Influenza News: Ohio State University Unveils MG53, A Human Protein Based Therapeutic To Stop Lethal Lung Damage From Influenza Attacks

Influenza News: A new study by researchers from Ohio State University Wexner Medical Center have uncovered a therapeutic called MG53 that is derived from a naturally occurring human protein to treat and stop the raging lung inflammation that can contribute to death from an influenza infection.


 
In animal vivo studies involving mice, all untreated animals given a lethal dose of influenza died within days. However all but one of the infected mice treated with the experimental therapy not only survived, but remained energetic and kept weight on despite having high levels of the flu virus in its lungs.
 
The novel experimental treatment is a heavy dose of MG53, part of a family of proteins that plays an essential role in cell membrane repair.
 
MG 53 has already identified as a potential therapy for conditions ranging from Alzheimer's disease to persistent skin wounds, MG53 was found in this study to prevent death from a lethal flu infection by blocking excessive inflammation without having any effect on the virus itself.
 
The study team is currently testing the effects of the therapy in mice infected with SARS-CoV-2, the coronavirus that causes COVID-19.
 
Dr Jacob Yount, Associate Professor of microbial infection and immunity at The Ohio State University and co-lead author of the study told Thailand Medical News,"I haven't ever seen anything like this before. Even though these mice had the same viral load as the untreated mice, they did not get very sick with the lethal dose of the flu."
 
Dr Yount, whose lab studies the immune response against viral infections, co-led the work with Dr Jianjie Ma, professor of cardiac surgery at Ohio State, who discovered MG53 and its role in cell repair and has been developing the protein as a therapeutic agent.
 
The research collaboration between the two labs in Ohio State's College of Medicine on this work grew out of a proposal by Dr Matthew Sermersheim, a graduate student in Dr Ma's lab, to expand on the investigation of MG53's links to inflammation.
 
In a previous published study, Dr Sermersheim showed that the lungs of mice lacking the MG53 gene and infected with flu responded with extensive inflammation compared to normal mice, indicating that MG53 has a protective role in the immune response. https://www.nature.com/articles/s41467-020-17177-6
 
In that study it was found that TRIM family proteins play integral roles in the innate immune response to virus infection. MG53 (TRIM72) is essential for cell membrane repair and is believed to be a muscle-specific TRIM protein. In the study, Dr Sermersheim showed that human macrophages express MG53, and MG53 protein expression is reduced following virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. MG53 knockout mice infected with influenza virus show comparable influenza virus titres to wild type mice, but display increased morbidity accompanied by more accumulation of CD45+ cells and elevation of IFNβ in the lung. The study found that MG53 knockdown results in activation of NFκB signalling, which is linked to an increase in intracellul ar calcium oscillation mediated by ryanodine receptor (RyR). MG53 inhibits IFNβ induction in an RyR-dependent manner. That study establishes MG53 as a new target for control of virus-induced morbidity and tissue injury.
 
In this new research, the study team put MG53 to the test against influenza, which, along with other respiratory viruses, is a top-10 cause of death worldwide.
 
The study team infected mice with a dose of an H1N1 strain of influenza and treated half with a placebo. Using recombinant human MG53, a molecule Dr Ma's lab has been developing as a drug, the researchers treated the other half of mice with seven daily injections beginning 24 hours after infection. The untreated mice showed an aggressive loss of weight and died within nine days, but 92% of the treated mice lost very little weight, remained active and returned to their normal weight by two weeks after infection.
 
Dr Ma said, “The protein has a way to recognize tissue that's been injured and it can go there directly. We are basically enhancing a natural anti-inflammatory mechanism in the body so that when you face the crisis of an aggressive virus infection, the body can better defend itself."
 
Even with the strikingly different outcomes, the viral loads in both sets of mice were similar meaning an MG53-based agent is not an anti-viral drug. Even teeming with the flu virus, the airways of treated mice showed little tissue damage.
 
Although the study team is still working to fully identify how this protection occurs, they determined that MG53 stops an immune response mishap called a "cytokine storm," which leads to tissue damage.
 
The study also showed that MG53 mitigates an infection-related cell-death process called pyroptosis, which also promotes inflammation and lung dysfunction.
 
Dr Yount added, "A lot of the lung damage with the flu virus is actually caused by excessive inflammation from our own immune response. If you can dampen that hyperactive immune response, you'll have less tissue damage, even though the virus is still replicating at really high levels."
 
It should be noted that lung tissue damaged by inflammation is deadly because it allows fluid and cells to build up in airways, preventing the lungs from absorbing oxygen.
 
Dr Ma's previous work in animal models suggests driving up levels of MG53 in the body for therapeutic purposes is safe.
 
Animal models including mice in his lab have genetically engineered to over-produce the protein live longer and healthier lives than normal mice. Though the scientists envision MG53 as part of a cocktail of drugs targeting deadly viral infections, they caution that much more research is needed before a therapy is available for humans.
 
Dr Ma added, "We need better anti-inflammatory tissue repair therapies. We do not have COVID-19 data yet, but even with influenza, which hits us on a seasonal basis, this application could make quite a bit of difference."
 
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