Respiratory viral infections in infants can have devastating effects acutely on airway function, but may also impact the longterm function of the lung in both children and adults. The most common respiratory infection that is the predominant cause of hospitalization in children (>90%) is respiratory syncytial virus (RSV) infection. The initiation of the proper anti-viral responses are mandatory for successfully clearing this pathogen with minimal pathophysiologic responses. In the present proposal we will focus on the earliest immune responses to RSV infection involving the initial activation of toll- like receptors (TLRs) on dendritic cells (DCs) followed by the upregulation of important instructive signals that initiate the acquired immune responses. Recent findings have identified that notch/notch ligand induced activation has a profound role on the activation and differentiation of mature T cells. The upregulation of specific notch ligands on DCs is MyD88-dependent and provides a critical step in mature T cell differentiation. However, little is known about the role of Notch/notch ligand activation pathways for the generation of effective immune responses during virus infections. Our hypothesis for this proprosal is that TLR-mediated notch ligand delta-like 4 is required for the initiation of the appropriate immune response, and without it RSV infection becomes more pathogenic and results in an altered immune environment. These studies will specifically address several novel mechanistic questions by progressing through 3 specific aims that will 1) determine the critical TLR-induced DC activation pathway during RSV infection for anti-viral instructive signals;2) identify the role of delta- like 4 in the development of RSV-induced immune responses and pulmonary pathology; 3) determine the differential role of plasmacytoid versus conventional DC populations for the expression of delta-like 4 and T cell activation in RSV infection. Together these individual specific aims, which are independent of one another yet clearly integrated, will each address our overall hypothesis. We will investigate these observations mechanistically using a combination of studies in gene knockout mice, specific neutralizing antibodies, and cell transfer experiments along with DC and T lymphocyte isolation. The use of specific novel reagents and advanced techniques will allow our highly integrated group of investigators to specifically target these mechanisms in a logical translational manner.

Public Health Relevance

Our studies will investigate a set of PAMP molecules known as toll-like receptors (TLRs) and their cell signaling mechanisms related to the production of cytokines, chemokines, and notch ligands. Understanding these important signaling mechanisms will allow the assessment of alterations during disease related to a lack of RSV clearance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073876-05
Application #
8206794
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Kim, Sonnie
Project Start
2008-01-15
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$364,793
Indirect Cost
$119,768
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mukherjee, Sumanta; Rasky, Andrew J; Lundy, Phil A et al. (2014) STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease. J Immunol 192:996-1003
de Almeida Nagata, Denise E; Demoor, Tine; Ptaschinski, Catherine et al. (2014) IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis. Am J Pathol 184:1807-18
Reed, Michelle; Morris, Susan H; Jang, Sihyug et al. (2013) Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection. J Immunol 191:2526-37
Jang, Sihyug; Smit, Joost; Kallal, Lara E et al. (2013) Respiratory syncytial virus infection modifies and accelerates pulmonary disease via DC activation and migration. J Leukoc Biol 94:5-15
Morris, Susan; Swanson, Michele S; Lieberman, Andrew et al. (2011) Autophagy-mediated dendritic cell activation is essential for innate cytokine production and APC function with respiratory syncytial virus responses. J Immunol 187:3953-61
Reynolds, Nathanael D; Lukacs, Nicholas W; Long, Nancy et al. (2011) Delta-like ligand 4 regulates central nervous system T cell accumulation during experimental autoimmune encephalomyelitis. J Immunol 187:2803-13
Mukherjee, Sumanta; Lindell, Dennis M; Berlin, Aaron A et al. (2011) IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease. Am J Pathol 179:248-58
Lindell, Dennis M; Morris, Susan B; White, Maria P et al. (2011) A novel inactivated intranasal respiratory syncytial virus vaccine promotes viral clearance without Th2 associated vaccine-enhanced disease. PLoS One 6:e21823
Kallal, Lara E; Schaller, Matthew A; Lindell, Dennis M et al. (2010) CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC. Eur J Immunol 40:1042-52
Jang, Sihyug; Schaller, Matthew; Berlin, Aaron A et al. (2010) Notch ligand delta-like 4 regulates development and pathogenesis of allergic airway responses by modulating IL-2 production and Th2 immunity. J Immunol 185:5835-44

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