Medical study provides new insights on sepsis

Despite the best efforts of Intensive Care Unit (ICU) staff and physicians and the most advanced life-support, Dr. Bryan Yipp witnesses a lot of deaths in the ICU that are attributed to sepsis. 

“Sepsis is the body’s overwhelming immune response to an infection and sometimes that response can cause death,” says Yipp, BSc’99, MSc’05, MD’05, PGME’10, a critical care physician and clinician-scientist at the Cumming School of Medicine. “While many cases involve people with long-term illnesses, seemingly healthy people can be at work or home one moment and then within hours be admitted to ICU.”

Earlier this year, 41-year-old NASCAR race champion Kyle Busch died after pneumonia progressed to sepsis. Yipp says a recent discovery in his lab, published in SCIENCE, could lead to new treatments for this often-fatal condition.

Cells behaving like birds

When someone is septic, their immune cells cluster together, clogging up the circulatory system and reducing or stopping blood flow. When that happens, organs begin to fail. Researchers analysed the clustering behaviour by combining two well-known scientific techniques.  

“We saw immune cells carry out complex swarming behaviours like bird murmuration. Just like the aerial ballet performed by a flock of birds, the synchronization of the cells was powerful and mesmerizing to watch. But then we wondered, how are we going to make any sense out of it?” says Yipp, who is the principal investigator on the study. “We developed a new method of combining microscopy with digital informatics to create something we coined ‘cellular behavioromics.’” 

Instead of treating the cellular images like pictures, the team noted each cell’s features including the shape and size, the speed in which it moved, and the direction it took. Researchers then assigned numbers to those features and started feeding that data into a bioinformatics pipeline.

“Our approach enabled us to sort out the cells. We found 18 different clusters of behaviours involved in the cellular swarms during sepsis,” says Dr. Luke Brown, PhD’26, first author on the study. “Understanding cell behaviour can provide insight on new treatments including when to administer the treatment.” 

Stopping the cellular swarm from harming the host 

Yipp says the new understanding prompted his team to look at treatment options at varying intervention points that could prevent cells from clustering. 

“The findings allowed us to propose targeted therapeutics to block bad host responses and allow good host responses to improve survival during sepsis,” says Yipp. “Currently, the treatment gold standard for sepsis is to administer antibiotics within an hour of deciding that someone is septic. We wondered whether an additional medication used in conjunction with the antibiotics would be beneficial.” 

Findings from the research, conducted in mice, showed promising results. A well-known, safe asthma medication prevented certain cells from clustering. Yipp says while there is still a lot of investigating to do, the fact that sepsis affects and often kills millions of people world-wide each year, like Kyle Busch, shows the real-life importance of using innovative computational biology to discover new therapeutics. 

This work was supported by the Canadian Institutes of Health Research (CIHR), a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant and a UCalgary Eyes High Doctoral Recruitment Scholarship to Brown. Additional acknowledgements are detailed in the paper.