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Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection.

ABSTRACT: Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not been examined. In this study, primary isolated DCs from cord blood and adult peripheral blood were compared after RSV infection. Transcriptional profiling and biological network analysis identified transforming growth factor beta (TGF-?) and associated signaling molecules as differentially regulated in the two age groups. TGF-?1 was decreased in RSV-infected adult-blood DCs but increased in RSV-infected cord blood DCs. Coculture of adult RSV-infected DCs with autologous T cells induced secretion of gamma interferon (IFN-?), interleukin 12p70 (IL-12p70), IL-2, and tumor necrosis factor alpha (TNF-?). Conversely, coculture of cord RSV-infected DCs and autologous T cells induced secretion of IL-4, IL-6, IL-1?, and IL-17. Addition of purified TGF-?1 to adult DC-T-cell cocultures reduced secretion of IFN-?, IL-12p70, IL-2, and TNF-?, while addition of a TGF-? chemical inhibitor to cord DC-T-cell cocultures increased secretion of IL-12p70. These data suggest that TGF-? acts as a major regulator of RSV DC-T-cell responses, which could contribute to immunopathology during infancy.

SUBMITTER: Thornburg NJ

PROVIDER: S-EPMC3004333 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection.

Thornburg Natalie J NJ Shepherd Bryan B Crowe James E JE

Journal of virology 20101006 24

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not be ...[more]

PMID: 20926560

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Project description:Human respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory tract disease in infants worldwide. As a first line of defense against respiratory infections, innate immune responses, including the production of type I and III interferons (IFNs), play an important role. Upon infection with RSV, multiple pattern recognition receptors (PRRs) can recognize RSV-derived pathogen-associated molecular patterns (PAMPs) and mount innate immune responses. Retinoic-acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) have been identified as important innate receptors to mount type I IFNs during RSV infection. However, type I IFN levels remain surprisingly low during RSV infection despite strong viral replication. The poor induction of type I IFNs can be attributed to the cooperative activity of 2 unique, nonstructural (NS) proteins of RSV, i.e., NS1 and NS2. These viral proteins have been shown to suppress both the production and signaling of type I and III IFNs by counteracting a plethora of key host innate signaling proteins. Moreover, increasing numbers of IFN-stimulated genes (ISGs) are being identified as targets of the NS proteins in recent years, highlighting an underexplored protein family in the identification of NS target proteins. To understand the diverse effector functions of NS1 and NS2, Goswami and colleagues proposed the hypothesis of the NS degradasome (NSD) complex, a multiprotein complex made up of, at least, NS1 and NS2. Furthermore, the crystal structure of NS1 was resolved recently and, remarkably, identified NS1 as a structural paralogue of the RSV matrix protein. Unfortunately, no structural data on NS2 have been published so far. In this review, we briefly describe the PRRs that mount innate immune responses upon RSV infection and provide an overview of the various effector functions of NS1 and NS2. Furthermore, we discuss the ubiquitination effector functions of NS1 and NS2, which are in line with the hypothesis that the NSD shares features with the canonical 26S proteasome.

Dataset Information

Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection.

Publications

Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection.

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