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.

Public Health Relevance

Pneumonia, either viral or bacterial, is the leading cause of death among children under 5 years of age. Influenza virus causes an estimated 500,000 deaths annually, in addition to hospitalizations and loss of productivity from infected people, and bacterial infections are a common complication following respiratory virus infection. This study aims to discover new treatment options for complex infections of the lung.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brown University
United States
Zip Code
Bryner, Darshan; Criscione, Stephen; Leith, Andrew et al. (2017) GINOM: A statistical framework for assessing interval overlap of multiple genomic features. PLoS Comput Biol 13:e1005586
Cabral, Damien J; Wurster, Jenna I; Flokas, Myrto E et al. (2017) The salivary microbiome is consistent between subjects and resistant to impacts of short-term hospitalization. Sci Rep 7:11040
Nakka, Priyanka; Archer, Natalie P; Xu, Heng et al. (2017) Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case-Control and Family-Based Studies in Multiethnic Populations. Cancer Epidemiol Biomarkers Prev 26:1531-1539
Gamradt, Pia; Xu, Yun; Gratz, Nina et al. (2016) The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes. PLoS Pathog 12:e1006032
Criscione, Steven W; Teo, Yee Voan; Neretti, Nicola (2016) The Chromatin Landscape of Cellular Senescence. Trends Genet 32:751-761
Sugden, Lauren Alpert; Ramachandran, Sohini (2016) Integrating the signatures of demic expansion and archaic introgression in studies of human population genomics. Curr Opin Genet Dev 41:140-149