Research Matters column: Translational approaches key to sepsis research

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. It is considered the No. 3 killer in the U.S., after cardiovascular disease and cancer. The Centers for Disease Control and Prevention estimates that 270,000 sepsis deaths occur annually, and the National Institutes of Health estimates one in every three inpatient deaths is due to sepsis.

The culprits behind this problem are invading pathogens that activate an array of defense mechanisms in the host resulting in a systemic inflammatory/immunological response. The purpose of such a response is to clear such pathogens. However, sometimes this response overshoots and causes self-damage to normal tissues or organs, including the lungs, kidney, heart, and brain, leading to acute respiratory distress syndrome, renal injury or failure, heart attack, and septic encephalopathy (also known as sepsis-induced delirium and cognitive impairment).

Originally thought to be simply induced by an inflammatory cytokine storm, sepsis is now recognized as a far more complicated process involving both pro- and anti-inflammatory pathways and culminating with nonimmunological responses in the circulatory, neuro/autonomic, and metabolic systems. Thus, it has broad implications in multiple areas, including cardiovascular disease, neuroscience, infectious disease and the microbiome. Of particular note, these four areas are in perfect alignment with the major research directions being taken by USF Health.

During the past two decades, significant research efforts have been devoted to understanding the molecular pathobiology of sepsis. However, despite advances in basic science research, which heavily employ rodent models, no new drugs or diagnostic technologies have entered the market for specific treatment of clinical sepsis. The failure of multiple drug trials has been attributed, in large part, to different host responses in humans and rodents.

Tremendous controversy has developed around the translational (bench-to-bedside) value of rodent studies. The argument was escalated by an article entitled “Genomic responses in mouse models poorly mimic inflammatory diseases” (PNAS 110:23507-3512, 2013). When not long after, the same journal published a counter argument entitled “Genomic responses in mouse models greatly mimic human inflammatory diseases” (PNAS 112:1167-1172, 2015), the battle was joined.

More time would be needed to share the long story of how I fought my battle in sepsis research, but I do want to share a recent experience. One of my grant applications did not fare well in its A0 version because a reviewer cited a major concern that my project was a “mouse-only” study. So, I revised the proposal by adding a specific aim to study human blood and cell samples, and the A1 application received a fundable score!

In July 2019, the National Institutes of Health: National Institute of General Medical Sciences sent out a Notice of Information (NOT-GM-19-054) calling for “applications that will provide new knowledge of the mechanistic complexity of sepsis in humans and that will test strategies for translating this knowledge into improved diagnostics and therapies for sepsis patients.” The notice provided a long list of specific topics encouraged for further investigation, along with a short list of areas considered low priority. Guess what made the top of the low-priority list?  Studies using rodent models of sepsis!

Needless to say, translational approaches are the key to sepsis research.

Sarah Yuan, MD, PhD
Deriso Chair in Cardiovascular Disease
Professor and Chair, Department of Molecular Pharmacology & Physiology,
and Professor of Surgery
USF Health Morsani College of Medicine