Mechanisms and Consequences of Nucleic Acid Sensing in Erythroid Progenitors - PROJECT SUMMARY This proposed research intends to elucidate the mechanisms and consequences of nucleic acid-sensing in human erythroid progenitors and, ultimately, the outcomes of innate immune activation on erythroid cell biology and function. Erythroid cells are typically considered inert oxygen transporters, and thus their potential contribution to host immunity has been largely ignored. While erythropoiesis typically occurs in the bone marrow of healthy adults, immature, nucleated erythroid progenitors and precursors escape sequestration and circulate during normal fetal development and in response to critical illness. Recent findings challenge the current paradigm that erythroid cells are immunologically inactive, and instead suggest that circulating erythroid progenitors are immunomodulatory. However, there is limited knowledge of underlying mechanisms, leaving a critical gap in our understanding of innate immunity and erythroid cell biology. Preliminary research from the PI and her lab suggests that human erythroid progenitors sense and respond to viral mimetics via activation of nucleic acid-sensing pattern recognition receptors and downstream signaling pathways. This proposed research will test the hypothesis that erythroid progenitors possess innate antiviral immune functions, and that activation of immune signaling pathways in erythroid progenitors impacts differentiation, maturation, and function of mature erythroid cells. This hypothesis will be tested through systematic investigation of both DNA-sensing (Aim 1) and RNA-sensing (Aim 2) pathways utilized by erythroid progenitors to contribute to host antiviral defense. Further, these studies propose to characterize the downstream consequences of nucleic acid sensing on erythroid cell function and development (Aim 3). The long-term goal of this research is to gain a deeper understanding of the interplay between immunity, inflammation, and red blood cell biology. All of the proposed experiments will be conducted by undergraduate students under the close mentorship and supervision of the PI, enabling students to gain valuable hands-on experience and begin building a long-term career in biomedical research.
