Grant: Discovery Grants Program - Individual

The respiratory tract is composed of various populations of structural and immune cells, that play a critical role in homeostatic and immune processes. For example, during infection by influenza A virus (IAV), both structural and immune cells express a broad spectrum of receptors that allow the detection and response of the virus, setting the tone of the immune response by secreting a myriad of cytokines, including type I (IFN-I, IFN-alpha/beta) and type III (IFN-III, IFN-lambda) interferons, that participate in the pulmonary antiviral response. Yet, our fundamental understanding of the regulatory mechanisms governing the pulmonary antiviral immunity remain largely unknown. The long-term objectives of my NSE research program are to further understand the regulatory mechanisms involved in pulmonary antiviral responses and to identify the cell-specific intrinsic factors, or environmental signals, shaping the lung immunity using influenza A virus (IAV) as a model of respiratory infection.  Although all cells will be considered, in this program, we will mainly focus on dissecting the regulatory mechanisms involved in IFN-I and IFN-III production by alveolar macrophages (AM), the lung tissue-resident macrophages. AM play a critical role in lung homeostasis and surveillance and are among the first cells to sense and respond to invading microbes. We and others have recently shown that AM have a unique ontogeny and arise from fetal progenitors. We have also demonstrated that this unique origin has consequences on AM functions, such as immunometabolism and antibacterial response. However, how AM ontogeny affects their antiviral response remains poorly characterized. Here, we hypothesize that the fetal ontogeny of AM dictates their capacity to produce and respond to IFN-I and IFN-III, resulting in short- and long-term impact on AM functions. To test this hypothesis, we have designed the following short-term objectives. 1. Elucidate how AM fetal origin affects IFN-I production in response to influenza A virus. 2. Determine how AM fetal origin influences IFN-III production in response to influenza A virus. 3. Dissect the short- and long-term effects of IFN-I signaling on fetal-derived AM. This program will uncover and generate important fundamental insights into the biology of alveolar macrophages and increase our understanding of the pathways and mechanisms involved in IFN-I and IFN-III responses, ultimately opening new areas of investigations for future research.