Evidence in both humans and mice shows that immunoregulatory mechanisms are transmitted from mothers to their newborns via breast milk. However, early childhood infections by certain pathogens such as respiratory syncytial virus (RSV) compromise these protective mechanisms thereby predisposing to disease (asthma) later in life. Our preliminary data suggest a role for virus-induced Th2 responses in impairment of immunoregulatory mechanisms in newborn mice. In previous studies we have shown the importance of regulatory T cells (Tregs) expressing (mTGF-?) in maintaining immune tolerance in the airways of mice. Given the important role of Tregs in suppressing unwarranted allergic responses in the airways, we investigated whether RSV infection compromises immune tolerance mechanisms in early life. 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. A role for induced Tregs (iTregs) in maternally-transferred tolerance was presented in this study. If RSV infection in newborns can promote allergic disease, we asked whether Treg-mediated immune suppression is compromised by viral infection in the newborns. Indeed, our preliminary data provide evidence of RSV-mediated breach of maternally-transferred tolerance. Since RSV infection promotes Th2 responses, we reasoned that Tregs might change phenotype and function due to instability of Tregs in the context of inflammation. Our preliminary data show the presence of Tregs co- expressing Foxp3 and GATA-3 in RSV infected lungs, which is attenuated in IL-4R-deficient mice. We also show impairment of suppressive function of Tregs isolated from RSV-infected lungs. Additionally, we have observed that dendritic cells isolated from the lungs of infected mice have a more activated phenotype compared to those from uninfected lungs and when exposed to RSV are less efficient in inducing Tregs. These observations lead us to formulate the major hypothesis of this proposal, which is that RSV infection impairs maternally-acquired tolerance mechanisms in newborns. To address this hypothesis we will:
Aim 1. Investigate the role of virus-induced Th2 cytokines in impairment of tolerance and Treg function in newborn mice.
Aim 2. Study the contribution of the CX3CR1 pathway engaged by the viral glycoprotein G 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 virus-infected lungs of mice and non-human primates.
The goal of this application is to understand the mechanisms by which recurrent infection by respiratory syncytial virus in newborns impairs regulatory T cells in the airways with effects on airway immune tolerance and increased risk for asthma.
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