Metabolic changes that “rewire” part of the immune system can intensify sepsis, the body’s dysregulated response to infection. This discovery may lead to new ways to block metabolic changes contributing to excessive and ineffective inflammation, reset the immune system, and bring sepsis under control, researchers at Vanderbilt Health reported January 15 in the journal Nature Immunology.
“Metabolism is potentially a means by which we could intervene in immune dysfunction in ICU (intensive care unit) patients including those with sepsis,” said the paper’s first and co-corresponding author, Matthew Stier, MD, PhD, assistant professor of Medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt Health.
“I think we can make great progress and great strides by aligning cutting-edge basic science tools with ICU patient samples to understand these mechanisms and prioritise therapies for future interventions,” he said.
Sepsis is characterised by the massive production and release of inflammatory molecules, including cytokines, that if unchecked, can lead to tissue damage, septic shock, organ failure, and death.
Despite decades of research focused on stopping this “cytokine storm” and hyperinflammation, “we have unfortunately not been able to identify successful drug therapies in sepsis,” said Stier, a physician-scientist who focuses on immunologic and metabolic dysfunction in critical illness. Targeting the inflammatory aspect of sepsis is likely important, but by itself may not be sufficient.
“We provide antibiotics and great supportive care to weather the cytokine storm,” he said, “but that doesn’t fully resolve the problem. It keeps people alive while we wait for their bodies to fix themselves — or not.”
In critical illness, including sepsis, the body’s normal metabolic processes become impaired. This includes immunometabolism, the energy-generating processes that fuel the immune system.
At the same time, the immune system’s protective functions become exhausted, resulting in an acquired immunosuppression, which leaves patients vulnerable to secondary infections, persistent organ dysfunction, repeated hospitalisations and death.
While prior research has defined the characteristics of metabolism and immune dysfunction, this study was among the first to explore the mechanisms of immunometabolic dysfunction in sepsis and their association with immunosuppression, often called “immunoparalysis.”
Stier and his colleagues used cutting-edge technologies, including single-cell sequencing and flow cytometry, to study immune cells collected from the blood of critically ill patients.
The blood samples were collected and stored through the Sepsis Clinical Resource and Biorepository (SCARAB), a unique, highly collaborative ICU biobank developed by Julie Bastarache, MD, and Lorraine Ware, MD, professors of Medicine in the Division of Allergy, Pulmonary and Critical Care Medicine.
Two of the most important elements of the body’s immune responses are CD4+ T “helper” cells, inflammatory “foot soldiers” of the immune system that are distinguished by the CD4 surface protein they express, and regulatory T (Treg or “suppressor”) cells, which guard against over-active immune responses.
To study the impact of critical illness and sepsis on these cells, the Vanderbilt Health team used SCENITH, a flow cytometry-based method developed by French researchers that enables researchers to functionally profile energy metabolism with single-cell resolution.
“This technique allowed us to do something prior studies hadn’t done … to look at the metabolism of every single cell set on its own and identify subset-specific metabolic adaptations,” Stier said.
The key finding: Treg cells undergo metabolic “reprogramming” in patients with critical illness and sepsis, leading to altered tryptophan metabolism and response to reactive oxygen species in a way that enhances their immunosuppressive capability, at the expense of CD4+ T “helper” cells.
“The metabolic turmoil of critical illness appears to give Treg cells a survival and functional advantage, contributing to the harmful immunoparalysis seen in sepsis,” he said.
“This is very much a preclinical paper,” Stier cautioned. Yet it demonstrates the feasibility of deeply dissecting immunometabolic mechanisms using ICU patient biospecimens and highlights the importance of such insights to prioritise future therapeutic targets in critical illness and sepsis, he said.
