UNDERSTANDING PLACENTAL IMMUNITY: CYTOKINE CONTROL OF CONGENITAL VIRAL INFECTION

During the critical developmental period of pregnancy, there are substantial consequences to viral infection. Following maternal infection, certain viruses can traverse the placental barrier, establish infection in the fetus, and cause adverse pregnancy outcomes or congenital disease. To combat this, the placenta has evolved potent defenses including the constitutive secretion of antiviral factors called cytokines. Previous work has identified antiviral cytokines in the placenta that restrict congenital viral infections without inducing excessive inflammation or immune pathology, such as Type III interferons (IFNλ). However, our understanding of how specific cytokines and cytokine signaling networks contribute to innate antiviral immunity in the placenta is incomplete. We utilized primary human trophoblast organoids, a cutting-edge model that recapitulates the cellular architecture and physiology of the placenta, to study placental cytokine signaling during viral infection. Initially, TO cultures were infected with Zika virus as a model of congenital infection, however, we later explored TO infection with other emerging RNA viruses associated with adverse pregnancy outcomes. Within this dissertation, we identified Interleukin 27 (IL-27) as a novel antiviral cytokine at the maternal-fetal interface with a breadth of activity against different emerging viruses. We examined the protective effects of placental IL-27 signaling using an in vivo mouse model of congenital ZIKV infection and revealed that in addition to restricting placental ZIKV burdens, IL-27 protected against pathologic fetal outcomes early in gestation. This body of work further demonstrates the critical role of placental cytokine interplay in congenital virus regulation. We uncovered evidence of IL-27 and IFNλ signaling interplay in the placenta, which had the capacity to restrict or promote trophoblast infection in a virus-dependent manner. Overall, our work highlights placental IL-27 signaling as a fundamental biological process in human pregnancy and provides new insight into the complex immunological crosstalk at the maternal-fetal interface. Future studies should continue to explore the distinct and shared contributions of cytokines to protective antiviral immunity in the placenta, as this knowledge could ultimately be leveraged to improve pregnancy and congenital infection outcomes worldwide.

Author dc:creator

• Merlino, Madeline, Sophia

Advisor dc:contributor.advisor

• Jurado, Kellie, A

• Microbiology
• Immunology and Infectious Disease
• Life Sciences

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62691

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62691