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New method to assist fast-tracking of vaccines for pre-clinical tests

Scientists in Australia have developed a method for the rapid synthesis of safe vaccines, an approach that can be used to test vaccine strategies against novel pandemic pathogens such as SARS-CoV-2, the virus that causes COVID-19. 

Led by Professor Richard Payne at the University of Sydney and Professor Warwick Britton (pictured) at the Centenary Institute, the team has demonstrated application of the method with a new vaccine for use against tuberculosis (TB), which has generated a powerful protective immune response in mice. 

Researchers are keen to develop the vaccine strategy further to assist in the rapid pre-clinical testing of new vaccines, particularly for respiratory illnesses. 

“Tuberculosis infects 10 million and kills more than 1.4 million people every year,” said joint first author Dr Anneliese Ashhurst from the University of Sydney. “Historically, it is the leading cause of death worldwide from a single infectious agent. So far, a TB vaccine that is highly effective and safe to use in all populations has eluded medical science.” 

The only current vaccine for tuberculosis, the Bacille Calmette-Guerin vaccine, uses an injected live bacterium. It is effective in infants but has reduced effectiveness in adolescents and adults and poses significant health risks for immunocompromised patients, particularly for people living with HIV/AIDS. 

Protein-based vaccines have been shown to be very safe, but they must be mixed with enhancers, or adjuvants, to make them effective, which is not straightforward. 

Dr Ashhurst said: “The challenge is to ensure that our immune cells see both the protein and adjuvant simultaneously. To overcome this difficulty, for the first time we have developed a method that synthesises the protein with an attached adjuvant as a single molecule.” 

The vaccine strategy and synthetic technology could be deployed to rapidly generate new vaccines for pre-clinical testing for a range of diseases, the researchers say, including the respiratory pathogen that causes COVID-19. 

Their results are published today in the Proceedings of the National Academy of Sciences of the United States of America

HOW IT WORKS 

In order for vaccines to be effective, they need to stimulate behaviour in protective T-cells that allows them to recognise the pathogen as an antigen, or foreign body. In the case of tuberculosis, our immune system needs to respond quickly to the bacteria that causes TB – Mycobacterium tuberculosis – to reduce infection in lungs. 

Using the method developed by the Sydney scientists, an inhaled vaccine provides a low-dose immune-stimulating molecule – containing a synthesised bacterial protein attached directly to an adjuvant – to the immune cells in the lungs. 

A major hurdle overcome by the scientists was the difficulty in fusing hydrophobic (water-repellent) adjuvants with a water-soluble protein antigen. 

“We got around this problem of keeping hydrophobic and hydrophilic molecules together in a vaccine by developing a way to permanently bind the protein and adjuvant together as a single molecule using synthetic chemistry. Our approach overcomes the solubility problems faced by other methods,” said Professor Payne from the School of Chemistry and Deputy Director of the ARC Centre for Innovations in Peptide & Protein Science (CIPPS). 

The team says that synthesising an entire bacterial protein with attached adjuvant has not been achieved before. 

Professor Britton from the Tuberculosis Research Program at the Centenary Institute said: “As well as providing a rapid method to develop a range of vaccines for pre-clinical testing, we expect that this pulmonary vaccination approach will be particularly beneficial for protecting against respiratory diseases.” 

He said: “We hope that an inhaled vaccine for tuberculosis using a protein-based immunisation will allow us to develop a universal and safe approach to combatting this deadly disease.” 

The other major advantage with this method is that vaccines for a range of diseases can be developed rapidly and safely in the laboratory. 

“We don’t need to grow the actual pathogen in the lab to make the vaccine,” said Dr Ashhurst, who holds a joint position in the School of Chemistry and the School of Medical Sciences. “Using this new method, we can rapidly and safely synthesise highly pure vaccines in the lab and take them straight into animal models for pre-clinical testing.” 

Research paper: Synthetic protein conjugate vaccines provide protection against Mycobacterium tuberculosis in mice.

Read more about the Centenary Institute’s TB related medical research here.

Gut microbiome link to deadly lung disease

Research led by the Centenary Institute, the University of Technology Sydney and the University of Queensland has shown for the first time a link between chronic obstructive pulmonary disease (COPD), an often fatal lung condition, and the gut microbiome.

The findings, published in the high impact science journal ‘Nature Communications’, suggest that the gut may be helpful in diagnosing COPD and may also be a potential source of new therapeutic targets to help treat the chronic respiratory disorder.

“It’s already known that the lung microbiome is a contributing factor in COPD,” said Professor Phil Hansbro (pictured), senior author of the study and Director of the Centenary UTS Centre for Inflammation.

“We wanted to see if the gut environment was also somehow involved–to determine whether the gut could act as a reliable indicator of COPD or if it was connected in some way to the development of the disease.”

In the study, the researchers compared the microbiome and metabolite profiles of stool samples from COPD patients with healthy individuals. Revealed were significant differences between the two groups.

COPD patients exhibited increased levels of the bacteria Streptococcus and Lachnospiraceae in their stool samples. Also identified in individuals with COPD was a unique metabolite signature–formed by the chemical by-products of the metabolic process.

“Our research indicates that the gut of COPD patients is notably different from healthy individuals,” said first author on the paper Dr Kate Bowerman, University of Queensland.

“This suggests that stool sampling and analysis could be used to non-invasively diagnose and monitor for COPD,” she said.

The study’s researchers believe that the altered gut microbiome found in COPD patients could also support the gut as a potential target for new treatments.

“The ‘gut-lung axis’ describes the common immune system of the lung and gastrointestinal tract. This means that activity in the gut can impact activity in the lung. Our COPD findings suggest that the gut microbiome should now also be considered when looking for new therapeutic targets to help treat lung disease,” said Professor Hansbro.

COPD, a life threatening inflammatory disorder of the lungs, is the third most common cause of death globally. More than 3 million lives are lost every year to COPD.

Researchers involved in the study were affiliated with The University of Queensland, Hunter Medical Research Institute, University of Newcastle, The Prince Charles Hospital, Centenary Institute and University of Technology Sydney.

Publication: Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease.

Read more about our COPD related medical research here.

Professor Phil Hansbro on 60 Minutes

Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation has featured on the current affairs program 60 Minutes, explaining his critical research on bushfire smoke, its impact on the health of Australians and how his work could potentially lead to new prevention and treatment strategies.

“What we’re trying to do is to work out the important effects of bushfire smoke on your health and how it potentially affects different people in different ways– such as healthy people, people with asthma and emphysema, older people and those who are pregnant and their offspring,” said Professor Hansbro.

“Once we have this knowledge, we can then evaluate possible prevention and treatment measures including use of new anti-inflammatory drugs that may be able to help alleviate the effects of excessive smoke inhalation,” he said.

The full 60 Minutes story, titled ‘The Big Smoke’, can be accessed online (in two parts) via the Nine Network’s website.

A short video of Professor Hansbro on 60 Minutes can also be accessed on Twitter.

Human enzyme DPP4 does not enable COVID-19 infection

Research from the Centenary Institute has found that the human enzyme dipeptidyl peptidase (DPP4) does not bind to the spike protein of the SARS-CoV-2 virus and so cannot enable COVID-19 infection in our bodies.

DPP4, which is known to be the key receptor for the MERS-coronavirus (Middle East respiratory syndrome), had been identified as a potential binding target of the SARS-CoV-2 spike protein. The spike protein forms the spikes of the ‘crown’ after which coronaviruses are named. If DPP4 had been able to bind, it would have suggested an alternate port of entry for SARS-CoV-2 into human cells, thus exacerbating COVID-19.

“We already know that SARS-CoV-2 cell entry depends on the interaction between the virus’ spike and the human enzyme ACE2. We needed to find out if DPP4 was also acting as a gateway for COVID-19,” said senior author on the paper, Professor Mark Gorrell, Head of the Liver Enzymes in Metabolism and Inflammation Program at the Centenary Institute.

“Our findings however put to rest the suggestion that DPP4 could be a co-receptor or alternate receptor for SARS-CoV-2 entry. There was no binding detected between the two molecules in our study and so we can be reassured that ACE2 is the sole method for SARS infection.”

The publication, which is in pre-print, is accessible online: A Novel Purification Procedure for Active Recombinant Human DPP4 and the Inability of DPP4 to Bind SARS-CoV-2.

Further Information on the Centenary Institute’s coronavirus activity can be found here.

Enzyme insight could lead to new diabetes treatment

Research led by the Centenary Institute has discovered that the lack of an enzyme in the liver called sphingosine kinase 2 (SphK2) results in pronounced insulin resistance and glucose intolerance, both symptoms of early stage type 2 diabetes.

The findings raises the possibility of a new treatment approach for diabetic patients whose glucose blood levels are dangerously high.

In the study, reported in the science journal ‘Proceedings of the National Academy of Sciences of the United States of America (PNAS), the researchers were able to demonstrate that the enzyme SphK2 was crucial to the blood glucose regulation process.

“Using mouse models, we found that a lack of SphK2 in the liver causes an accumulation of a fat product, sphingosine that, in turn, impairs insulin function in the liver,” said senior author of the study, Dr Yanfei (Jacob) Qi, Head of the Lipid Cell Biology Laboratory at the Centenary Institute.

It is insulin that signals to fat, liver and muscle cells to take-up glucose from the blood. Insulin resistance is when the cells do not respond to the insulin properly and fail to lower glucose levels adequately, potentially resulting in the development of Type 2 diabetes.

“Our study has been able to demonstrate that the enzyme SphK2 is a key player in the regulation of insulin. Future research can now look at targeting both SphK2 and sphingosine, by either genetic or pharmacological means. If we can help normalise their levels in the body we can then aid the management of both insulin resistance and diabetes,” said Dr Qi.

It is estimated that approximately 1.8 million Australians suffer from some form of diabetes  with the disease associated with a reduced life span, blindness, amputation, increased risk of heart disease as well as a poorer quality of life.

“Our findings are important as they may provide us with a completely new way to treat diabetes and to help change lives for the better,” said Dr Qi.

Publication: Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.

Reducing cirrhosis threat for high-risk drinkers

Research led by the Centenary Institute has shown that a healthy weight and coffee consumption may help lower the risk of high-risk drinkers developing alcohol-induced cirrhosis (scarring of the liver), which causes approximately 300,000 deaths globally each year.

Also found by the researchers in this multi-national GenomALC Consortium–involving QIMR Berghofer Medical Research Institute and the Southern California Institute for Research and Education (SCIRE)–is that susceptibility to cirrhosis among high-risk drinkers is affected by a family history of alcohol-induced liver disease.

“Only a minority of high-risk drinkers, approximately 10-15 percent, actually end up developing alcohol-induced cirrhosis. But the survival time for those individuals who do develop this devastating disease can be as low as 1-2 years,” said Clinical Associate Professor Devanshi Seth, Head of the Centenary Institute Alcoholic Liver Disease Research Program and senior author of the published study.

“The best way to reduce harm from alcohol (including cirrhosis) is by reducing or cutting out alcohol. High-risk drinking is chronic alcohol use above the recommended guidelines that may result in cirrhosis. Unfortunately, individuals may not be aware of the dangers that heavy drinking entails. The aim of our study was to identify risks associated with cirrhosis in heavy drinkers and to gain insights into additional measures that could help in preventing or reducing cirrhosis in patients whose drinking places them at risk,” she said.

Lead author of the study, which was published in the prestigious science journal ‘American Journal of Gastroenterology’, was Dr John Whitfield from QIMR Berghofer Medical Research Institute.

Dr Whitfield says their study found evidence that an increased risk of developing alcohol-induced cirrhosis could be inherited, especially from fathers.

“Our study showed that risk of cirrhosis was significantly increased in individuals if the father was a chronic alcohol user and had died from liver disease. We also found that high-risk drinkers who consumed coffee were less likely to develop cirrhosis, while tea drinking only marginally lowered the risk,” Dr Whitfield said.

Dr Timothy Morgan, co-senior author of the study and researcher at the SCIRE notes that they’ve also been able to show that obesity and diabetes are both independently linked with an increased risk of alcohol-induced cirrhosis. “High-risk drinkers who have diabetes in middle age are particularly likely to progress to cirrhosis,” he said.

Clinical Associate Professor Seth believes that their findings may have major public health consequences. “Measures such as maintaining a healthy bodyweight, intensive treatment of diabetes or pre-diabetic states, and encouragement of coffee consumption may be useful lifestyle interventions to reduce the risk of alcohol-induced cirrhosis for high-risk drinkers.” she said.

The research was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) a part of the National Institutes of Health (NIH), USA.

Read the full media release here.

Publication: Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers.

Gene discovery linked to alcohol-induced liver disease

The findings of an international study led by the Centenary Institute suggests that the possibility of high-risk drinkers developing alcohol-induced cirrhosis is in part related to genetic factors.

“Only a small proportion of high-risk drinkers, about 15 percent, actually develop cirrhosis but those who do are at high risk of death and require substantial health-care support,” said senior author of the published study Clinical Associate Professor Devanshi Seth, Head of the Centenary Institute Alcoholic Liver Disease Research Program and also affiliated with Drug Health Services, Royal Prince Alfred Hospital, Sydney Local Health District.

“We wanted to see if certain high-risk drinkers had a genetic predisposition for alcohol-induced cirrhosis. High-risk drinking is chronic alcohol use above recommended guidelines,” said Clinical Associate Professor Seth.

Reported in the science journal ‘Hepatology’ the study was undertaken by a multi-national GenomALC Consortium involving the Southern California Institute for Research and Education (SCIRE) and other research collaborators.

Identified by the study researchers is a new gene associated with alcohol-induced cirrhosis. The novel FAF2 gene is associated with a reduced cirrhosis risk for heavy drinkers. Also confirmed by the study were four additional genes, three previously found to be associated with an increased risk and one with reduced risk of cirrhosis in heavy drinkers.

“Interestingly, a commonality of these genes, including the novel FAF2, is that they appear to affect the lipid (fat) metabolism pathway,” said Clinical Associate Professor Seth.

“The findings are important as due to heavy drinking, it is the build-up of lipid droplets in the liver, that can cause inflammation, and which may then lead to serious liver complications such as cirrhosis in some drinkers,” she said.

The researchers believe that the identified genes are influencing the body’s ability to regulate lipid droplets in the liver and are therefore influencing cirrhosis risk levels.

“This new understanding opens the door to the future development of exciting new drug treatments that can potentially target these specific genes and lipid processes, and reduce the chances of at-risk individuals contracting this devastating disease,” said Dr Timothy Morgan, co-senior author of the study and researcher at the SCIRE.

Clinical Associate Professor Seth says, “Abstaining or reducing alcohol use remains the most effective treatment, however fully understanding the genetic mechanics of alcohol-induced cirrhosis is also key to improving patient diagnosis and treatment decisions.”

“Identifying these genes at an individual level, in combination with assessing lifestyle options, means that we will now be able to predict an individual’s risk profile and then better personalise an appropriate treatment response,” she said.

The research was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) a part of the National Institutes of Health (NIH), USA.

Read the full media release here.

Publication: Genome-wide association study and meta-analysis on alcohol-related liver cirrhosis identifies novel genetic risk factors.

Gene discovery may explain female melanoma survival advantage

Centenary Institute scientists have discovered that genes on the X chromosome may be key to the improved survival rates of females with melanoma–as compared to their male counterparts. The findings could ultimately lead to more effective treatments for what is an aggressive and potentially deadly form of skin cancer.

We know that survival from melanoma is strongly related to gender with females having a survival rate almost twice that of males,” said Dr Abdullah Al Emran (pictured), researcher in the Melanoma Oncology and Immunology Program at the Centenary Institute and lead author of the study.

“Many explanations such as behavioural differences in sun exposure and other factors have been previously proposed for this gender difference but none had withstood critical scrutiny. We believed that further examination of the role of the X chromosome was warranted.”

What the researchers explored were a number of genes on the X chromosome–and more specifically those genes that had been found to escape a cellular process called ‘X-inactivation’.

A normal regulatory process in the body, X-inactivation is where one of a female’s two X chromosomes is inactivated or silenced during embryonic development. Only one functional copy of the X chromosome is required in each body cell.

This ‘silencing’ process is not perfect however–between 10-20% of the genes on the silenced X chromosome are still able to be expressed. As a result of this phenomena females have a double expression of many genes involved in immune responses when compared to males.

“Our study found that two of these genes on the X chromosome that manage to escape inactivation–the genes KDM6A and ATRX–were both associated with improved survival rates for women with melanoma. We believe that their high expression levels aid the body’s immune system in helping to fight cancer,” said Dr Emran.

Notably, the researchers were also able to show a clear link of the gene KDM6A to components of the immune system believed to be important in the killing of melanoma. This was particularly so in the production of interferon gamma, a key protein activated by the immune system to help kill cancer cells.

Professor Peter Hersey, Head of the Melanoma Oncology and Immunology Program at the Centenary Institute, together with co-senior study author Dr Jessamy Tiffen, also from the Centenary Institute, believe the research findings are significant in pointing to KDM6A as a major regulator of immune responses. The focus will now be on how KDM6A is regulated.

“We want to fully know how KDM6A is regulating immune responses and boosting the production of interferon gamma. Understanding these processes will potentially allow the translation of this knowledge into more effective treatments for all melanoma patients,” said Professor Hersey.

Read the full media release here.

Publication:

Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts. https://www.mdpi.com/2072-6694/12/8/2082

Pathway to eliminating antibiotic-resistant tuberculosis in the Pacific

Australian researchers, including from the Centenary Institute have been awarded funding for a major project that aims to eliminate both active and latent tuberculosis (TB) found on Kiribati, an island nation in the central Pacific Ocean. The project will also support multidrug-resistant TB control education and management through the Pacific region.

Led by Professor Barend Marais of the University of Sydney, Professor Warwick Britton AO, Head of the Centenary Institute’s Tuberculosis Research Program will be a Chief Investigator (CIB) on the project with colleagues from the NHMRC Centre of Research Excellence in Tuberculosis Control.

“A TB hotspot, Kiribati has extremely high rates of tuberculosis. The capital Tarawa, one of the most densely populated areas in the Pacific, has a TB incidence rate among the highest in the world,” said Professor Britton.

“Our project will ensure that every person over the age of 2 will be screened for TB disease or infection in Tarawa with appropriate treatment strategies then implemented. Our integrated project will also provide a pathway towards drug resistant TB prevention and TB elimination  more broadly within the Pacific, through a program of training and mentoring.”

“Overall, this program will be a catalyst in regional TB elimination efforts, helping save lives and overcoming a disease which has devastating impact on communities,” he said.

The Federal Government’s announcement regarding the project funding can be accessed online.

TB is a leading cause of death globally responsible for approximately 1.5 million deaths annually.

Read more about Professor Britton and his research here.

Image Credit: Vladimir Lysenko. https://commons.wikimedia.org/w/index.php?curid=39278217

Decreasing atherosclerosis risk

Co-operation between cardiovascular researchers from the University of Zurich with researchers from the ‘Liver Enzymes in Metabolism and Inflammation Program’ at the Centenary Institute have produced a breakthrough in understanding how atherosclerotic plaques (fatty deposits in arteries) form and stabilise.

The researchers showed that mice lacking an enzyme called FAP were healthier and developed lower rates of atherosclerosis. The researchers also discovered that the atherosclerotic plaques that did form in these mice were more stable and therefore less dangerous.

“Drugs that target FAP are being developed for cancer therapy, heart fibrosis, liver fibrosis, rheumatoid arthritis and Metabolic Syndrome complications,” said Head of the Centenary Institute’s ‘Liver Enzymes in Metabolism and Inflammation Program’, Professor Mark Gorrell who collaborated on the research.

“This new discovery is encouraging regarding the safety of those new drugs, and may also help people who are at risk of, or have, coronary plaques,” he said.

The research has been published in the leading international cardiology journal, Cardiovascular Research.

Read the full publication here: https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvaa142/5836831

Read more about the Centenary Institute ‘Liver Enzymes in Metabolism and Inflammation Program’ here: https://www.centenary.org.au/cen_program/liver-enzymes-in-metabolism-and-inflammation-program/