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Cutting edge: Eosinophils do not contribute to respiratory syncytial virus vaccine-enhanced disease.

ABSTRACT: Respiratory syncytial virus (RSV) infection of BALB/c mice previously immunized with a recombinant vaccinia virus (vacv) expressing the attachment (G) protein of RSV (vacvG) results in pulmonary eosinophilia, which mimics the response of formalin-inactivated RSV-vaccinated children, as well as increased weight loss, clinical illness, and enhanced pause (Penh). We show that RSV infection of eosinophil-deficient mice previously immunized with vacvG results in the development of increased weight loss, clinical illness, and Penh similar to that in wild-type controls. These measures of RSV vaccine-enhanced disease are dependent upon STAT4. Interestingly, neither IL-12 nor IL-23, the two most common STAT4-activating cytokines, proved necessary for the development of disease. We demonstrate that IFN-gamma, which is produced following STAT4 activation, contributes to clinical illness and increased Penh, but not weight loss. Our results have important implications for future RSV vaccine design, suggesting that enhancing a Th1 response may exacerbate disease.

SUBMITTER: Castilow EM

PROVIDER: S-EPMC2596668 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Cutting edge: Eosinophils do not contribute to respiratory syncytial virus vaccine-enhanced disease.

Castilow Elaine M EM Legge Kevin L KL Varga Steven M SM

Journal of immunology (Baltimore, Md. : 1950) 20081101 10

Respiratory syncytial virus (RSV) infection of BALB/c mice previously immunized with a recombinant vaccinia virus (vacv) expressing the attachment (G) protein of RSV (vacvG) results in pulmonary eosinophilia, which mimics the response of formalin-inactivated RSV-vaccinated children, as well as increased weight loss, clinical illness, and enhanced pause (Penh). We show that RSV infection of eosinophil-deficient mice previously immunized with vacvG results in the development of increased weight lo ...[more]

PMID: 18981084

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Project description:UnlabelledRespiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants. Despite over 50 years of research, to date no safe and efficacious RSV vaccine has been licensed. Many experimental vaccination strategies failed to induce balanced T-helper (Th) responses and were associated with adverse effects such as hypersensitivity and immunopathology upon challenge. In this study, we explored the well-established recombinant vaccinia virus (rVV) RSV-F/RSV-G vaccination-challenge mouse model to study phenotypically distinct vaccine-mediated host immune responses at the proteome level. In this model, rVV-G priming and not rVV-F priming results in the induction of Th2 skewed host responses upon RSV challenge. Mass spectrometry-based spectral count comparisons enabled us to identify seven host proteins for which expression in lung tissue is associated with an aberrant Th2 skewed response characterized by the influx of eosinophils and neutrophils. These proteins are involved in processes related to the direct influx of eosinophils (eosinophil peroxidase [Epx]) and to chemotaxis and extravasation processes (Chil3 [chitinase-like-protein 3]) as well as to eosinophil and neutrophil homing signals to the lung (Itgam). In addition, the increased levels of Arg1 and Chil3 proteins point to a functional and regulatory role for alternatively activated macrophages and type 2 innate lymphoid cells in Th2 cytokine-driven RSV vaccine-mediated enhanced disease.ImportanceRSV alone is responsible for 80% of acute bronchiolitis cases in infants worldwide and causes substantial mortality in developing countries. Clinical trials performed with formalin-inactivated RSV vaccine preparations in the 1960s failed to induce protection upon natural RSV infection and even predisposed patients for enhanced disease. Despite the clinical need, to date no safe and efficacious RSV vaccine has been licensed. Since RSV vaccines have a tendency to prime for unbalanced responses associated with an exuberant influx of inflammatory cells and enhanced disease, detailed characterization of primed host responses has become a crucial element in RSV vaccine research. We investigated the lung proteome of mice challenged with RSV upon priming with vaccine preparations known to induce phenotypically distinct host responses. Seven host proteins whose expression levels are associated with vaccine-mediated enhanced disease have been identified. The identified protein biomarkers support the development as well as detailed evaluation of next-generation RSV vaccines.

Project description:Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.

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Cutting edge: Eosinophils do not contribute to respiratory syncytial virus vaccine-enhanced disease.

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Cutting edge: Eosinophils do not contribute to respiratory syncytial virus vaccine-enhanced disease.

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