(11) Defining the Role of Toll Like Receptor 8 in Placental Macrophage Responses to Group B Streptococcus Infection

Background: Infection during pregnancy is strongly associated with preterm birth and increased morbidity and mortality for pregnant people and their offspring. The United States has one of the highest rates of pregnancy related mortality amongst industrialized nations and based on data collected by the CDC, infection or sepsis was the second leading cause of these pregnancy-related deaths. Group B Streptococcus (GBS) is a leading cause of infection during pregnancy and in the neonate with extremely limited preventive, diagnostic and therapeutic strategies for management. Complications of GBS ascension result from intrauterine infection of the fetal membrane, placenta and fetus, even when there has not been obvious membrane rupture. Macrophages at the maternal fetal interface are the most common resident professional phagocyte of the placenta and fetal membranes and are critical for maintenance of pregnancy and protection against ascending pathogens. Through pathogen recognition and effector functions, they orchestrate innate immune responses to intrauterine infection and act at the interface with the adaptive immune system to activate T-cells. Little is known about the relative contributions of macrophage subpopulations to the response to intrauterine infection, or how these contributions change throughout pregnancy.

Objectives: To define the role of the endosomal Toll-like receptor (TLR) 8 in the placental macrophage immune response to GBS.

Design/Methods: Utilized immortalized THP-1 cells treated with PMA (to behave functionally more like macrophages) in placental conditioned media, we infected with GBS and measured immune responses.

Results: Using knock-out cell lines for various TLRs (including 2, 4, and 8), we have started to define the role of TLR8 in the inflammatory response to GBS. We Have profiled both NF-kB and IRF responses of the placental conditioned macrophages to show the relative roles of TLR2 and TLR4 in comparison to TLR8. In addition, we have defined a potential role of TLR8 in inflammasome activation of the placental conditioned macrophages in response to GBS.

Conclusions: Together, we have defined the role of TLR8 in the placental conditioned macrophage response to GBS. These data provide insight into a potential mechanism for aiding in the inflammation associated with GBS infection during pregnancy via modulation of TLR8 activity.