Allergic sensitization is a significant risk factor for asthma, but allergic sensitization alone is insufficient for the development of the asthma phenotype. Respiratory viruses are implicated in the development of asthma, and serve as the most common trigger for asthma exacerbation. The airway epithelium serves as the primary barrier between inhaled pathogens or environmental antigens and the host immune system, and is the major target of many viruses. In this context, epithelial cells can function as components of the innate immune system, serving as the orchestrator of innate immune responses. Prior work by our group and others demonstrate that there are intrinsic differences in airway epithelial cells (AEC) from adults and children with asthma, notable for alterations in the response to viral infection, and infiltration with innate immune cells such as MCs (MCs). Our overall hypothesis is that AECs from subjects with asthma have an altered response to respiratory viral infection that leads to the activation of innate immune cells that propagate airway inflammation and hyperresponsiveness. The reasons that allergic sensitization progresses to asthma in some individuals, and how allergic sensitization alters innate immune function remains incompletely understood. We propose a ?feed-forward? loop in which an intrinsically abnormal epithelial response to viral infection leads to the generation of cytokines and chemokines that activate and reprogram innate immune cells including MCs, recruited macrophages and innate lymphoid cells (ILC). We postulate that these immune cells also feed forward by regulating epithelial-derived cytokine production. We will directly address our hypothesis using primary AECs from children and adults with and without asthma and/or allergic sensitization. We will use air-liquid-interface organotypic cell cultures to model respiratory viral infection in vitro using co-culture models with human MCs and macrophages. In vivo models using allergic sensitization followed by viral exacerbation will examine the contribution of epithelial-derived cytokines to the recruitment and retention of MCs and recruited macrophages.
In specific aim 1, we investigate the differences in innate immune cells residing in the airways of subjects with asthma, relative to non-asthmatic control subjects with and without allergic sensitization. We examine the contribution of innate cells as key sources of Th2 cytokines in asthma.
In specific aim 2, we determine how viral infection of the airway epithelium, acting through toll-like receptor (TLR)3 and RIG-I-like receptor (RLR) signaling pathways, reprograms the phenotype and function of innate immune cells.
In specific aim 3, we use in vivo models to understand how epithelial-derived cytokines act through MCs and recruited macrophages to regulate the development of airway inflammation and AHR. The completion of these studies using phenotyped AECs will move the field forward through a better understanding of the function of the epithelium in the innate immune response to viral infection leading to the development and progression of asthma.
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