Calming the COVID-19 storm

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Calming the COVID-19 storm

Our scientific teams with expertise in inflammation, infection and immunity hold vital clues to help tackle deadly virus outbreaks—like COVID-19.

Inflammation is a normal, protective reaction to infection—and a critical first step in activating the body’s full immune response. However, if uncontrolled, inflammation can lead to a range of debilitating and life-threatening conditions—acute respiratory syndromes, sepsis, chronic obstructive pulmonary disease, inflammatory bowel disease, lupus, pneumonia, endometriosis, infertility and even cancer.

The life-threatening acute respiratory distress syndrome (ARDS) in severe COVID-19 cases results from hyper-inflammation, similar to that seen during other SARS, MERS and avian influenza outbreaks. While most infections can be mild and cleared quickly, this is not true of all cases. The effect on our aged and immune-compromised communities has been devastating. Restricting this inflammation could help save lives before antiviral therapies and vaccines are developed and ready.

Several research teams at Hudson Institute are working on different approaches to curb this hyper-inflammation. In addition, we are investigating why some patients are affected more severely by COVID-19 than others—including the differences seen in adults and children.

When it comes to responding to a new infectious disease, there are many different pieces of the puzzle. In this issue, we look at some of the innovative approaches underway at Hudson Institute.

COVID-19 facts

The coronavirus pandemic will affect millions globally
The life-threatening acute respiratory distress syndrome (ARDS) in severe COVID-19 cases results from hyper-inflammation
The infection is most severe in the aged and immune-compromised
The SARS CoV-2 virus appears to have originated in bats and passed to humans via an intermediary mammal
COVID-19 is the most severe global pandemic since ‘Spanish’ influenza in 1918–1919, which killed between 50-100 million people and infected about a third of the world’s population.

Inflammation and infectious diseases

Severe COVID-19 infection presents as excessive lung inflammation, involving the build-up of cells and fluid in the lungs. This phenomenon, known as ARDS, restricts breathing and causes damage to the lungs. Severely affected patients will need ventilator assistance in intensive care.

COVID-19 has similar characteristics to severe Influenza A virus (IAV) infections, including the damaging lung inflammation that causes ARDS. Associate Professor Ashley Mansell and Dr Michelle Tate are collectively using their knowledge of severe inflammation from IAV studies to repurpose and develop potential drugs to treat COVID-19. The team has been sought out by international biotech companies due to their specialist expertise.

How we are tackling acute inflammation

Identifying the molecular mechanisms of SARS CoV-2 induced inflammation
Examining how COVID-19 results in severe lung inflammation
Developing and testing new, and repurposed, anti-inflammatory compounds to treat ARDS in COVID-19.

Why is research into inflammation caused by infectious diseases needed?

“At the moment there are no effective treatments to address the devastating effect of inflammation caused by COVID-19,” A/Prof Mansell said. “There is a desperate worldwide need to identify and develop new therapies as quickly as possible.”

Dr Michelle Tate added, “Inflammation is involved in nearly every disease known to humankind and yet we understand very little of how, why and where this occurs and what causes it. If we understand the how and why, we can try and target it to reduce disease.”

COVID-19 MAY NOT BE OUR BIGGEST WORRY

There’s still the threat of an avian influenza virus emerging which may make COVID-19 look like a bad cough.

The current pandemic highlights several concerning facts

The world is poorly prepared for new and sudden emerging infectious diseases.
While vaccines are highly effective, the timeframe to develop, test, make and distribute a new vaccine for an emerging disease like COVID-19 is at least 12-18 months.
The world currently lacks approved and effective anti-inflammatory drugs to treat emerging inflammatory infectious diseases.
It is impossible to contain an infectious disease in a global community without strict quarantine measures that severely damage the economy. We have to be prepared with strategies and treatments when pandemics arise. A range of measures is needed to tackle a new virus on the scale of COVID-19 and ‘buy’ time until a vaccine is ready.

A/Prof Ash Mansell
Research Group Head, Pattern Recognition Receptors and Inflammation Research group

Dr Michelle Tate
Research Group Head, Viral and Immunity and Immunopathology Research group

Funders
NHMRC, commercial partners

Further funding is needed for this team to pursue research into repurposing existing drugs and for the methods of delivery to patients, including inhalers and nebulisers.

Help our researchers discover new treatments to save the lives of the most vulnerable COVID-19 patients.

Using our immune system to fight COVID-19

There is something unusual about the initial—or innate— immune response to COVID-19 compared to usual influenza patterns.

The disease severity is surprisingly low in children, but high in older people. Our innate immune response provides early antiviral protection and shapes the immunity required later for vaccine responses. But, if uncontrolled, the resulting hyper-acute inflammation from excess cytokines can lead to potentially lethal ARDS.

A Hudson Institute and Monash Health collaboration between Professor Paul Hertzog, Dr Sam Forster, Professor Phil Bardin, Professor Marcel Nold and Professor Jim Buttery will study the innate immune response of COVID-19-infected patients admitted to Monash Health wards, comparing those who have mild disease and recover, with those who suffer severe disease requiring intensive care. The study will compare disease in adults and children.

This collaboration demonstrates the benefits of the Institute’s location onsite at Melbourne’s largest healthcare network, Monash Health—enabling this exciting translational project to occur.

How we are tackling acute inflammation

Does the antiviral interferon response (inflammatory signalling proteins) align with disease severity?
Which inflammatory cytokines influence development of severe lung disease?
Does the immune cell response dictate protection, or drive long-term immunity?
How does the lung microbiome influence the innate immune response including inflammation?

Why is research into the innate immune response needed?

“We don’t understand why some people have mild disease and recover, while others develop life-threatening illness,” Prof Paul Hertzog said. “This includes the apparent ‘resistance’ of young people and sensitivity of older patients.” This study aims to study everything from patient genetics, to the nature of their immune cells and the molecules they produce.

Understanding early immune responses to COVID-19 will help scientists design vaccines to optimise successful protection.

Prof Hertzog said the response to the COVID-19 pandemic highlights the global scientific community’s ability to work at pace, thanks to the latest cutting-edge technology and highly skilled scientists. “We have seen remarkable advances in the ability of the international scientific community to respond to a crisis such as this pandemic. The virus was isolated and its whole genome sequenced in three days, enabling tests to be available quickly, and vaccine projects to begin at an unprecedented pace,” he said. “Nevertheless, a vaccine would take at least 12 to 18 months to develop.”

In the interim, he said there was much more work to be done around the potential to harness innate immunity to fight pandemic and/or drug-resistant infections or respond to health issues by developing better immune biomarkers for disease diagnosis and surveillance, or immunotherapeutics and vaccines for treatment and prevention.

The benefit of targeting the innate immune response is the existence of common elements regardless of the infection—COVID, SARS, EBOLA, and antibiotic-resistant bacteria. This complements approaches that do target specific infections, such as antiviral drugs, vaccines and antibiotics.

Professor Paul Hertzog
Centre Head, Centre for Innate Immunity and Infectious Diseases

Collaborators
Dr Sam Forster, Research Group Head, Microbiota and Systems Biology
Professor Phil Bardin, Research Group Head, Respiratory and Lung; Head of Unit, Respiratory and Sleep, Monash Health
Professor Marcel Nold, Research Group Head, Interventional Immunology in Early Life Diseases; paediatrician, Monash Health
Professor Jim Buttery, Head of Unit, Infection and Immunity, Monash Children’s Hospital

Funders
This project requires funding for analysis.

Hyper-acute inflammation in COVID-19

Sepsis is a hyper-acute inflammatory response leading to life-threatening organ dysfunction.

Sepsis is usually caused by bacterial infections; however, the COVID-19 pandemic illustrates that hyper-acute inflammation can also be part of viral infections. Many critical COVID-19 patients develop dangerous levels of hyper-acute inflammation, and this is associated with a high death rate.

The Nucleic Acids and Innate Immunity research group, headed by Dr Michael Gantier, is looking for treatments to help prevent chronic and hyper-acute inflammation.

Nucleic acids are the root cause of toxic inflammation in chronic diseases like lupus, or acute sepsis. This team is working with potential drugs targeting inflammation driven by nucleic acids, by validating the anti-inflammatory properties of these drugs in preclinical models of sepsis and chronic inflammation.

How we are tackling acute inflammation

Selection of molecules that can be quickly repurposed as anti-inflammatory drugs to prevent chronic inflammation and sepsis
Development of new treatments that build on ‘good’ inflammation to help the body’s immune system successfully fight pathogens and cancer
Understanding how chronic inflammation driven by nucleic acids controls cancer development.

Why do we need to research life-threatening inflammation?

“It is clear that the world is not prepared to deal with the number of ARDS patients generated by COVID-19,” Dr Gantier said.

The body’s immune response to some infections can be toxic to patients, damaging major organs. This triggers a chain of responses that can ultimately result in organ failure and death.

“In critical COVID-19 patients, the progression from ARDS to death directly relates to out-of-control inflammation from damaged tissues,” Dr Gantier said. “This progression is slow (over a week), allowing a window of opportunity to prevent the inflammatory storm and protect these patients. This is a primary focus for us.”

Dr Michael Gantier
Research Group Head, Nucleic Acids and Innate Immunity

Funders
Noxopharm

Further funding is needed to pursue research into validating the drugs identified by this lab, to treat diseases driven by chronic and acute inflammation.

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