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Mechanisms of respiratory syncytial virus modulation of airway immune responses.

ABSTRACT: Respiratory syncytial virus (RSV) most often causes severe respiratory disease in the very young and the elderly. Acute disease can also cause exacerbations of asthma in any age group. Recent findings provide insight into how the innate and adaptive immune systems respond to RSV infection and provide preliminary evidence that these effects vary significantly by RSV strain and host. Components of cell signaling pathways that induce inflammatory cytokine expression during the innate immune response and alter epithelial cell polarity through activating transcription factors, namely NF-?B, are now more clearly understood. New studies also reveal how RSV infection skews T helper (Th) cell differentiation away from the cell-mediated Th1 subset and towards the Th2 subset. There are also new data supporting preferential Th17 differentiation during RSV infection. In addition, effective immune system regulation of IL-10 expression and T regulatory cell (Treg) airway accumulation are essential for effective RSV clearance.

SUBMITTER: Lotz MT

PROVIDER: S-EPMC3432290 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Mechanisms of respiratory syncytial virus modulation of airway immune responses.

Lotz Matthew T MT Peebles R Stokes RS

Current allergy and asthma reports 20121001 5

Respiratory syncytial virus (RSV) most often causes severe respiratory disease in the very young and the elderly. Acute disease can also cause exacerbations of asthma in any age group. Recent findings provide insight into how the innate and adaptive immune systems respond to RSV infection and provide preliminary evidence that these effects vary significantly by RSV strain and host. Components of cell signaling pathways that induce inflammatory cytokine expression during the innate immune respons ...[more]

PMID: 22692775

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Project description:UnlabelledInduction of long-lasting immunity against viral respiratory tract infections remains an elusive goal. Using a nonhuman primate model of human respiratory syncytial virus (hRSV) infection, we compared mucosal and systemic immune responses induced by different DNA delivery approaches to a novel parenteral DNA prime-tonsillar adenoviral vector booster immunization regimen. Intramuscular (i.m.) electroporation (EP) of a DNA vaccine encoding the fusion protein of hRSV induced stronger systemic immune responses than intradermal EP, tattoo immunization, and conventional i.m. DNA injection. A single EP i.m., followed by two atraumatic tonsillar immunizations with the adenoviral vector, elicited strong systemic immune responses, an unique persistent CD4(+) and CD8(+) T cell response in the lower respiratory tract and protection from intranasal hRSV challenge. Thus, parenteral DNA priming followed by booster immunization targeted to a mucosal inductive site constitutes an effective vaccine regimen for eliciting protective immune responses at mucosal effector sites.ImportanceThe human respiratory syncytial virus (hRSV) is the most common cause of severe respiratory tract disease in infancy and leads to substantial morbidity and morality in the elderly. In this study, we compared the immunogenicity and efficacy of several gene-based immunization protocols in rhesus macaques. Thereby, we found that the combination of an initially parenterally delivered DNA vaccine with a subsequent atraumatic tonsillar adenoviral vector immunization results in a strong systemic immune response accompanied by an exceptional high T-cell response in the mucosa. Strikingly, these animals were protected against a RSV challenge infection controlling the viral replication indicated by a 1,000-fold-lower viral load in the lower respiratory tract. Since mucosal cellular responses of this strength had not been described in earlier RSV vaccine studies, this heterologous DNA prime-tonsillar boost vaccine strategy is very promising and should be pursued for further preclinical and clinical testing.

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.

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Mechanisms of respiratory syncytial virus modulation of airway immune responses.

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Mechanisms of respiratory syncytial virus modulation of airway immune responses.

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