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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095569-03
Application #
8500163
Study Section
Virology - B Study Section (VIRB)
Program Officer
Stemmy, Erik J
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$485,623
Indirect Cost
$163,898
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Coleman, Christopher M; Sisk, Jeanne M; Mingo, Rebecca M et al. (2016) Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. J Virol 90:8924-33
Luke, Thomas; Wu, Hua; Zhao, Jincun et al. (2016) Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci Transl Med 8:326ra21
Coleman, Christopher M; Sisk, Jeanne M; Halasz, Gabor et al. (2016) CD8+ T cells and Macrophages Regulate Pathogenesis in a Mouse Model of MERS-CoV Disease. J Virol :
Wirblich, Christoph; Coleman, Christopher M; Kurup, Drishya et al. (2016) One-Health: A Safe, Efficient Dual-use Vaccine for Humans and Animals against MERS-CoV and Rabies Virus. J Virol :
Nita-Lazar, Mihai; Banerjee, Aditi; Feng, Chiguang et al. (2015) Desialylation of airway epithelial cells during influenza virus infection enhances pneumococcal adhesion via galectin binding. Mol Immunol 65:1-16
Kindrachuk, Jason; Ork, Britini; Hart, Brit J et al. (2015) Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob Agents Chemother 59:1088-99
Coleman, Christopher M; Frieman, Matthew B (2015) Growth and Quantification of MERS-CoV Infection. Curr Protoc Microbiol 37:15E.2.1-9
Hart, Brit J; Dyall, Julie; Postnikova, Elena et al. (2014) Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 95:571-7
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) Treating MERS-CoV during an outbreak. Lancet Infect Dis 14:1030-1

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