Prince, J. | bioRxiv Science

bioRxiv2019

Heart rate variability as an indicator of autonomic nervous system disturbance in tetanus

Autonomic nervous system dysfunction (ANSD) is a significant cause of mortality in tetanus. Currently diagnosis relies on non-specific clinical signs. Heart rate variability (HRV) may indicate underlying autonomic nervous system activity and represents a potentially valuable non-invasive tool for ANSD diagnosis in tetanus. HRV was measured from 3 5-minute ECG recordings during a 24-hour period in a cohort patients with severe tetanus, all receiving mechanical ventilation. HRV measurements from all subjects - 5 with ANSD (Ablett Grade 4) and 4 patients without ANSD (Ablett Grade 3) - showed HRV was lower than reported ranges for healthy individuals. Comparing different severities of tetanus, raw data for both time and frequency measurements of HRV were reduced in those with ANSD compared to those without. Differences were statistically significant in all except root mean square standard deviation RMSSD (p=0.07) indicating HRV may be a valuable tool in ANSD diagnosis.

pathology↗

bioRxiv2019

Extracellular CIRP as a Novel Endogenous TREM-1 Ligand to Fuel Inflammation

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently-discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation in sepsis is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis and ischemia-reperfusion. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and FRET assay confirmed eCIRPs interaction with TREM-1 in macrophages. TREM-1 inhibition, either by its siRNA or a decoy peptide LP17, dramatically reduced eCIRP-induced inflammation. We developed a novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 Ab crosslinking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis and intestinal ischemia-reperfusion, improved acute lung injury, and increased survival. Thus, we have discovered a novel TREM-1 ligand and developed a new peptide M3 to block eCIRP-TREM-1 interaction and improve the outcome of sepsis and sterile inflammation.

immunology↗