Author Interviews, Infections, PLoS / 27.03.2016
Exploiting Pathway in Host Cells May Combat Emerging Viral Infections
MedicalResearch.com Interview with:
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Dr. Cameron Stewart[/caption]
Dr. Cameron Stewart PhD
Team Leader within the Emerging Infectious Diseases Program
CSIRO Biosecurity Flagship
Commonwealth Scientific and Industrial Research Organisation
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Stewart: Hendra and Nipah viruses (referred to jointly as henipaviruses) are deadly cousins of the more common mumps, measles, and respiratory syncytial viruses, all members of the paramyxovirus family. Henipavirus outbreaks are on the rise, but little is known about the viruses, partly because research has to be undertaken under extreme containment conditions. Our team performs research at the largest high containment facility in the Asia-Pacific region, the CSIRO Australian Animal Health Laboratory in Geelong, Australia.
To understand the henipavirus infection cycle and to identify targets for new antiviral therapies, we performed a genome-wide screen to identify the host molecules required by henipaviruses for infection. The host gene with the largest impact, called fibrillarin, codes for a protein present in the nucleolus. Inhibiting fibrillarin impaired henipavirus infection greater than 1,000-fold in human cells. We examined closely which step of the viral life cycle was blocked by interfering with fibrillarin function, and found it was required for the early synthesis of viral RNA. Results from our study suggest that fibrillarin could be targeted therapeutically to combat henipavirus infections. This research was undertaken by an international team of researchers from CSIRO, the Victorian Centre for Functional Genomics, Duke-NUS, the University of Georgia and the Centers for Disease Control and Prevention.
Dr. Cameron Stewart[/caption]
Dr. Cameron Stewart PhD
Team Leader within the Emerging Infectious Diseases Program
CSIRO Biosecurity Flagship
Commonwealth Scientific and Industrial Research Organisation
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Stewart: Hendra and Nipah viruses (referred to jointly as henipaviruses) are deadly cousins of the more common mumps, measles, and respiratory syncytial viruses, all members of the paramyxovirus family. Henipavirus outbreaks are on the rise, but little is known about the viruses, partly because research has to be undertaken under extreme containment conditions. Our team performs research at the largest high containment facility in the Asia-Pacific region, the CSIRO Australian Animal Health Laboratory in Geelong, Australia.
To understand the henipavirus infection cycle and to identify targets for new antiviral therapies, we performed a genome-wide screen to identify the host molecules required by henipaviruses for infection. The host gene with the largest impact, called fibrillarin, codes for a protein present in the nucleolus. Inhibiting fibrillarin impaired henipavirus infection greater than 1,000-fold in human cells. We examined closely which step of the viral life cycle was blocked by interfering with fibrillarin function, and found it was required for the early synthesis of viral RNA. Results from our study suggest that fibrillarin could be targeted therapeutically to combat henipavirus infections. This research was undertaken by an international team of researchers from CSIRO, the Victorian Centre for Functional Genomics, Duke-NUS, the University of Georgia and the Centers for Disease Control and Prevention.






Dr. Richard Deth[/caption]
MedicalResearch.com Interview with:
Dr. Richard Deth PhD
Professor of Pharmacology
Department of Pharmaceutical Sciences
Nova Southeastern University
Medical Research: What is the background for this study?
Dr. Deth: Vitamin B12 plays a crucial role in regulating and promoting methylation reactions (the attachment of a carbon atom to molecules), including DNA methylation. Recent research has identified methylation of DNA and consequential changes in gene expression as crucial factors in brain development, as well as in memory formation and maintenance of brain function during aging. More specifically, the cause(s) of neurodevelopmental disorders such as autism remain obscure, although numerous studies have demonstrated oxidative stress and low plasma levels of the antioxidant glutathione (GSH) in autism.
Medical Research: What are the main findings?
Dr. Deth: We found that brain levels of vitamin B12, especially the methylation-regulating form known as methylB12, decrease significantly with age, even though blood levels don’t show a similar decrease. Importantly, much lower levels of methylB12 were found in subjects with autism and schizophrenia compared to normal subjects of a similar age. Animal studies showed that impaired GSH formation is associated with decreased brain B12 levels.
Dr. Srivas Chennu[/caption]
Dr. Dai Fukumura[/caption]
MedicalResearch.com Interview with:
Dai Fukumura, M.D., Ph.D.
Joao Incio, M.D.
and Rakesh K. Jain, Ph.D
Edwin L. Steele Laboratory
Department of Radiation Oncology
Massachusetts General Hospital
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Fukumura: This study focused on pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, which accounts for almost 40,000 cancer death in the U.S. ever year. Half of those diagnosed with this form of pancreatic cancer are overweight or obese, and up to 80 percent have type 2 diabetes or are insulin resistant. Diabetic patients taking metformin – a commonly used generic medication for type 2 diabetes – are known to have a reduced risk of developing pancreatic cancer; and among patients who develop the tumor, those taking the drug may have a reduced risk of death. But prior to the current study the mechanism of metformin’s action against pancreatic cancer was unclear, and no potential biomarkers of response to metformin had been reported.
We have uncovered a novel mechanism behind the ability of the diabetes drug metformin to inhibit the progression of pancreatic cancer. Metformin decreases the inflammation and fibrosis characteristic of the most common form of pancreatic cancer. We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumor-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells that produce the extracellular matrix and by reprogramming immune cells to reduce inflammation. Our findings in cellular and animal models and in patient tumor samples also indicate that this beneficial effect may be most prevalent in overweight and obese patients, who appear to have tumors with increased fibrosis.
Dr. David Gallego Ortega PhD[/caption]
MedicalResearch.com Interview with:
David Gallego Ortega, PhD
Group Leader, Tumour Development Group Cancer Division
Garvan Institute of Medical Research
Conjoint Lecturer, St Vincent’s Clinical School, Faculty of Medicine, UNSW, Australia
National Breast Cancer Foundation and Cure Cancer Foundation Australia Fellow
Medical Research: What is the background for this study? What are the main findings?
Dr. Ortega: We have identified a protein that 'goes rogue’ in breast cancer. The protein, called Elf5, ‘tricks' the immune system producing inflammation so that the immune cells now help the breast cancer cells to spread throughout the body.
Cancer spread, or metastasis, is the ultimate cause of death of
Dr. Sandra Wilks[/caption]
MedicalResearch.com Interview with:
Dr Sandra A. Wilks PhD
Senior Research Fellow
IfLS Knowledge Mobilisation Fellow in Healthcare Technologies
Faculty of Natural and Environmental Science & Faculty of Health Sciences
Centre for Biological Sciences,
University of Southampton,
Southampton, UK
Medical Research: What is the background for this study? What are the main findings?
Dr. Wilks: The use of indwelling Foley urinary catheters for extended periods of time results in high risks of urinary tract infections (UTI) and catheter blockages. Blockages are often caused by the presence of Proteus mirabilis, a urease-producing bacterium which results in an increase of the urine pH and the development of crystalline biofilms. Biofilms develop when bacteria attach to a surface, forming a community structure, held together by extracellular polymeric substances (EPS). Once in a biofilm, bacteria exhibit high resistance to the action of antibiotics and are protected by other stress factors. The crystalline biofilms resulting from the presence of Proteus are highly complex environments and cause complete blockage of the catheter within days. Such blockages cause pain and trauma for patients, and result in high demands on healthcare resources.
In this study, we have used an advanced microscopy technique (episcopic differential interference contrast, EDIC microscopy developed by Best Scientific) to track the development of these crystalline encrustations on two commonly used catheter materials; silicone and hydrogel latex. We have identified four distinct stages to crystalline biofilm formation;
Dr. Camron Bryant[/caption]
MedicalResearch.com Interview with:
Camron D. Bryant, Ph.D.
Assistant Professor
Laboratory of Addiction Genetics
Department of Pharmacology and Experimental Therapeutics & Psychiatry
Boston University School of Medicine
Boston, MA 02118
Medical Research: What is the background for this study? What are the main findings?
Dr. Bryant: The addictions, including addiction to psychostimulants such as methamphetamine and cocaine, are heritable neuropsychiatric disorders. However, the genetic factors underlying these disorders are almost completely unknown. We used an unbiased, discovery-based genetic approach to fine map a novel candidate genetic factor influencing the acute stimulant response to methamphetamine in mice. We then directly validated the causal genetic factor using a gene editing approach. The gene - Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) - codes for an RNA binding protein that is involved in alternative splicing of hundreds of genes in the brain. Based on a genome-wide transcriptome analysis of differentially expressed genes within the striatum - a crucial brain region involved in the stimulant properties of amphetamines - we predict that Hnrnph1 is essential for proper neural development of the dopamine circuitry in the brain. These findings could have implications for understanding not only the addictions but also other neuropsychiatric disordersthat involve perturbations in the dopaminergic circuitry. (e.g., ADHD and schizophrenia) as well as neurodegenerative disorders such as Parkinson's disease.
Dr. McHugh[/caption]
MedicalResearch.com Interview with:
Leo McHugh, Ph.D.
Director, Bioinformatics
Immunexpress
Seattle, Washington
Medical Research: What is the background for this study? What are the main findings?
Dr. McHugh: Sepsis is the leading cause of child mortality in the world, and in developing countries kills more adults than breast cancer, prostate cancer and HIV combined. Approximately 30% of people admitted to ICU have sepsis, and up to 50% of these patients die. It’s a major cost burden also, costing the US health system $17 billion per year. The best way to reduce costs and improve patient outcomes is to detect sepsis early and with confidence, so that appropriate treatments can be applied. Each hour delay in the detection of sepsis has been reported to correspond to an 8% increase in mortality. So the need for a rapid and accurate diagnostic is recognized. Traditional methods rely on detection of the specific pathogen causing the infection, and these methods often take more than 24 hours, and find a pathogen in only 30% of clinically confirmed cases because they’re trying to detect a minuscule amount of pathogen or pathogenic product in the blood. Our approach was to use the host’s own immune system, which is highly tuned to respond to the presence of pathogens. Around 30% of all genes are dysregulated in sepsis, so there is a huge signal base to draw from. The trick with using multi marker host response is to pick out the specific combination of gene expression patterns that cover the broad range of patients that present with sepsis and who may present either early or late in the episode, thus with different gene activation patterns.
This paper describes a simple combination of such genes that can be used to detect sepsis and performs over the full range of patients irrespective of stage of infection or severity of infection. In it’s current format, the test is manual and takes 4-6 hours, and is a great advance on the current tools, however the methods we’ve used are specifically designed to meet requirements to port this assay onto a fully automated Point of Care platform that could deliver a result in under 90 minutes.
Dr. Melody Ding[/caption]
MedicalResearch.com Interview with:
Ding Ding (Melody), Ph.D., MPH
NHMRC Early Career Senior Research Fellow
Sydney University Postdoctoral Research Fellow
Prevention Research Collaboration
Sydney School of Public Health
The University of Sydney
Medical Research: What is the background for this study? What are the main findings?
Response: The study followed a large sample (around 200,000) of Australian adults aged 45 or older. Participants reported their lifestyle behaviours (smoking, excessive alcohol use, physical inactivity, unhealthy diet, prolonged sitting, short/long sleep duration) at baseline (2006-2009) and were followed up for around 6 years (up to June 2014). Based on linked administrative data (death records), we found a clear relationship between the total number of lifestyle risk behaviours and the risk of mortality---the more risk behaviours, the higher risk for mortality. This pattern of associations was consistent in men and women, participants in different age groups, of different socioeconomic status, and with and without major chronic disease.
Certain behavioural risk factors have synergistic associations with mortality and appear more harmful together than individually. For example, if people only sit for long hours (defined as >7 hours a day), without having other co-occurring risk behaviours, the risk for mortality was only elevated by 15%, and if people are only physically inactive without having other co-occurring risk behaviours, the risk for mortality was elevated by 60%. However when the two risk factors were combined, say if one is not physically active AND
Dr. Meyerhans[/caption]
MedicalResearch.com Interview with:
Andreas Meyerhans, PhD
ICREA Research Professor at the University Pompeu Fabra
Infection Biology Group
Department of Experimental and Health Sciences
Universitat Pompeu Fabra
Barcelona Spain
Medical Research: What is the background for this study? What are the main findings?
Dr. Meyerhans: In brief, chronic HIV infections lead to a dampening of HIV-specific killer cells. This phenomenon is named exhaustion and is mediated by inhibitory proteins, such as PD-1, on the cell surface. A consequence of exhaustion is a reduction of the immune control over virus expansion.
We have studied the effect of blocking the negative signaling from the inhibitory proteins by means of PD-1/PD-L1 pathway inhibition on effector and regulatory T cells (Treg). We found that one can augment antiviral immune control only when the virus load was well controlled in the HIV-infected individuals i.e. by antiviral drugs. In that case, PD-1/PD-L1 pathway blockage led to an expansion of anti-HIV killer cells over Treg cells. This latter are suppressive white blood cells also subject to the same inhibitory pathway regulation. In contrast, when blood cells from viremic HIV-infected individuals were analyzed, Treg cells expanded efficiently and thus reduced the effector to regulatory T cell ratio that controls HIV. Taken together, our data point to Treg cells as an important component in the outcome of PD-1/PD-L1 pathway inhibitor therapies and suggest a net gain in anti-HIV immune responses only when the HIV loads are well controlled during the administration of these novel compounds.






