Comparison of cytokine responses to group B <i>Streptococcus</i> infection in a human maternal-fetal interface organ-on-a-chip system and <i>ex vivo</i> culture model of human gestational membranes

Adverse pregnancy outcomes represent a global health burden. Bacterial infection and subsequent inflammation in gestational membranes lead to immunological and physiological changes that contribute to adverse pregnancy outcomes. Although animal models of infection during pregnancy are useful to interrogate tissue and cellular level changes in host responses, these models also have numerous drawbacks, including cost, complexity, and ethical considerations. The advent of organ-on-a-chip models provides cutting-edge new approaches to model host-pathogen interactions in multicellular organ and tissue environments. In this work, we employ an organ-on-a-chip model of the maternal-fetal interface as a tool to study immunological responses to infection with the perinatal pathogen, Group B <i>Streptococcus</i> (GBS). Furthermore, we validate the organ-on-a-chip assays using an <i>ex vivo</i> culture model of primary human gestational membranes. GBS infection leads to enhanced production of EGF, FGF-2, G-CSF, GRO-α, IL-6, IL-8, MCP-1, MIP-1α, TNF-β, IL-10, IL-17F in gestational membranes and both the maternal and fetal chambers of the organ-on-a-chip model. Additionally, GBS infection is associated with enhanced TNF-α, RANTES, IL-12p70, IP-10, MIG, FLT3L, GM-CSF, IL-1β, IL-2, PDGF-AB/BB, and IL-17E/IL-25 cytokine production in gestational membranes and the maternal compartment of the organ-on-a-chip model. Gestational membranes challenged with GBS produce IL-15, IL-27, M-CSF, MCP-3, MDC, and MIP-1β, a result that was not seen in the organ-on-a-chip model. GBS infection leads to enhanced production of eotaxin, IFN-γ, IL-1α, IL-4, IL-12p40, IL-13, and SCD40L in the maternal and fetal chambers of the organ-on-a-chip model, but not the gestational membranes <i>ex vivo</i>. Together, these results indicate that GBS infection induces comparable production of a repertoire of cytokines and chemokines in both models, with some salient differences, underscoring the utility of these complementary approaches to study immunological responses to infection at the maternal-fetal interface.