Study shows how vascular system is first to break down, along with inflammatory response
Researchers at TGen, part of City of Hope, and Mayo Clinic now have a better idea of what happens to the brain in the earliest stages of sepsis-associated encephalopathy (SAE), thanks to a new study published October 2 in the Nature journal Translational Psychiatry.
Sepsis is a deadly syndrome that can arise from overactivation of the immune system in response to harmful bacterial, viral, or fungal infection. Most recently in the news as the cause of death of NASCAR driver Kyle Busch, sepsis affects an estimated 49 million people around the world annually and is a leading cause of hospitalization and death.
When patients develop SAE, they are at increased risk of death or long-term cognitive impairment. Many sepsis survivors report having “brain fog,” mood changes or even PTSD-like symptoms.
“It has been difficult to pinpoint exactly what happens in the brain during the earliest stages of SAE,” said John Fryer, Ph.D., a professor and director of TGen’s Immunology and Microbiome Division, director of the Center for Accelerated Nanotherapeutics, and a senior author of the paper. “This study provides insights on what occurs at the tissue level in the acute period of SAE and how that might relate to the human condition.”
The study, in a sepsis model where pigs were infected with E. coli, now shows that the brain’s vascular system is affected first in SAE, along with rapid inflammatory activation of support and immune cells such as astrocytes and microglia.
Surprisingly, the brain’s neurons were not affected at this early stage, just hours after infection, said Kimberly Olney, Ph.D., a postdoctoral fellow in Fryer’s lab and lead author of the paper.
“In our study, we identified that it is the blood-brain barrier that immediately breaks down, and that the immune cells are immediately being activated,” Olney explained. “It’s extremely beneficial, for future studies where we want to find ways to prevent brain fog and cognitive problems, that we understand what’s happening prior to the neurons being disrupted.”
The findings could also shed light on the cause of lingering cognitive effects found in long COVID patients, said J. Hudson Barnett, a researcher at the Department of Neurologic Surgery and Neuroscience Graduate Program at the Mayo Clinic and co-author of the study.
“It has some distinct features, but the assumption would be that there might be overlap with what happens with an acute wave of inflammation and those long-term brain fog effects in both conditions,” said Barnett.
The research team used single-nucleus RNA sequencing to pinpoint the exact molecular shifts in vascular and glial cells. They show that the earliest stages of SAE are characterized by a profound shift away from genetic activity related to metabolic and structural maintenance in the brain tissue, and toward an inflammatory genetic program.
Sepsis also appears to “rewire” intracellular signaling in the brain tissue, increasing the number and strength of cell-to-cell interactions, the team found.
The next step is to analyze human tissue and understand how those molecular changes compare to their animal models, said Olney.
The Mayo Clinic and the ASU Team Science Grant funded this research.
By Becky Ham
Posted on Thursday, October 08, 2026
SOURCE: https://www.tgen.org/news/tgen-mayo-study-offers-glimpse-at-early-sepsis-stages-in-the-brain/