Project Grant F30HL184772

DECIPHERING THE IMPACT OF EARLY LIFE IMMUNE STIMULATION ON SHAPING LONG-TERM HEMATOPOIESIS - PROJECT SUMMARY HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) EMERGE DURING EMBRYOGENESIS AND SUSTAIN THE BLOOD SYSTEM LIFELONG VIA THE GENERATION OF ALL MATURE BLOOD AND IMMUNE CELLS. DURING DEVELOPMENT, HEMATOPOIETIC STEM CELLS (HSCS), WHICH CAN FORM ALL BLOOD CELLS, EMERGE ALONGSIDE HSC-INDEPENDENT PROGENITOR CELLS (HPCS), WHICH ARE MORE LIMITED IN THEIR DIFFERENTIATION REPERTOIRE. BOTH POPULATIONS ARE CRITICAL FOR SUSTAINING THE ADULT HEMATOPOIETIC AND IMMUNE SYSTEM, YET THE FORMATION AND ESTABLISHMENT OF FUNCTIONALITY OF HSPC POPULATIONS AND THEIR PROGENY DURING DEVELOPMENT REMAINS INCOMPLETELY UNDERSTOOD. THE HEMATOPOIETIC SYSTEM IS DYNAMIC AND RESPONDS TO MANY EXTRINSIC FACTORS INCLUDING INFECTIONS. THESE EXTRINSIC FACTORS ARE KNOWN TO IMPRINT AND SHAPE SUBSEQUENT HSPC RESPONSES IN ADULTS. HOWEVER, FETUSES CAN ALSO BE EXPOSED TO THESE EXTRINSIC FACTORS. MATERNAL INFECTION DURING PREGNANCY CAN CAUSE FETAL EXPOSURE TO PRO-INFLAMMATORY SIGNALS AND PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPS), MOLECULAR STRUCTURES THAT ARE RECOGNIZED AS FOREIGN BY THE IMMUNE SYSTEM TO PROMPT IMMUNE RESPONSES. HOW THESE EXPOSURES MAY IMPACT THE DEVELOPMENT AND EDUCATION OF THE NASCENT HEMATOPOIETIC SYSTEM IN THE SHORT- AND LONG-TERMS REMAINS POORLY UNDERSTOOD. AS STERILE INFLAMMATORY SIGNALING ACTS DURING EMBRYONIC HSPC FORMATION, THE INFLAMMATION INDUCED BY MATERNAL INFECTION AND PAMP EXPOSURE COULD ALTER THE FORMATION OR FUNCTION OF HSCS, HPCS, AND THEIR RESPECTIVE PROGENY. MATERNAL INFECTION CORRELATES WITH POSTNATAL INCIDENCE OF INFECTION, DECREASED IMMUNITY AND DISEASE RISK, INDICATING IT IS AN IMPORTANT BUT UNDERSTUDIED ASPECT OF HUMAN HEALTH. HERE, WE WILL EXAMINE THE EFFECTS OF ADP-HEPTOSE, A NEWLY IDENTIFIED GRAM-NEGATIVE BACTERIA- ASSOCIATED PAMP, ON PRENATAL- AND NEONATAL-LIKE HEMATOPOIESIS USING ZEBRAFISH. WE HAVE ESTABLISHED THAT ADP- HEPTOSE ACTIVATES NFB SIGNALING AND CAN IMPACT BOTH MYELOID AND LYMPHOID LINEAGES. THIS PROPOSAL AIMS TO 1) DECIPHER THE ACUTE IMPACTS OF ADP-HEPTOSE EXPOSURE ON THE NASCENT HEMATOPOIETIC SYSTEM AND 2) IDENTIFY THE EFFECTS OF DEVELOPMENTAL ADP-HEPTOSE EXPOSURE ON THE POSTNATAL HEMATOPOIETIC SYSTEM. IN LARVAL ZEBRAFISH, WE WILL DECIPHER THE ACUTE RESPONSE OF HEMATOPOIETIC AND IMMUNE CELLS TO ADP-HEPTOSE AND THE DEVELOPMENTAL ORIGIN OF THE RESPONSIVE CELLS. IN JUVENILE AND ADULT ZEBRAFISH, WE WILL IDENTIFY LONG-TERM CONSEQUENCES OF PERINATAL ADP-HEPTOSE EXPOSURE. WE WILL FIRST EVALUATE THE CONSEQUENCES TO BASAL POSTNATAL HEMATOPOIESIS BY EXPLORING CHANGES TO THE HEMATOPOIETIC CELLULAR LANDSCAPE, TRANSCRIPTOME, AND CLONALITY, IN NAIVE, PRENATAL-EXPOSED AND NEONATAL-EXPOSED ANIMALS. WE WILL ALSO ASSESS THE IMPACT ON POSTNATAL HEMATOPOIETIC AND IMMUNE CELL FUNCTION BY COMPARING THE RESPONSE TO ADP-HEPTOSE SECONDARY EXPOSURE AND THE REGENERATIVE RESPONSE FOLLOWING FIN WOUNDING IN NAIVE, PRENATAL-EXPOSED AND NEONATAL-EXPOSED ZEBRAFISH. OUR FINDINGS WILL HELP ELUCIDATE HOW COMMON PERINATAL INFECTIONS IMPACT THE FORMATION, EARLY EDUCATION, AND LONG-TERM LANDSCAPE AND FUNCTIONALITY OF THE HEMATOPOIETIC AND IMMUNE SYSTEM WHICH WILL ILLUMINATE CAUSES OF RISK FOR CHILDHOOD INFECTION AND DISEASE.