Postdoctoral Fellow National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, Maryland, United States
Disclosure(s):
Elisha Segrist, PhD: No financial relationships to disclose
Introduction/Rationale: Tight regulation of uterine immunity is necessary to prevent infection and promote reproduction. How local tissue factors, including the cervicovaginal microbiota, influence uterine immunity is poorly understood. At other barrier sites, interferon lambda (IFN-L) is induced by the microbiota and controls barrier function, tissue immunity, and anti-viral immunity. IFN-L is constitutively expressed in the uterus and placenta and protects the placenta from virus infection. However, the source of immune stimulation that drives basal IFN-L expression and the additional functions of IFN-L outside of antiviral immunity in the uterus and placenta are largely unknown.
Methods: We leveraged spectral flow cytometry to investigate the effect of the cervicovaginal microbiota on uterine immunity using gnotobiotic mice and a model of new intravaginal commensal exposure. We performed spectral flow cytometry and single cell RNA sequencing (scRNAseq) on IFN-L signaling deficient mice to investigate the effect of IFN-L on uterine immunity. Next, we evaluated the anti-bacterial effect of IFN-L in nulliparous and pregnant mice using Streptococcus agalactiae.
Results: We found that IFN-L regulates uterine type 17 immune cell abundance in a microbiota-dependent manner. Our scRNAseq data revealed that loss of homeostatic IFN-L signaling resulted in decreased expression of genes involved in the defense responses to viruses and bacteria. We found that IFN-L did not influence bacterial burden in nulliparous mice. But, during pregnancy, IFN-L protects the placenta and fetus from ascending bacterial infection and from infection induced necrosis. Furthermore, loss of IFN-L signaling during bacterial infection in pregnancy had long term impacts on offspring health and fitness.
Conclusion: Overall, we find that IFN-L is a key immunoregulator in nulliparous animals and a key anti-bacterial factor in pregnant animals. Future work will explore how the microbiota influences uterine IFN-L signaling.
