The Immune Response to Pathogens is Controlled by the Cytokine-Induced Epigenetics Signature

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Project Summary/Abstract: A lingering conundrum associated with studying host defense transcription profiles is how do specific cells ?remember? whether or not they should be actively transcribing specific genes, which would facilitate their participation in an inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post-translational modifications of histones, as mechanisms to regulate the expression profiles of cell derived mediators during an inflammatory response. We have addressed epigenetic mechanisms that result in the immunopathology caused by influenza, using both normal and infected human cell-based systems and an experimental model of infectious influenza. The latter model will be used to guide our human cell based system. We present data that the cytokine environment established by influenza induces the expression of specific epigenetic machinery that controls the expression of host defense mediators. We identified that interferon beta serves in an autocrine/paracrine manner to cause the expression of Setdb2, an epigenetic- based lysine methyl transferase that is responsible for setting a suppressive histone mark, resulting in host anti-bacterial defense gene silencing. While this sequence of events is likely beneficial against the primary influenza infection, the unintended result is that the defense system that target bacterial infections is impaired. This scenario may provide the mechanism whereby secondary bacterial pneumonia is associated with initial influenza infections. Our data reveals that in both human and mouse models of influenza this same epigenetic pathway can be identified We hypothesize that during the evolution of primary influenza pneumonia a cytokine environment characterized by high levels of IFN-B is established to control the primary viral infection; however, this process engages an epigenetic-based mechanism, which suppresses M? pro- inflammatory responses, rendering the host susceptible to secondary bacterial infection. This hypothesis will be investigated via the following specific aims: To determine the mechanism(s) whereby the influenza-induced IFN-B/STAT1 pathway results in the expression of a chromatin modifying lysine methyltransferase, SETDB2, in primary human cells. To investigate a novel mechanism whereby SETDB2 is guided to promoter sites on targeted genes via binding to specific transcription factors, resulting in chromatin modifications at precise promoter locations. To assess the suppressive role of Setdb2 expression on M? activity during a primary influenza infection, which decreases both phagocytosis and T cell function and mechanistically contributes to the host susceptibility to secondary bacterial infection. .