Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

IL-1 receptor antagonist rytvela protects against Group B Streptococcus (GBS)-induced preterm birth and fetal loss in mice. (#100)

Peck Y Chin 1 , William D Lubell 2 , David M Olson 3 , Sylvain Chemtob 4 , Jeffrey A Keelan 5 , Sarah A Robertson 1
  1. Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia
  2. Department of Chemistry, Université de Montréal, Montréal, Québec, Canada
  3. Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, Edmonton, AB, Canada
  4. Departments of Pediatrics, Opthalmology and Pharmacology, CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada
  5. Division of Obstetrics and Gynaecology, The University of Western Australia , Subiaco, WA, Australia

Premature birth is a common and critical health issue in fetal-maternal medicine with long-term consequences especially for early preterm neonates. The pathophysiology is poorly understood and the causal factors often uncertain, but inflammatory mechanisms are clearly implicated. Toll-like receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery and pro-inflammatory cytokine interleukin-1 beta (IL-1b) has been identified as a major upstream product following the activation of the TLR pathway. Previously we have shown that inhibition of IL-1 signaling using rytvela, a non-competitive allosteric peptide inhibitor of IL-1 receptor (IL-1R) signaling, can prevent preterm birth caused by the TLR4 ligand lipopolysaccharide in mice. Here we evaluate the efficacy of rytvela in preterm birth elicited by Group B Streptococcus (GBS), a gram-positive bacteria commonly associated with spontaneous preterm birth in women, that activates inflammation via TLR2 and TLR8. We investigated (1) whether inhibition of IL-1 signalling using rytvela may prevent the parturition cascade caused by GBS-induced inflammation and (2) the consequences of in utero exposure to rytvela for resulting progeny. Pregnant C57Bl/6 mice (n=8-16 dams per group) were administered intrauterine heat-killed GBS (5x109 IU/100 µl) or PBS, with or without co-administration of rytvela (ip), on gestational day (GD) 16.5 and allowed to progress to birth. Rytvela treatment acted to reduce the rate of GBS-induced preterm delivery from 62% (9/16) to 12% (1/8)(p<0.05). Viable litter size at birth was increased from 2.7±0.8 to 5.4±0.7 pups per litter (p<0.05), and postnatal survival at 1 week was increased from 44% to 62%. These results demonstrate that intervention with rytvela to suppress the IL-1-induced inflammatory cascade can mitigate GBS-induced preterm birth and perinatal death. The data support continued investigation of the IL-1 pathway as a potential target for new prevention or treatment options in women at risk of preterm delivery.