Prenatal inflammation as a driver of chronic disease
We discovered a developmentally-restricted hematopoietic stem cell (drHSC) that only exists during early life but is responsible for producing innate-like immune cells that persist into adulthood (Beaudin et al, Cell Stem Cell, 2016). Innate-like lymphocytes, including B1 B cells, γδ-T cells, and recently described innate lymphoid cells (ILCs), play critical roles in mediating tolerance and rapid response to infection, and have also been implicated in autoimmunity and atopic disorders. The identification of a transient cell of origin that generates a distinct component of adult immunity defines a “critical window” for immune development. A critical developmental window is defined as an early sensitive period during which phenotype can be shaped by intrinsic or extrinsic factors. We hypothesize that developmental perturbation shapes susceptibility for disease across the lifespan by altering hematopoietic and immune development during a critical window. We have recently demonstrated that maternal immune activation (MIA) with a single low-dose intraperitoneal injection of poly (i:c) during gestation results in specific expansion drHSCs and their progeny in neonates and abnormal persistence of the drHSC into adulthood (López et al, 2022). How perturbation of the fetal HSC compartment and establishment of developmentally-restricted immune progeny will affect the functional characteristics of the developing and adult immune system are poorly understood. Currently, our lab uses lineage tracing approaches, gene expression profiling, and ex vivo functional assays to define how the maternal immune response influences immune function across the lifespan. By determining how early life events shape the developing HSC compartment and fetal-derived immune cells, this work will take an innovative approach to identifying the molecular and cellular drivers of disease susceptibility from early life.
Regulation of tissue resident macrophage development by IL-7R signaling
Recent fate-mapping experiments have revealed that the adult macrophage system is “layered”. In addition to classical adult monocyte-derived macrophages, “tissue-resident” macrophages self-maintain across the lifespan through in situ proliferation, independent of contribution from bone marrow-derived monocytes. Lineage tracing experiments have provided direct evidence for a fetal origin of these tissue resident populations in situ, but how distinct waves of hematopoietic cell production during fetal development contribute to adult tissue resident macrophage compartments remains unclear. Furthermore, inadequate understanding of the cellular and molecular mechanisms governing fetal macrophage differentiation has limited dissection of tissue macrophage function and heterogeneity in normal adult tissue homeostasis and disease. The appearance of tissue macrophages so early in ontogeny suggests they both educate and are educated within the local tissue microenvironment across development, both to support normal development and acquire critical tissue homeostatic functions. Our lab is interested in investigating the mechanisms that regulate the development of distinct tissue-resident macrophages across ontogeny in order to gain insight into their function and heterogeneity in development and adult immunity. We have recently identified interleukin-7 (IL-7)signaling as a novel regulator of fetal macrophage development during a very restricted developmental window. We are currently investigating the cellular and molecular events that are regulated by IL-7 signaling during fetal myeloid development using a combination of molecular and genetic approaches in vivo and ex vivo.
Translation of maternal inflammation by the fetal immune system: how does the fetus “see” and “translate” prenatal inflammation.
In collaboration with Dr. Kirk Jensen at UC Merced, our lab has used Toxoplasma gondii (T. gondii), a common intracellular TORCH pathogen to model prenatal infection and perturbation of fetal hematopoietic development. During pregnancy, T. gondii can cross the placental barrier and cause spontaneous abortion; in the absence of vertical transmission, maternal inflammation has been linked to fetal resorption and lowered birth weights. Protective immunity may be generated in surviving offspring at the expense of fetal wasting but the mechanisms that underlie this interaction are not well understood. We have used this congenital toxoplasmosis model to dissect the signaling mechanisms that regulate the fetal hematopoietic response, as well as to define regulation of inflammation across the maternal-fetal interface. We combine mouse genetics with in vivo and ex vivo assays to compare the response of a complex infection to single cytokines and break down the complex interactions of the maternal and fetal immune systems during congenital infection.
Deciphering The Developing Immune Response To Congenital CMV Infection
The cochlea is a delicate and structurally complex part of the inner ear peripheral auditory system that is developmentally sensitive to early life infection and inflammation. Sensorineural hearing loss (SNHL) from cochlear dysfunction is a prevalent symptom of congenital infections, such as cytomegalovirus (CMV). The mechanisms underlying CMV-associated SNHL are poorly understood, but surprisingly, evidence suggests that cochlear inflammation is sustained long after active viral infection, contributing to progressive SNHL. The long-term goal of this project is to define the mechanisms by which CMV infection impinges on cochlear immune development in early life and drives pathogenesis in SNHL. Our research focuses on the role of fetal-derived resident tissue macrophages (RTMs) that have been shown to be distributed across key areas of the cochlea, and are required for cochlea development. We aim to elucidate into RTMs mediate cochlea tissue and CMV-associated SNHL, pathological mechanisms of CMV on RTMs and cochlea tissue, and the link between fetal-derived RTMs and tissue architecture.
Disruption of innate lymphoid cell development as a driver of allergic asthma
Innate Lymphoid Cells (ILCs) are a family of innate-like lymphocytes that include NK-cells and other helper-like ILCs, including ILC1, ILC2 and ILC3 subsets. While NK-cells can be categorized as the innate counterparts of cytotoxic CD8+ T-cells, helper-like ILCs are the innate counterparts of T-helper cell subsets.
At barrier sites, ILC2s quickly respond to alarmins (tissue-damage signals) during infection and produce large amounts of IL5 and IL13 cytokines to recruit/activate eosinophils and induce smooth muscle contraction and mucus hyper production in the lung. Recently, ILC2s have been shown to play an important role in the development of allergic airway hyper-responsiveness through disregulated production of these same cytokines.
Using our model of Maternal Immune Activation (MIA), we have demonstrated that prenatal inflammation alters the establishment of a fetal precursor to all ILC lineages and leads to a robust expansion of ILC2s in the neonatal lung. This expansion of neonatal lung ILC2s is accompanied by activation and hyperproduction of IL5 and IL13 cytokines in the same ILC2s, driving a complete remodeling of the lung immune landscape. We are now investigating if these alterations to ILC2 establishment and function during early fetal and neonatal life drive lasting changes to allergic airway hyperreponsiveness across the lifespan.”