Infections of the respiratory tract with viruses such as influenza or respiratory syncytial virus are a constant challenge to human health, particularly to children, the elderly, and the immunocompromised. Deregulation of the inflammatory response developed to control and clear the infection leads to life threatening disruption of the respirator tract physiology and loss of integrity of the mucosal barrier, thereby largely contributing to the high degree of morbidity associated with these infections. Understanding the mechanisms that regulate the inflammatory response to infection is essential to identify targets for therapeutic intervention. Our data indicate that neutrophils that are recruited to the lung early upon respiratory viral infections play an essential role in regulating the extent of the inflammatory response. Interestingly, a fraction of these neutrophils produce the regulatory cytokine IL-10, and IL-10 expression by these cells is stimulated by the antiviral cytokines type I interferons produced in the lung during infection. As neutrophils are massively recruited to the lung at the early stages of viral infections, we hypothesize that in response to the antiviral inflammatory environment, a population of neutrophils acquire a regulatory phenotype that significantly contributes to protection from lung damage and associated pathologies. Supporting this hypothesis, mice bearing IL-10 deficient myeloid cells developed a more severe lung inflammation and showed enhanced morbidity. Here, we will use cutting edge technology to characterize IL-10-producing neutrophils present in the lung of mice infected with respiratory syncytial virus (Aim 1), we will determine whether type I IFN priming is required for the neutrophil protective activity (Aim 2), and we will test whether neutrophil-produced IL-10 modulates the inflammatory response to virus infection (Aim 3). Overall, this exploratory R21 grant aims at morphologically and phenotypically characterizing pulmonary IL-10-producing neutrophils present during respiratory viral infections, and to advance our understanding of their function in lung protection. These studies should guide future identification of molecular targets for the harnessing of the neutrophil protective activities in patients.
Control of the host inflammatory response during infection is essential to limit immune-mediated pathology and tissue destruction. We have identified a population of IL-10-producing neutrophils candidate to provide protection from excessive inflammation during virus infection. In this exploratory study we will characterize these IL-10 producing neutrophils, we will study the impact of type I IFNs in their activity, and we will test whether neutrophil-produced IL-10 aids in the maintenance of lung homeostasis during virus infection with the goal of identifying novel candidate pathways to mediate tissue protection.
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