Metabolic changes that “rewire” part of the immune system can intensify sepsis, the body’s dysregulated response to infection, which kills 200,000 to 300,000 people in the United States every year.
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 Jan. 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 prioritize therapies for future interventions,” he said.
Stier, a physician-scientist who focuses on immunologic and metabolic dysfunction in critical illness, is a member of the Vanderbilt Center for Immunobiology and the Vanderbilt Institute for Infection, Immunology and Inflammation (VI4).
Sepsis is characterized 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,” Stier said. 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 hospitalizations 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 prioritize future therapeutic targets in critical illness and sepsis, he said.
The paper’s co-corresponding author, Jeffrey Rathmell, PhD, a pioneer in immune and cancer cell metabolism research who founded the Vanderbilt Center for Immunobiology, currently is chair of the Ben May Department for Cancer Research and director of the Ludwig Center at the University of Chicago.
In addition to Rathmell, Bastarache and Ware, the paper’s co-authors included Allison Sewell, Erin Mwizerwa, RN, Chooi Ying Sim, MSN, RN, Samanthan Tanner, RN, Casey Nichols, Heather Durai, Erin Jennings, PhD, MLS, Paul Lindau, MD, PhD, Erin Wilfong, MD, PhD, Sarah Obeidalla, MEd, Eric Kerchberger, MD, and Dawn Newcomb, PhD.
The research was supported in part by National Institutes of Health grants R01DK105550, R01HL136664, R01HL118979, R01AI153167, T32HL094296, T32CA009582, T32AR059039, R35HL150783, RF1AG075341, R01HL158906, R01HL164937, K08AR080808, KL2TR002245, T32GM007347 and T32GM152284, and by the Vanderbilt Center for Immunobiology Human Immunology Discovery Initiative.
SCARAB is supported by a four-year, $1.9-million grant (R33GM144915) awarded in 2022 by the National Institute of General Medical Sciences of the NIH.
