Each year in the United States, 1.7 million people develop — and an estimated 350,000 deaths result from — sepsis, an out-of-control inflammatory response to infection.
Sepsis disproportionately affects newborn babies, older adults, and people with impaired immune function, cancer, chronic lung disease, heart failure and certain blood disorders. An estimated 1 million patients whose spleens have been removed or who have reduced spleen function are especially vulnerable.
“Sepsis is a swift and burdensome killer of the youngest and oldest, and those in between,” said Jacek Hawiger, MD, PhD, an internationally known authority on inflammatory mechanisms of disease at Vanderbilt University Medical Center.
Currently, there is no specific drug to treat sepsis. But hope is on the horizon, thanks to a “peptide genomic therapy” Hawiger and his colleagues have developed.
In a paper published Oct. 10 in the journal Frontiers in Immunology, they report that the survival rate from sepsis nearly doubled in mice given the therapy in combination with an antibiotic, compared to an antibiotic-only control group.
“Our peptide genomic therapy offers a new way to treat sepsis by targeting its basic inflammatory mechanisms,” said Hawiger, Distinguished Professor of Medicine and the Louise B. McGavock Professor in the Division of Allergy, Pulmonary and Critical Care Medicine.
Hawiger co-authored the paper with longtime research colleagues Huan Qiao, MD, PhD, Jozef Zienkiewicz, PhD, and Yan Liu, MD, MS.
In response to allergic, autoimmune, metabolic or — in this case — microbial triggers, intracellular proteins called transcription factors are ferried into the nuclei of immune and nonimmune epithelial and vascular cells. Here, they reprogram gene expression, and ramp up production of inflammatory molecules, including cytokines, chemokines, their receptors and signaling proteins.
If unchecked, the inflammatory response can quickly get out of control, causing tissue swelling, damage and — in the case of septic shock — multiple organ failure and death. Nearly 40% of patients die within 90 days of developing septic shock, which occurs when blood pressure drops too low to sustain life.
The spleen, a major blood-filtering immune organ, plays a key role in responding to and controlling invasive bacterial infections that otherwise could lead to sepsis.
Patients with impaired spleen function, or from whom the spleen has been removed due to trauma, cancer or blood disorders such as sickle cell disease, are at increased risk of developing potentially lethal viral and bacterial pneumonias in their lungs.
Hawiger and his colleagues have been investigating sepsis since the mid-1990s. Their peptide genomic therapy, which they have shown can suppress immune activation and inflammation, is administered with a nuclear transport checkpoint inhibitor (NTCI), a cell-penetrating peptide they developed a decade ago.
The NTCI peptide, a combination of two human protein fragments called cSN50.1, suppresses the transport of inflammatory transcription factors into the nucleus.
In the current study, the researchers analyzed 485 gene orthologs, ancestral genes in mice that in humans are responsible for immunodeficiencies. Their therapy reprogrammed 227 of these genes in the spleen, and the peptide suppressed numerous inflammatory molecules.
In addition, peptide genomic therapy with the NTCI peptide and antibiotic increased bacterial clearance — removal of sepsis-triggering bacteria — by 12 times in the blood, 11 times in the lungs, and 9 times in the spleen.
Survival from sepsis increased from 44% among mice treated with antibiotic alone, to 80% among those that received antibiotic plus peptide genomic therapy with NTCI peptide.
“These extensive preclinical studies of sepsis and its innovative treatment developed in our laboratory provide a solid foundation for much-needed clinical trials in this life-threatening and/or debilitating condition,” Hawiger said.
The research was supported by the endowed Louise B. McGavock Chair, the Department of Medicine’s Immunotherapy Program, and the Department of Veterans Affairs.
