Highly pathogenic respiratory viruses, like the influenza virus and Severe Acute Respiratory Coronavirus (SARS-CoV), represent significant threats to the overall public health and to global economic stability. They cause an acute lung injury (ALI) that rapidly progresses to ARDS, the former most notably in the elderly. Moreover, after virus clearance many SARS and H5N1 patients developed an organizing phase diffuse alveolar damage (DAD) that oftentimes progresses to pulmonary fibrosis (PF), another devastating end stage lung disease effecting 5 million people globally, characterized by dysregulated cell proliferation during wound repair. We have developed a genetically tractable model of induced acute lung injury using the SARS-CoV. We will use this model to study the host factors and cell types that determine the progression from acute lung injury to pulmonary fibrosis. Our preliminary studies demonstrate that the Epithelial Growth Factor Receptor (EGFR) is a key mediator of acute lung injury after infection with the SARS Coronavirus and EGFR is a key intermediate in the regulation of both the innate and wound healing response to acute lung injury.
In Aim 1 we will identify how EGFR over activation causes exacerbated disease.
In Aim 2 we will examine whether inhibition of EGFR signaling can protect the host from disease progression and in Aim 2 we will identify the cell type where EGFR is necessary for disease progression. These studies will allow us to identify the cells that are responsible for the development of acute lung disease and ARDS. The current therapy for pulmonary fibrosis is blunt and treats the whole individual rather than targeting a specific cell population. These therapies work in only a fraction of the patients and can potentially produce more damage than they treat. These studies will identify the specific cell types that lead to acute lung disease induction and progression, allowing for cell directed therapies and targets interventions.

Public Health Relevance

Acute respiratory distress syndrome (ARDS) and pulmonary fibrosis affect millions of people around the world every year and there are few therapies that can ameliorate these diseases. Infection by the SARS Coronavirus, a highly pathogenic respiratory virus, produces acute lung injury which develops into ARDS and pulmonary fibrosis. We have identified a novel mediator of acute lung injury, the epithelial growth factor receptor (EGFR), and using state of the art mouse models of disease, identify the mechanism of EGFR induced injury. These findings will be highly significant since other respiratory viruses such as the Influenza virus and Respiratory Syncytial Virus produce similar lung pathologies;therapeutic targets arising for one disease may be useful in combating multiple diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI095569-04
Application #
8683089
Study Section
Virology - B Study Section (VIRB)
Program Officer
Stemmy, Erik J
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kim, Won-Keun; Jain, Deepika; Sánchez, Melissa D et al. (2014) Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation. Am J Respir Crit Care Med 189:437-48
Coleman, Christopher M; Liu, Ye V; Mu, Haiyan et al. (2014) Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine 32:3169-74
Coleman, Christopher M; Matthews, Krystal L; Goicochea, Lindsay et al. (2014) Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J Gen Virol 95:408-12
Matthews, Krystal L; Coleman, Christopher M; van der Meer, Yvonne et al. (2014) The ORF4b-encoded accessory proteins of Middle East respiratory syndrome coronavirus and two related bat coronaviruses localize to the nucleus and inhibit innate immune signalling. J Gen Virol 95:874-82
Coleman, Christopher M; Frieman, Matthew B (2014) Coronaviruses: important emerging human pathogens. J Virol 88:5209-12
Frieman, Matthew (2014) The art of war: battles between virus and host. Curr Opin Virol 6:76-7
Coleman, Christopher M; Frieman, Matthew B (2013) Emergence of the Middle East respiratory syndrome coronavirus. PLoS Pathog 9:e1003595