Praveena Thirunavukkarasu

Congrats Praveena on your NHMRC Investigator Grant funding

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BDI researchers awarded more than $10 million in NHMRC Investigator Grant funding

Six Monash Biomedicine Discovery Institute (BDI) researchers have collectively been awarded more than $10 million in National Health and Medical Research Council (NHMRC) Investigator Grants, announced today by Federal Minister for Health and Aged Care The Hon Mark Butler MP.

The Investigator Grant scheme is the NHMRC’s largest funding scheme and is a major investment in Australia’s health and medical research workforce.  It provides Australia’s highest-performing researchers, across the spectrum of health research and at all career stages, with consolidated funding for their salary, if required, and a significant research support package for five years.

This funding will support researchers at the Monash BDI to continue their outstanding discovery research, ranging from investigating ways to restore vision following damage to the visual cortex; innovating bacteriophage therapies to combat antimicrobial resistance; treating inflammatory bowel disease with natural killer T cells; through to  investigating long-acting therapies for hypertension and more.

Monash BDI researchers (L-R top) Prof Kate Denton, Prof Marcello Rosa, Prof James Whisstock, (L-R bottom) Dr Andrew Freeman, Dr Sue Nang, Dr Praveena Thirunavukkarasu.

Monash BDI researchers (L-R top) Prof Kate Denton, Prof Marcello Rosa, Prof James Whisstock, (L-R bottom) Dr Andrew Freeman, Dr Sue Nang, Dr Praveena Thirunavukkarasu.

Professor John Carroll, Director of Monash BDI, expressed his congratulations and said that these awards are intensely competitive.

“It’s fantastic to see our research leaders supported by the NHMRC. This funding plays a key role in enabling our scientists to make vital discoveries that drive advancements in human health and lead to the development of new treatments,” Professor Carroll said.

“I offer my sincere congratulations to all of our Investigator Grant recipients and commend the tremendous effort invested by all of our applicants,” he added.

The six Monash BDI projects are among 31 projects awarded more than $57 million in funding to Monash Medicine Nursing and Health Sciences (MNHS) researchers in the latest NHMRC Investigator Grants. Read more on the MNHS recipients here.

The six Monash BDI researchers to receive funding were:

Professor Kate Denton, Cardiovascular Disease Program, Department of Physiology, Long-acting therapies to treat hypertension and organ injury, $3,014,025 (Leadership 3)

Hypertension affects one in three adults globally and is the leading cause of cardiovascular disease (CVD). While treatments exist, many patients struggle with medication adherence, leading to uncontrolled blood pressure and higher CVD risk. This research aims to develop long-lasting therapies to reduce pill burden and improve hypertension treatment. Key programs include reprogramming kidney function early in life to prevent hypertension, analysing nerve regrowth after renal denervation to assess lasting blood pressure effects, and removing senescent cells to reduce CVD risk after hypertensive pregnancy. These strategies could transform treatment for hypertension and organ injury, and reduce the associated healthcare burden.

Professor Marcello Rosa, Neuroscience Program, Department of Physiology, Pathways to vision following lesions of the primary visual cortex, $3,014,025 (Leadership 3)

Research on cortical blindness in primates has challenged the long-held belief that little can be done to restore vision after damage to the primary visual cortex. Over 20 years, Professor Rosa has demonstrated that some visual function remains in surviving cortical areas, identified neural pathways that support this, and developed an implantable device for other types of blindness. In the next five years, Professor Rosa will investigate microstimulation as a strategy for partial vision restoration, study how visual rehabilitation works at the neuronal level, and explore how visual pathways reorganise in early versus mature life to identify potential therapeutic targets for the preservation of visual function.

Professor James Whisstock, Infection Program, Department of Biochemistry and Molecular Biology, In situ studies of the immune synapse, $2,000,000 (Leadership 3)

Immune cells form synapses to kill virally infected and cancerous cells, where receptor organisation impacts immune function. However, predicting these functions requires high-resolution, spatial information about immune synapse structure. This research uses cryogenic electron tomography and proteomics to identify key proteins and their spatial arrangement in the synapse. Additionally, it aims to improve biologics (for example, antibodies) to better access the synapse and modulate immune responses. This information will, in turn, be of use in the development of novel biologics or small molecules that enhance or inhibit immune cell function.This will guide the development of better and more specific immune cell therapies (for example, CAR-T cells).

Dr Andrew Freeman, Immunity Program, Department of Anatomy and Developmental Biology, Unlocking the therapeutic potential of anti-inflammatory mesenchymal stromal cells through a refined mode of action, $688,405 (Emerging Leadership 1)

Multipotent mesenchymal stromal cells (MSCs) show potential for treating inflammatory diseases due to their immunomodulatory effects. However, most clinical trials have not succeeded, partly due to a misunderstanding of MSC mechanisms. Recent research suggests that MSC-induced anti-inflammatory effects occur through efferocytosis, where immune cells uptake apoptotic MSCs and reprogram immune cells. Preliminary data shows that bioactive factors released via a specific transmembrane channel during MSC apoptosis additionally contribute to inflammation suppression. This project aims to identify these mediators and the macrophage pathways involved through screening technologies, offering new insights into MSC mode of action that will guide future MSC-based therapies or cell-free alternatives for treating inflammatory conditions.

Dr Sue Chin Nang, Infection Program, Department of Microbiology, Innovating bacteriophage diagnostics and therapy to combat antimicrobial resistance: A cell-free synthetic biology approach, $688,405 (Emerging Leadership 1)

Antimicrobial resistance poses a major global health threat, with antimicrobial-resistant pathogens projected to cause 10 million deaths annually by 2050. Bacteriophages (phages), viruses that target bacteria, show promise as alternatives to antibiotics, but current methods for identifying and producing therapeutic phages are slow and labor-intensive. This research aims to revolutionise phage therapy by developing a cell-free phage therapy platform to accelerate clinical application. By combining synthetic biology with advanced PCR techniques, the project will enable rapid screening of therapeutic phages and optimise phage production, providing an essential solution to combat antimicrobial resistance and safeguard modern medicine.

Dr Praveena Thirunavukkarasu, Immunity Program, Department of Biochemistry and Molecular Biology, Natural Killer T cells to treat Inflammatory Bowel Disease, $688,405 (Emerging Leadership 1)

Inflammatory Bowel Disease (IBD), including Ulcerative colitis and Crohn’s disease, affects more than 6.8 million people globally. Despite extensive research, new treatments have been slow due to a limited understanding of mechanisms controlling gut inflammation. One potential mechanism involves T cell-mediated lipid immunity via the CD1d molecule, which presents lipids to Natural Killer T (NKT) cells. Dysregulated NKT responses contribute to IBD progression. Notably, our human gut microbiota produces numerous bioactive lipids with immense immunomodulatory potential. This research aims to explore how gut microbiota-derived lipids interact with CD1d and NKT cells to modulate immune responses. Ultimately, this research program will lead to the development of innovative lipid-based, small molecule-based and antibody-based therapeutic agents to treat IBD by alleviating inflammation.

For the full list of national recipients, visit the NHMRC website (NHMRC 2025 Grant Application Round) and read the NHMRC media release.

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From Spanish flu to today: how immune cells keep up with a changing virus

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In a breakthrough for influenza research, scientists have discovered immune cells that can recognise influenza (flu) viruses even as they mutate, raising hopes for a longer-lasting vaccine and a universal protection against future flu pandemics.

The flu virus is constantly evolving, meaning immunity from past infections or vaccinations may not fully protect against new strains. These mutations are why last year’s flu vaccine may no longer be effective, requiring annual updates to keep up with the latest variants.

But what if our immune system could recognise a broader range of flu viruses, providing longer-lasting protection? New research suggests that certain immune cells, a subset of T cells, might hold the key.

Research led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and Monash University’s Biomedicine Discovery Institute (BDI) has uncovered how specific T cells, which play a critical role in fighting infections, can detect multiple flu strains, even those that have evolved over a century. This process, known as cross-reactivity, could be crucial in developing more effective immunity against influenza.

In the study, published in Science Immunology, researchers analysed samples from individuals with different flu viruses and identified a subset of T cells that recognise a particular protein present in influenza A viruses, from the 1918 Spanish flu to the latest 2024 H5N1 strains.

The University of Melbourne’s Dr Oanh Nguyen, Senior Research Fellow at the Doherty Institute and co-author of the study, explained the molecular mechanisms that enable these T cells to recognise multiple influenza variants.

“We tested how people’s T cells respond to a specific part of the influenza virus that changes frequently. Over the last 100 years, this region has evolved into 12 different forms,” said Dr Nguyen.

“We found that some individuals have T cells that can recognise up to nine of these variants, while others have T cells that can only detect a couple.”

Professor Jamie Rossjohn, Immunologist at Monash BDI and co-senior author of the study, explained how the team uncovered the molecular details behind this immune response.

“This work reveals an untapped ability of the immune system to respond to flu viruses, even as they change over time,” said Professor Rossjohn.

“We used an advanced technique called crystallography to determine how T cells see flu viruses at the molecular level. We observed specific interactions between the T cells and the flu proteins that determine why some T cells are better at detecting a wide range of strains than others.

“While our findings deepen our understanding of how T cells react to changing flu viruses, they are also highly relevant for understanding immune responses to other rapidly evolving viruses such as SARS-CoV-2.”

T cell receptor footprint on MHC molecule presenting a flu peptide. Credit: Dr Dene Littler.

T cell receptor footprint on MHC molecule presenting a flu peptide. Credit: Dr Dene Littler.

The flu remains a major global health threat. According to the WHO, flu causes 3 to 5 million cases of severe illness and up to 650,000 respiratory deaths each year, particularly among vulnerable populations.

The University of Melbourne’s Professor Katherine Kedzierska, Head of the Human T cell Laboratory at the Doherty Institute, said a universal vaccine, one that protects against multiple strains for longer periods, would be a game changer.

“This research is hugely significant. It shows how certain T cells can recognise multiple flu strains, which is a big step towards understanding universal protective immunity – not just for the flu, but potentially for other viral diseases too,” said Professor Kedzierska.

“Harnessing these cross-reactive responses could be the key to a vaccine that offers longer-lasting protection and reduces the risk of future flu pandemics.”

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Where there is smoke …. there is fire – Congrats to co-first author Wael

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Researchers discover how cigarette smoke impairs critical lung immune cells

Cigarette smoking is widespread and deadly, yet our understanding of how cigarette smoke actually causes serious respiratory illnesses in incomplete, which has severely hampered the development of effective treatments. In the Journal of Experimental Medicine (JEM) Australian researchers reveal how multiple chemicals found in cigarette smoke and e-cigarettes alter the function of a key type of immune cell found in the lungs.

The study suggests that these alterations make cigarette smokers, and those exposed to second- and third-hand smoke, more susceptible to respiratory infections, and exacerbate smoking-related inflammatory diseases such as chronic obstructive pulmonary disease (COPD).

Cigarette smoking is known to impair the immune system’s response to infections and promote inflammation in the lungs that can lead to or exacerbate COPD, the third leading cause of death worldwide. COPD patients are more susceptible to influenza infections that can, in turn, exacerbate the underlying disease by increasing airway inflammation and promoting the destruction of the lung’s air sacs. There are currently no effective treatments for COPD.

According to Dr Wael Awad, from Monash University’s Biomedicine Discovery Institute, until now the mechanisms underlying the skewed immune responses in people exposed to cigarette smoke, and how they are related to smoke-associated diseases like COPD remain unclear,” says Dr Awad, first author on the new JEM study.

Professor Jamie Rossjohn of Monash University’s Biomedicine Discovery Institute co-led the study with Professor David P. Fairlie of the Institute for Molecular Bioscience at University of Queensland, Professor Alexandra J. Corbett of the University of Melbourne, based at the Peter Doherty Institute for Infection and Immunity, and Professor Philip M. Hansbro of the Centenary Institute and University of Technology Sydney.

In their study, the researchers looked at the effects of cigarette smoke on Mucosal-Associated Invariant T (MAIT) cells, a type of immune cell found in the lungs and other tissues of the body. MAIT cells help fight off bacterial and viral infections and can promote inflammation or tissue repair.

MAIT cells are activated by a protein called MR1 that is found in almost every cell of the body. MR1 recognizes chemicals produced by bacteria and presents them at the surface of infected cells in order to activate MAIT cells and initiate an immune response. “We suspected that some of the more than 20,000 chemicals present in cigarette smoke that smokers inhale might also bind to MR1 and influence the activity of MAIT cells in the lungs”, Dr Awad said.

The researchers used computer modeling to predict which components of cigarette smoke might be recognized by MR1 and then found that several of these molecules not only bound to the protein but also either increased or decreased in amounts on the surface of cells. These chemicals, including benzaldehyde derivatives that are also used as flavorings in e-cigarettes, blocked activation of human MAIT cells by compounds produced by bacteria.

Unveiling the Molecular Impact of Smoking on Lung Health. This illustration explores how smoke components in cigarette and e-cigarette smoke obscures critical chemicals that bind MR1 and disrupt T cell functions in the lungs. Image: Erica Tandori

The research team then studied the effects of cigarette smoke on MAIT cells from human blood and mice and showed they reduced MAIT cell function. Mice repeatedly exposed to cigarette smoke developed symptoms of lung disease and this was worsened if also infected by influenza. Researchers found that long-term exposure to cigarette smoke altered the protection provided to mice by their MAIT cells, making them less able to fight off influenza infections and more prone to the development of COPD disease.

“We found that mice lacking MAIT cells were also protected from cigarette smoke-induced COPD, showing reduced levels of lung inflammation and no tissue deterioration in their lung’s air sacs” Profesor Hansbro said.  “This study demonstrates the power of collaboration and the insights we can gain with inter-disciplinary science,” Professor Corbett said.

“Overall, our study reveals that components of cigarette smoke can bind to the protein MR1 and reduce the functions of protective immune cells called MAIT cells. This increases susceptibility to infections worsens progression of lung disease” Awad says. The researchers now plan to investigate exactly which MAIT cell pathways are impacted by cigarette smoke, in order to learn how to better treat COPD and other lung diseases.

Read the full paper in Journal of Experimental Medicine: Cigarette smoke components modulate the MR1-MAIT axis. DOI: 10.1084/jem.20240896

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Unlocking the potential to better target cancer with immunotherapy

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Monash University-led research is unlocking new ways for immunotherapy to better target cancer.

Cancer immunotherapy has revolutionised treatment for patients, whereby the body’s own immune system is harnessed to destroy cancer cells.

Typically, several molecules restrain the ability of T cells to target cancer cells and developing approaches to limit this restraining effect can lead to improved effectiveness of cancer immunotherapy.

Research published in Science Immunology has determined the structure of how an inhibitory molecule, LAG3, interacts with its main ligand and provides a new targeted approach to improving the effectiveness of immunotherapy for certain forms of cancer.

The publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for development of blocking LAG-3 therapeutics.

Led by Professor Jamie Rossjohn at Monash University’s Biomedicine Discovery Institute (BDI), in collaboration with Immutep, this research resolves how the human LAG-3 receptor binds to HLA II molecules.

First author Dr Jan Petersen said: “The way the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for many years.

“However, the resolution of the interface between another important checkpoint molecule, LAG-3, and its main ligands, HLA-II molecules, has remained elusive.

“Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”

A diagram of a cell Description automatically generated with medium confidence

Figure 1: Human LAG-3 homodimer (with domains D1, D2, D3 and D4) binding to two separate HLA-II (MHC-II) molecules on the surface of an antigen-presenting cell (APC), imposing a distinct 38° offset angle.

Dr Frédéric Triebel, Immutep’s CSO, added: “These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”

Read the full paper published in Science Immunology, titled Crystal Structure of the Human LAG-3–HLA-DR1–Peptide Complex 

 

About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

About Immutep
Immutep is a clinical-stage biotechnology company developing novel LAG-3 immunotherapy for cancer and autoimmune disease. We are pioneers in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and our diversified product portfolio harnesses its unique ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com.

DOI: 10.1126/sciimmunol.ads5122

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Monash study unravels another piece of the puzzle in how cancer cells may be targeted by the immune system

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Effective immunity hinges on the ability to sense infection and cellular transformation. In humans, there is a specialised molecule on the surface of cells termed MR1. MR1 allows sensing of certain small molecule metabolites derived from cellular and microbial sources; however, the breadth of metabolite sensing is unclear.

Published in PNAS, researchers at the Monash University Biomedicine Discovery Institute (BDI) have identified a form of Vitamin B6 bound to MR1 as a means of engaging tumour-reactive immune cells. The work involved an international collaborative team co-led by researchers from the University of Melbourne.

 

Monash BDI authors on the study (L-R): Dr Patricia Illing, Dr Wael Awad, Dr Mitchell McInerney .

Monash BDI authors on the study (L-R): Dr Patricia Illing, Dr Wael Awad, Dr Mitchell McInerney .

According to Dr Illing, “Our findings suggest that Vitamin B6 molecules displayed by MR1 represent a means for the immune system to detect altered cellular metabolism/metabolite levels that may distinguish cancer cells,” she said.

“Identification of small molecules/metabolites able to activate immune cells with cancer reactivity is a key step in understanding how small molecule sensing might contribute to anti-cancer immunity.”

Central to this study were the unbiased mass spectrometry analysis of small molecules bound to MR1, the structural resolution of the interactions between MR1 and Vitamin B6, and immunological assays performed by lead authors Dr Mitchell McInerney and Dr Wael Awad at Monash Biomedicine Discovery Institute, and Dr Michael Souter and Mr Yang Kang at the University of Melbourne, Peter Doherty Institute.

While it’s not yet clear if the Vitamin B6 molecule can be utilised in therapeutics, “understanding the breadth of MR1 mediated immunity has the capacity to illuminate routes for therapeutic intervention,” Dr Illing said.

An important aspect of the finding is that MR1 differs very little across individuals – with few known genetic variants in the human population. “Thus, understanding immune activation mediated via MR1 may pave the way for therapeutic interventions with broad utility,” Dr Illing said.

She added that next steps for investigation will confirm whether Vitamin B6 and related molecules are displayed by the MR1 of cancer cells at altered levels to healthy body cells, thus enabling specific cancer targeting, or if other small molecules displayed by MR1 may help differentiate cancerous and healthy cells.

Read the full paper published in PNAS, titled MR1 presents vitamin B6–related compounds for recognition by MR1-reactive T cells
DOI: 10.1073/pnas.2414792121

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