Recurrent infections in early childhood by respiratory viruses such as respiratory syncytial virus (RSV) increase the risk for developing asthma later in life. In adults too, RSV is a significant health risk inducing 'flu-like' illnesses. The immunologi basis for why RSV infections in early life pose a risk for asthma has not been adequately investigated. Since asthma is a significant public health problem, it is important to understand the underlying factors that predispose to this disease. Our prior studies of immunoregulatory mechanisms that suppress allergic airways disease have shown the importance of regulatory T cells (Tregs) expressing membrane-bound TGF- (mTGF- ) in maintaining immune tolerance in the airways of mice. Importantly, the TGF- level in the breast milk of humans has been inversely associated with wheezing in infants. Given the crucial role of Tregs in suppressing unwarranted allergic responses in the airways, we investigated whether RSV infection compromises immune tolerance in early life by disabling Tregs. Using the same model of airway tolerance previously used by us to demonstrate the importance of mTGF- in airway tolerance, it was recently shown that mothers tolerized to the antigen (Ag) ovalbumin (OVA) can transfer OVA and TGF- to their newborns via breast milk showing a close correspondence with human data. This mechanism was found to induce immune tolerance in the newborn mice and based on the dependence on active TGF- signaling in the neonates, a role for induced Tregs (iTregs) was invoked. If RSV infection in newborns can promote allergic disease, we asked whether RSV compromises Treg phenotype and function in the newborns which is clearly evident in our ongoing experiments. Since RSV, in particular its glycoprotein G, has been associated with Th2 responses in infected hosts, we will study its role in the RSV-mediated impairment of Treg function. Collectively, we have exciting data that show the presence of Tregs expressing Foxp3 and GATA-3 in RSV infected lungs, which is promoted by Th2-type cytokines induced by the virus and attenuated by all trans retinoic acid (ATRA). Both in vitro and in vivo assays show severe impairment of Treg suppressive function when the cells are isolated from the lungs of infected mice. These observations lead us to formulate the major hypothesis of this proposal, which is that RSV infection impairs maternally-acquired tolerance mechanisms in newborns by compromising Treg function. To address this hypothesis we will:
Aim 1. Investigate the role of RSV-induced Th2 cytokines in impairment of tolerance and Treg function in neonates.
Aim 2. Study the contribution of the RSV G protein and its receptor CX3CR1 in impairment of Treg function in RSV-infected neonates.
Aim 3. Examine the ability of aerosolized liposome-encapsulated ATRA to restore Treg function and airway tolerance in RSV-infected lungs.

Public Health Relevance

The goal of this application is to understand the mechanisms by which viral infection impairs regulatory T cells that in turn compromise maternally-acquired immune tolerance in the airways. The study will serve as a model for studying respiratory illnesses caused by other respiratory viruses such as the influenza (flu) virus that may also similarly affect tolerance mechanisms in adults.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Davidson, Wendy F
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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