Follicular T helper cell function and antibody response in infants with severe Respiratory Syncytial Virus infections
The Ohio State University
Respiratory syncytial virus (RSV) causes 33.1 million episodes of acute lower respiratory infections, resulting in about 3.2 million hospital admissions, and 59 600 in-hospital deaths in children younger than 5 years during 2015, mostly in developing countries. In Argentina, bronchiolitis due to RSV is the number one cause of postneonatal mortality. An RSV-neutralizing monoclonal antibody, palivizumab, has been used prophylactically for 20 years for infants born prematurely or with heart malformations. However, its cost is prohibitive for low income countries, where most of the fatal cases of RSV disease occur. For this reason, a safe and effective, affordable preventive strategy against RSV is necessary. The RSV vaccine candidates are mostly evaluated based on their induction of RSV neutralizing antibodies. Furthermore, it is known that RS disease cannot generate an effective immune response. The generation of a competent anti-viral B cell response -and consequently an adequate antibody generationrequires co-stimulatory signals and cytokines provided by a subset of specialized CD4+ T cells named follicular T helper cells (Tfh). In accordance, the frequency of many circulating Tfh subsets has been negatively correlated with vaccine responses and severity in infectious and autoimmune disease. Of note, there are no published studies aimed at analyzing the phenotype and/or the function of Tfh cells in the scenario of human RSV infection. Considering both the critical role that Tfh cells play in the induction of B cell responses and the inability of B cells from RSV-infected infants to mount an effective immune response, we hypothesized that the Tfh cell compartment is compromised in the course of RSV infection. The main objective of this project is to characterize the Tfh cell compartment in terms of phenotype, gene expression signature and B cell help functionality during RSV infection in infants. To achieve this goal, we propose four specific aims: 1. To establish the frequency and extensive phenotype of circulating Tfh cells in peripheral blood from infants between 6-24 months of age hospitalized due to severe RSV infection and age-matched healthy children. 2. To analyze the particular gene expression signature of circulating Tfh cells from RSV children and healthy infants. 3. To evaluate the functional capacity of circulating Tfh cells in terms of the cytokine production involved in the T-B cell collaboration process. 4. To determine if there is an association between the frequency of circulating Tfh cells and the development of neutralizing antibodies against RSV detected in the plasma of RSV-infected children. The present project represents a unique opportunity to analyze, for the first time, whether the inefficient B cell response in the course of pediatric RSV infection is related to a defect in the compartment of Tfh cells. If the overall goal of defining the role played by Tfh cells in the B-cell help and promotion of antibodies-mediated protection of RSV infected patients is achieved, this study will expand our understanding of the immune dysfunction observed in these infants. We expect that these results will also open a pathway to new therapeutic interventions by identifying novel molecular targets implicated in T-B cell collaboration.