Natural protein reduced sepsis deaths by more than 70 per cent: preclinical study

Researchers in Australia have reported that restoring levels of a naturally occurring human protein – corticosteroid-binding globulin – sharply reduced mortality in a preclinical septic shock model, raising the prospect of the first natural anti-inflammatory therapy identified in more than 70 years

A naturally occurring protein in the human body could offer protection against sepsis, one of the leading causes of death worldwide. Researchers have reported that restoring levels of corticosteroid-binding globulin (CBG) reduced mortality by more than 70 per cent in a preclinical model of septic shock, a finding that could open a path to a novel therapeutic strategy for the condition.

The study, conducted by scientists at the University of Adelaide and the Central Adelaide Local Health Network, Australia, has investigated the biological role of CBG, a protein produced in the liver that transports the stress hormone cortisol through the bloodstream. Cortisol is central to the body’s physiological response to stress and inflammation. By controlling how this hormone circulates and becomes available to tissues, CBG plays a key part in regulating immune and inflammatory responses.

In septic shock, the body’s immune response to infection becomes dysregulated and excessive which can lead to widespread inflammation, profound drops in blood pressure and multi-organ failure. Despite the scale of the clinical challenge, few therapies specifically target the inflammatory cascade that drives this deterioration.

In the latest preclinical experiments, the research team restored depleted levels of CBG in an animal model that mimics the pathophysiology of septic shock. The intervention led to a reduction in hypotension, a decrease in organ damage and a marked improvement in survival outcomes.

“The results from our preclinical study were remarkable and show our therapy has the potential to reduce sepsis-related deaths significantly,” said Dr Stewart Ramsay, a research fellow at the University of Adelaide’s School of Medicine and the study’s lead author.

“This is a huge step forward in the search to identify a treatment for sepsis and in particular septic shock, which accounts for more than 20 per cent of all global deaths,” he said.

CBG is traditionally understood to function primarily as a transport protein that carries cortisol through the bloodstream. However, the Adelaide team’s research has suggested that the molecule may have additional biological roles that influence inflammatory pathways directly.

The investigators have spent more than a decade examining the clinical importance of CBG, with their work including studies of patients admitted to intensive care at the Royal Adelaide Hospital. These investigations showed that low CBG concentrations correlate strongly with disease severity. Patients with septic shock who displayed CBG deficiency experienced approximately a threefold increase in the risk of death.

The most recent study has provided further evidence that replenishing this protein may alter the trajectory of severe infection.

“In our most recent preclinical study, we saw marked protection from sepsis progression, with a significant reduction in hypotension and organ damage,” said Associate Professor Richard Young, senior author of the study and a senior research fellow at the University of Adelaide and the South Australian Health and Medical Research Institute.

“This suggests that CBG is triggering an anti-inflammatory response unrelated to the protein’s known function in the body, reinforcing our view that it could be the first natural anti-inflammatory discovered in more than half a century,” Young added.

Sepsis develops when the body’s immune system mounts an overwhelming response to infection. Instead of confining inflammation to the site of infection, the immune system activates system-wide pathways that damage tissues and organs. In its most severe form – septic shock – blood pressure falls to dangerously low levels and the patient can experience multiple organ failure.

The condition has become a major global health concern with the World Health Organization identifying sepsis as a priority area for international action due to its high mortality and the growing number of risk factors that accompany modern medical practice.

Incidence has continued to rise, in part, because advances in healthcare have increased the use of surgical procedures, implantable medical devices and immunosuppressive therapies. While these innovations have transformed the treatment of many diseases, they also create conditions in which severe infections can develop, alongside the increased likelihood of hospital acquired infections with increasing levels of antimicrobial resistance.

Despite this escalating burden, therapeutic progress in septic shock has remained limited. Current treatment strategies rely largely on antibiotics, intravenous fluids and drugs that support blood pressure, rather than therapies that directly address the underlying inflammatory cascade.

“Septic shock urgently requires novel treatments. Despite the high mortality rate, there have been no septic shock therapies introduced into clinical practice for decades and the treatments that we do have come with limited success,” said Professor David Torpy, professor of medicine at the University of Adelaide and head of the endocrine and metabolic unit at the Royal Adelaide Hospital.

“This natural therapy has the potential to save lives in patients with sepsis and septic shock, with minimal toxicity,” he said.

Following the promising preclinical findings, the research team has moved to prepare CBG for clinical testing in humans with the researchers initiating production of CBG suitable for first-in-human clinical trials.

The investigators have also suggested that the therapy could have applications beyond sepsis. Conditions such as severe burn injury can lead to profound depletion of circulating CBG which may contribute to inflammatory complications and poor outcomes.

“We are hopeful that this natural therapy has benefits that extend beyond sepsis to patients with severe burn injuries and other conditions where CBG is severely depleted,” said Dr Ramsay.

If confirmed in clinical trials, the discovery could mark an important shift in sepsis treatment. Instead of suppressing inflammation through synthetic drugs, clinicians might restore a naturally occurring protein that helps the body regulate its own immune response. Such an approach could offer a more physiological method to stabilise critically ill patients and reduce the global toll of a disease that remains one of medicine’s most persistent challenges.

For further reading please visit: 10.1210/endocr/bqag002