Altered Treg and cytokine responses in RSV-infected infants

Abstract

Background: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in children under one year of age in the United States. The host immune response is believed to contribute to RSV-induced disease. We hypothesize that severe RSV infection in infants is mediated by insufficient regulation of the host immune response of regulatory T cells (Tregs) resulting in immunopathology. Methods: Blood and nasal aspirates from 23 RSV-infected and 17 control infants under 1 year of age were collected. Treg frequencies were determined by flow cytometry from peripheral blood mononuclear cells. Analysis of 24 cytokines was measured by multiplex assay on nasal aspirates. Results: We demonstrate that the frequency of activated Tregs is significantly reduced in the peripheral blood of RSV-infected infants compared to age-matched controls. Surprisingly, Th17 related cytokines including IL-1β, IL-17A, and IL-23 were associated with a reduction in clinical symptoms of respiratory distress. In addition, the amount of IL-33 protein in nasal washes, a cytokine important in maintaining Treg homeostasis in mucosal tissues, was decreased in RSV-infected children. Conclusion: These results suggest that decreased Treg numbers and an inability to properly control the host inflammatory response results in severe RSV infection.

Haemophilus is overrepresented in the nasopharynx of infants hospitalized with RSV infection and associated with increased viral load and enhanced mucosal CXCL8 responses

“…The increase in IL6 and CXCL-8 responses in RSV patients colonized with Haemophilus as found in our study corroborates a recent in vitro study by Gulraiz et al They showed that release of IL6 and CXCL-8 after RSV infection, but not rhinovirus infection, was synergistically increased in Haemophilus influenzae pre-treated human bronchial epithelial cells [40], suggesting that the interaction between H. influenzae, CXCL8, and RSV may be specific for RSV infections. It should finally be noted that other cytokine responses than the ones studied here might be important for RSV pathogenesis, such as Thelper 1, T-helper 2, and T-regulatory cell type cytokines [43]. Their potential involvement with the nasopharyngeal microbiome during RSV pathogenesis can therefore not be confirmed within the current study.…”

Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

“…Inhibitory cytokines are also detected following RSV infection in mice, most commonly IL-10 [77,79]. Importantly, these same cytokines are elevated in the nasopharyngeal secretions of infants recently infected with RSV [73,[80][81][82]. The induction of many pro-inflammatory cytokines has been directly associated with CD8 T cell responses.…”

“…RSV infection in mice induces IL-10 production in the lung and airways that peaks at approximately 5 days post-infection, prior to the peak of the CD8 T cell response [19,77,79]. IL-10 is also detected in the nasopharyngeal secretions of hospitalized RSV-infected infants [73,81]. T cells are the major cellular source of IL-10, as RSV infection of either CD4 and CD8 T cell-depleted mice or Rag KO mice, which lack T cells, results in little detectable IL-10 in the lung and airways, respectively [19,79].…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…A higher ratio of T-helper lymphocyte type 1 cells to T-helper lymphocyte type 2 cells and increased interferon-γ production are a feature of Down syndrome [173]. Intriguingly, severe RSV infection is hypothesised to result from disturbance in regulatory T-cell mediated control of host immune function [174].…”