Early Origins of Childhood Asthma: Role of Perinatal Microbial Exposure and Innate Immunity
thesisposted on 01.05.2021, 00:00 authored by Benjamin Arthur Turturice
Asthma—defined by reversible expiratory airflow obstruction-- is the most common chronic disease of childhood in the United States. While many triggers (e.g. bacteria, viruses, allergens, and pollution) have been identified as causative agents of asthma, there is no single etiology that drives reversible obstruction children. The pathogenesis of childhood asthma likely stems from an individual x environment interaction that is highly complex. The focus of the studies of the Finn-Perkins lab described here was to identify microbial exposures and immunological differences at birth that are predictive of asthma development, asthmatic response to triggers, and severity of asthmatic symptoms. Although there is no known single etiologic agent, children with asthma have demonstrable skewing of T-cell responses toward Th2 or “allergic” processes. Using an unbiased approach, we assessed relationships between perinatal microbial exposure and Th2 responses to common air-borne allergens that are known asthma triggers. We identified a specific phyla of Gram negative organisms, Proteobacteria, with negative associations with Th2 responses. Further, increased abundance of Proteobacteria was significantly associated with reduced risk of wheezing childhood. Together, this is suggestive of a protective role of early exposure to Proteobacteria. While Th2 responses are a hallmark of childhood asthma, it is not clear what predisposes to this immunologic skewing later in childhood. There are many risk factors for childhood asthma that have been identified, and many of these are discernable at birth (e.g. sex, mode of delivery, gestational age…). We demonstrated that the pre/perinatal risk factors have additive effects and in using an unbiased approach, we were able to identify a transcriptional signature associated with pre/perinatal risk stratification. xiv Additionally, we determined that umbilical cord serum PGLYRP-1 concentrations were predictive of this transcriptional signature, current asthma at 7 years old, and FEV1/FVC at 12 years old. The concentration of PGLYRP-1 was associated with perinatal exposure to Proteobacteria and several Proteobacteria genera. Collectively, this suggests that early exposure to Proteobacteria enhances innate immunity and, through enhanced innate immunity, may protect against future development of asthma. Additionally, these findings demonstrate that accurate prediction of asthma risk may be capable at birth using a serological marker, PGLYRP-1.