Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization, and severe RSV bronchiolitis has been identified as a risk factor for th subsequent development of asthma in children. There is no currently available therapy for RSV bronchiolitis. Moreover, no vaccine is FDA-approved and the only prevention option for RSV infection is palivizumab, a monoclonal antibody directed against the RSV fusion protein. Given the frequency and severity of infection, the development of new treatment options is imperative. Our preliminary data suggest that exogenous prostaglandin (PG) I2 is a novel therapeutic target for RSV. Our group reported that mice that constitutively overexpress PGI synthase (PGIS) were significantly protected from RSV-induced illness. In addition, we found that mice which cannot signal through the PGI2 receptor (IP) had significantly exacerbated weight loss and delayed recovery after RSV infection. In a collaborative study of infants admitted with RSV bronchiolitis, we found that a functional polymorphism in the promoter region of the PGI synthase (PGIS) gene was associated with an increase in the urinary PGI2 metabolite and less severe RSV bronchiolitis. These data strongly support that endogenous PGI2 protects against RSV-induced illness. To pave the way for a clinical effectiveness study using PGI2 for the treatment of RSV infection, we must perform preclinical studies to determine how exogenous PGI2 regulates RSV-induced illness and determine the mechanisms by which exogenous PGI2 modulates host antiviral immunity. Interleukin 13 (IL-13) can be produced by T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s). During RSV infection, IL-13 mediates mucus production, which directly contributes to airway obstruction and respiratory failure. On the other hand, IL-10, which can be produced by T regulatory cells (Tregs), inhibits RSV-induced inflammation. RSV-specific CD8+ T cells are a major source of IFN-?, which limits viral replication. I found significantly decreased lung IL-13 accompanied by increased lung IL-10 and IFN-? in RSV-infected mice treated with exogenous PGI2. Accordingly, I hypothesize that exogenous PGI2 attenuates IL-13 producing- Th2 cells and ILC2s while enhancing IFN-?-producing CD8+ T cells and IL-10-producing Tregs during RSV infection, resulting in decreased RSV-induced illness.
In Aim 1, I hypothesize that exogenous PGI2 inhibits RSV-induced Th2 cell and ILC2 cytokine expression and proliferation, while enhancing Treg cytokine expression and proliferation, resulting in attenuated mucus production.
In Aim 2, I hypothesize that exogenous PGI2 enhances RSV-specific CD8+ T cell activation and proliferation, resulting in decreased viral replication during RSV infection. These studies will advance the field in that they will determine how PGI2, an FDA-approved agent, attenuates RSV illness. The current availability of PGI2 for human treatment highlights the clinical significance of my studies as this therapy could be immediately transferrable to RSV disease.

Public Health Relevance

Respiratory syncytial virus is the leading cause of infant hospitalization and bronchiolitis in the United States. Endogenous prostaglandin (PG) I2 protects against RSV-induced illness in both infants and mice. This study aims to determine the role of exogenous PGI2, an FDA-approved agent currently used in pulmonary hypertension, in the immune response to respiratory syncytial virus-induced illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AI118376-05
Application #
9626850
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kim, Sonnie
Project Start
2015-01-29
Project End
2021-01-28
Budget Start
2019-01-29
Budget End
2020-01-28
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
965717143
City
Nashville
State
TN
Country
United States
Zip Code
37240
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