Maternal microchimerism transfers cellular immunity to offspring

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Project Summary/Abstract Bidirectional transplacental exchange of cells between mother and fetus occurs ubiquitously during mammalian pregnancy. Breastfeeding allows further transfer of cells from mother to offspring. The long-term persistence of these genetically foreign cells results in microchimerism. Aside from reproductive fitness, little is known about the function of maternal microchimeric cells. Given the rapid physiological changes occurring during the perinatal period, these cells have the potential to alter the developmental trajectory of progeny. Maternal microchimeric cells traffic to the bone marrow and lymphoid organs in the developing fetus. Thus, these cells have the potential to provide protection against neonatal infection and aid in maturation of the immune system. Neonates are at high risk of developing sepsis or other serious infections, and infection alone accounts for ~35% of all mortality in the neonatal period. We have established tools with which to study microchimerism, especially as it relates to the development of the fetal immune system. Further knowledge is needed regarding neonatal immunity and how it may be shaped by the maternal immune system. Our overall hypothesis is that maternal microchimeric cells provide a means of vertically transferring adaptive cellular immunity from mother to offspring. To address this key unanswered area in development and immunology, we will utilize the clinically relevant pathogens Listeria monocytogenes, which causes serious infections in pregnant mothers as well as sepsis and meningitis in neonates, and Candida albicans, which causes fungal sepsis in premature neonates. We will interrogate how the transfer from mother to fetus of cellular immune responses directed against Listeria or Candida affect susceptibility to neonatal infection. We will further characterize the phenotype of these cells and their mechanism of transfer. The results of these studies could be directly translated to therapies aimed at boosting preconceptual and postnatal cellular immunity. This would be particularly helpful in high risk pregnancies to provide protection against infection in premature infants or those with congenital anomalies. The fellowship training plan will take place under the guidance of the sponsor, Sing Sing Way, M.D/Ph.D., an infectious disease pediatrician and established physician-scientist in the areas of reproductive immunology and prenatal infection. In turn, Cincinnati Children’s Hospital is a superb institution for the study of immunology and reproductive health with a proven track record of translational and clinical implementation of basic research discoveries. The primary investigator is a pediatric physician-scientist performing fellowship training in the Department of Neonatal-Perinatal Medicine. This focused three-year grant will serve to bolster his training as a physician-scientist by providing support for dedicated research time and career development.