolitinib) and the other for rheumatoid arthritis (tofacitinib). Both JAK inhibitors are currently being tested in clinical trials for the treatment of plaque psoriasis and alopecia areata, an autoimmune disease that causes hair loss. "What we've found is promising, though we haven't yet shown it is effective for male-pattern baldness," said Dr. Christiano. "More work needs to be done to test formulations of JAK inhibitors specially made for the scalp to determine whether they can induce hair growth in humans." Dr.

Banana-Derived Lectin Drug (BanLec) Is Genetically Re-Engineered to Eliminate Side Effects; May Combat Wide Range of Viruses; Therapeutic Molecule Reads “Sugar Code” on Viruses & Cells

A banana a day may not keep the doctor away, but a substance originally found in bananas and carefully re-engineered by scientists could someday fight off a wide range of viruses, new research suggests. And the process used to create the virus-fighting form of the molecule may help scientists develop even more drugs, by harnessing the "sugar code" that our cells use to communicate. That code gets hijacked by viruses and other invaders. The new research focuses on a protein called banana lectin, or BanLec, that "reads" the sugars present on the outside of both viruses and cells. Five years ago, scientists showed that BanLec could keep the virus that causes AIDS from getting into cells, but the drug also caused side-effects that limited its potential use. Now, in a new paper published in the October 22, 2015 issue of Cell, an international team of scientists reports how they have created a new form of BanLec that still fights viruses in mice, but does not cause irritation and unwanted inflammation.” In the new work, researchers succeeded in peeling apart these two side-effects by carefully studying the molecule in many ways, and pinpointing the tiny part that triggered these side effects. Then, they engineered a new version of BanLec, called H84T, by slightly changing the gene that acts as the instruction manual for building it. The result is a form of BanLec that worked against the viruses that cause AIDS, hepatitis C, and influenza in tests in tissue and blood samples, without causing inflammation. The researchers also showed that H84T BanLec protected mice from getting infected by flu virus. The new Cell article is titled “Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity.

Exosome Release by Leismania Parasite in Vector Sand Fly’s Gut Is Key to Protozoan's Infectious Life Cycle; Exosomes & Leismania Parasites Are Both Transmitted When Fly Takes Blood Meal; Exosomes Enhance Parasite Pathogenicity

A team of international scientists led by Dr. Martin Olivier from the Research Institute of the McGill University Health Centre (RI-MUHC) has discovered an important mechanism underlying the pathogenicity of leishmaniasis, a deadly parasitic disease caused by protozoans of the Leishmania genus that are transmitted by to humans by sandfly bites. The disease affects over 12 million people worldwide, and more than 1.3 million new cases are reported every year. In the new study, published online on October 22, 2015 in an open-access article in Cell Reports, the researchers describe how sub-cellular vesicles known as exosomes, boost the process by which the Leishmania parasite infects humans and other mammals. These findings could lead to the development of new potential vaccine targets and diagnostic tools for leishmaniasis and other parasitic diseases. The article is titled “Exosome Secretion by the Parasitic Protozoan Leishmania within the Sand Fly Midgut.” “Our study reports the first observation that a pathogen within its insect vector can release extracellular vesicles or exosomes that are an integral part of the parasite's infectious life cycle,'' states the study's lead author Dr. Olivier, a researcher from the Infectious Diseases and Immunity in Global Health Program of the RI-MUHC and a full Professor of Medicine at McGill University. "This means that any bacteria and parasites transmitted via insect blood meals could use a similar strategy to extend their successful infection.'' Exosomes are small, cell-derived vesicles that are present in all biological fluids, including blood, urine, saliva, etc. Exosomes have been the focus of numerous studies, particularly due to their apparent involvement in communication between cells, especially immune and tumor cells.

COVER STORY OF NOVEMBER JOURNAL OF VIROLOGY: Lethal Herpes Virus of Tortoises Has Newly-Discovered Seventh Distinct Herpes Genome Structure; Potential Vaccine Being Worked On

An inspired intuition of Frédéric Gandar, a Ph.D. student at the University of Liege in Belgium, and of his thesis supervisor Alain Vanderplasschen, Ph.D., to focus on a research topic that has rarely been explored in the scientific world, has paid major dividends. The study of Testudinid herpes virus 3 (TeHV-3), a herpes virus causing high mortality rates in several protected species of tortoises (including Hermann’s tortoise--image), has resulted in several significant discoveries and has been published as the cover article of the November 2015 issue of the prestigious Journal of Virology (JVI). This JVI cover article is titled “The Genome of a Tortoise Herpesvirus (Testudinid Herpesvirus 3) Has a Novel Structure and Contains a Large Region That Is Not Required for Replication In Vitro or Virulence In Vivo.” Up to the present, the approximately 250 herpes viruses that have been studied – these are found in oysters, as well as in humans – have been divided into six distinct genomic structures. But when Gandar and Dr. Vanderplasschen analyzed Testudinid herpes virus 3, the could not believe their eyes. This virus had an entirely new herpes virus genome structure. This would be the seventh known. The researchers are currently working on a vaccine against this disease that is decimating tortoise species, many of which are endangered. Dr. Vanderplasschen, an immunology and vaccinology researcher at the Faculty of Veterinary Medicine of the University of Liege, admits that nobody in industry would be likely to invest in this research. The reality is that the death of tortoises is not likely to be a source of concern for many people. This subject area also does not seem financially interesting to pharmaceutical companies, so they are not likely to be interested in investing. Fortunately for Gandar, Dr.

Landmark Clinical Trial Begins for Promising Anti-Sense Gene-Silencing Drug to Block Production of Mutant Huntingtin Protein That Causes Huntington’s Disease; Drug Developed by Isis Pharmaceuticals & Roche

On October 19, 2015, it was announced that patients in London are being dosed for the first time with an innovative new experimental drug for Huntington’s disease. This possible clinical breakthrough could be one of the most important developments since the gene for Huntington’s disease was discovered in 1993. The clinical trial of the revolutionary new “gene-silencing” treatment is being led by scientists at the University College London’s (UCL’s) Institute of Neurology. Huntington’s is a deadly degenerative brain disease that strikes in the prime of life. It kills brain cells, slowly draining patients of their movement control, personality, and thinking skills. It is one of the most common genetic brain diseases and it devastates entire families. Everyone with the mutated gene for the disease will fall ill with Huntington’s disease at some point. The disease is dominantly inherited and there is currently no cure and there is also no treatment that can prevent it or slow it down. The new drug being tested is called ISIS-HTTRx and it targets the root cause of the disease, a toxic protein called mutant huntingtin (HTT), which is coded for by a faulty gene (mutant HTT gene) in the patients’ brain cells. The drug is administered directly into the fluid that surrounds the brain and spinal cord at the base of the patients’ spine, and from there the drug migrates to the brain. In Huntington’s patients, the faulty HTT gene codes for messenger molecules, called messenger RNA, that trigger the production of mutant huntingtin protein the brain. But the drug is designed to bind with the messenger RNA molecules coded for by the faulty HTT gene, forcing the cells to dispose of them instead of the mRNA churning out the toxic protein.

Biomarker of Chronic Inflammation (GlycA) May Predict Risk of Premature Death Due to Severe Infections for Apparently Healthy Individuals

A single blood test could reveal whether an otherwise healthy person is unusually likely to die of pneumonia or sepsis within the next 14 years. Based on an analysis of 10,000 individuals, researchers have identified a molecular byproduct of inflammation, called GlycA (glycoprotein acetylation), which seems to predict premature death due to infections. The findings, published online on October 22, 2015 in an open-access article in Cell Systems, suggest that high GlycA levels in the blood indicate a state of chronic inflammation that may arise from low-level chronic infection or an overactive immune response. That inflammation damages the body, which likely renders individuals more susceptible to severe infections. The article is titled “The Biomarker GlycA Is Associated with Chronic Inflammation and Predicts Long-Term Risk of Severe Infection.” "As biomedical researchers, we want to help people, and there are few more important things I can think of than identifying apparently healthy individuals who might actually be at increased risk of disease and death," said co-senior author Dr. Michael Inouye, of the University of Melbourne, in Australia. "We want to short-circuit that risk, and to do that we need to understand what this blood biomarker of disease risk is actually telling us." Specific study findings outlined in the article abstract were that elevated GlycA was stable within individuals for up to 10 years, GlycA marked the levels of myriad inflammatory cytokines in the circulation, a gene network enriched for neutrophil functions was associated with GlycA, and GlycA strongly predicted risk of future hospitalization and death from infection. Dr.