Sepsis, the body’s response to a life-threatening infection affecting approximately 1.7 million adults in the United States each year, can lead to multiple organ failure with a high death rate.
No targeted therapy against this disease has been developed in recent decades. Now, however, a team led by biomedical scientists at the University of California, Riverside, offers some hope for future treatment during sepsis awareness month.
The researchers, led by Meera Nair and Adam godzik in the Medicine School, identified molecular biomarkers, pathways and immune cell dynamics associated with sepsis that could be therapeutically targeted to prevent the disease from leading to death. These blood cell biomarkers – the CD52 protein in lymphocytes; and the S100A9 protein involved in inflammatory processes – are present in all blood cells but highly expressed in people with sepsis. How these biomarkers change at the onset of sepsis – specifically, in the first six hours – could determine whether the patient survives or dies.
“These biomarkers were found to change uniquely within six hours in the blood of patients with sepsis and affected specific cellular pathways in specific immune cells,” said Nair, associate professor of biomedical sciences, who co-led the ‘study. to study published in the Journal of Leukocyte Biology. “Changes in CD52 expression have been associated with good results, which means promoting activation of protective immune cells. S100A9, on the other hand, acted as a molecular driver of fatal sepsis. We seem to have found a molecular driver and molecular protector of sepsis. “
According to Nair, the team also found that the molecular pathways of deadly sepsis and COVID-19 are converging.
“Severe COVID appears to trigger molecular pathways identical to sepsis,” she said. “Further analysis of these pathways can help us diagnose and treat both diseases. “
In particular, the research team also found that in people with sepsis, blood platelets – the types of cells involved in normal blood flow and clotting – have lost their function, as they do in COVID patients. . Researchers argue that if platelet function could be restored by targeting key regulators of this process, it could promote survival in both sepsis and COVID.
Nair explained that when a patient is diagnosed with sepsis and admitted to the intensive care unit, doctors use clinical scoring systems, such as APACHE-2 and SOFA scores, to help predict the severity of the condition. disease and the likelihood of death.
“Clinicians still cannot predict whether the patient will survive or die and what specific treatment to give to improve their chances of survival,” she said. “Unfortunately, there is no way to sort patients to determine whether they would benefit from one treatment over another. We wanted to solve this problem by finding molecular biomarkers that are better predictors of a patient’s survival or death. We seem to have found candidates.
The to study, done in partnership with clinicians from Riverside University Health System, or RUHS, involved drawing blood from five patients with sepsis. Dr. Walter Klein, co-author of the article and pulmonologist at RUHS, noted that clinical scoring systems do not provide specific treatment targets for patients.
“From a clinical point of view, the treatment of sepsis largely focuses on early detection, early systemic antibiotics / control of the source of infection and support for failing organ systems,” he said. -he declares. “What is lacking in the clinical field are specific therapies that reverse the patient’s deregulated immune response to infection. The importance of basic scientific research like this is, hopefully, to one day find individualized treatments that can quickly reverse the patient’s multiple organ failure and prevent mortality.
Unlike other studies which analyzed blood samples from patients with sepsis at time zero, when patients were first diagnosed with the disease, the research team analyzed blood samples from patients with sepsis. sepsis at time zero and six hours later – two different times of different sepsis results.
“We have two-step snapshots that show us how biomarkers evolve,” said Godzik, Bruce D. and Nancy B. Varner Presidential Chair in Cancer Research at UCR and Professor of Biomedical Sciences, who co-led the study. “We can improve this development in the right direction, towards survival. If the patient goes in the wrong direction, towards fatality, we can intervene to change the trajectory of the disease. With this work, we have gone beyond the static snapshot and moved to a more dynamic process.
Blood samples obtained from RUHS were processed on a single cell sequencer at UCR, allowing researchers to understand the behavior of each cell rather than an average of all cells.
“We found that many types of cells behaved differently in sepsis,” said Xinru Qiu, the co-first author of the article and a graduate student of the Godzik lab. “Using single cell sequencing, we were able to separately track the trajectory of different cell types. Single-cell resolution is like having a street-level view of an area versus a satellite view of it, and understanding each cell’s contribution was key in helping us find our results.
According to Godzik, when news reports indicate that someone has died from complications from an infection, it usually means the person died of sepsis.
“Thirty percent of all hospital deaths are caused by sepsis,” he said. “Sepsis is an unmet need without treatment. Our work provides a path for treatment because we have extended the view from single molecules to processes in cells. After all, it’s the molecular pathways involved that can be interrupted. Often people think that if a gene is a biomarker for a disease, a drug should target it. Well, not necessarily. If your car’s bumper – the tag or marker – gets destroyed in a car crash, you may need to repair the brakes – the way.
Nair stressed that the study was only possible through a multidisciplinary approach.
“As an immunologist, I teamed up with Adam, who is a computer biologist, and clinicians from RUHS,” she said. “It is only through such collaborative work that we can begin to unravel the complexity of deadly sepsis, offering insight into new treatments that could change the trajectory of sepsis patients who could face a fatal outcome. “
Next, the researchers plan to focus on the similarities between sepsis and COVID-19 and have already started research funded by the Center for Research on Health Disparities at the UCR.
“We are performing a molecular analysis of the long-term effects of COVID-19 on immune homeostasis,” said Nair. “We would like to see if the results of our research on sepsis could also apply to COVID-19. “
The research was funded by UCR School of Medicine, an innovation grant from the Dean of the School of Medicine at Bonenfant and the National Institutes of Health. Bonenfant completed his medical residency at the UCR School of Medicine in 2018.
The research paper is titled “Dynamic Changes in Transcriptional Signatures of a Single Human Cell During Fatal Sepsis”.