ABSTRACT While infection biology has largely focused on studying the immune response to a single infection it is becoming increasingly clear that many infections involve more than one pathogen. Therefore studying the effect of one pathogen on the response to another is of utmost clinical importance. Infection with the seasonal influenza virus leads to an estimated 500,000 deaths annually and during global pandemics these numbers are even higher. Bacterial pneumonia is a common complication following infection with influenza virus, which leads to increased morbidity and mortality (1). We propose that the ability to survive an infection is determined by two main factors, resistance (the ability to respond to and clear the pathogen) and tolerance (the ability to tolerate the effects of a given pathogen burden) (2). Myself and others have shown that infection with influenza virus compromises a variety of resistance mechanisms to many different bacterial pathogens. However, in a recent publication I have shown that during influenza virus/bacterial coinfection tolerance is also compromised (3). In a mouse model of influenza virus/Legionella pneumophila coinfection the pathogen load remained unchanged allowing us to focus on tolerance mechanisms. We found that by decreasing the inflammatory immune response and increasing the tissue repair response we were able to increase tolerance to coinfection. As these complex infections are very difficult to treat effectively this finding opens up a new avenue of research and potential treatments for human infectious disease. In this current study we will use a bioinformatics approach to explore the transcriptional profiles of coinfected lungs and lung epithelial cells by RNA-Seq (Aim1). We will use these transcriptional profiles to find and screen small molecule drugs (perturbagens) that increase tolerance to coinfection in an in vitro system (Aim2). We will then apply these findings to increasing tolerance in our in vivo model (Aim3). This study will allow us to discover novel mechanisms of tolerance and treatments viral/bacterial coinfections of the lung. This project has direct applications to human diseases. With the increase in organisms that are resistant to common antimicrobials new treatment regimens are necessary to combat infectious diseases. In addition, even with effective antimicrobial treatments damage can be caused that decreases tolerance, and we must focus on both treating the host and targeting the microbial pathogens. This is particularly true in the context of complex polymicrobial coinfections. Ultimately these findings can be applied to tolerance mechanisms of other lung diseases.