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Pulmonary eosinophils and their role in immunopathologic responses to formalin-inactivated pneumonia virus of mice.

ABSTRACT: Enhanced disease is the term used to describe the aberrant Th2-skewed responses to naturally acquired human respiratory syncytial virus (hRSV) infection observed in individuals vaccinated with formalin-inactivated viral Ags. Here we explore this paradigm with pneumonia virus of mice (PVM), a pathogen that faithfully reproduces features of severe hRSV infection in a rodent host. We demonstrate that PVM infection in mice vaccinated with formalin-inactivated Ags from PVM-infected cells (PVM Ags) yields Th2-skewed hypersensitivity, analogous to that observed in response to hRSV. Specifically, we detect elevated levels of IL-4, IL-5, IL-13, and eosinophils in bronchoalveolar lavage fluid of PVM-infected mice that were vaccinated with PVM Ags, but not among mice vaccinated with formalin-inactivated Ags from uninfected cells (control Ags). Interestingly, infection in PVM Ag-vaccinated mice was associated with a approximately 10-fold reduction in lung virus titer and protection against weight loss when compared with infected mice vaccinated with control Ags, despite the absence of serum-neutralizing Abs. Given recent findings documenting a role for eosinophils in promoting clearance of hRSV in vivo, we explored the role of eosinophils in altering the pathogenesis of disease with eosinophil-deficient mice. We found that eosinophil deficiency had no impact on virus titer in PVM Ag-vaccinated mice, nor on weight loss or levels of CCL11 (eotaxin-1), IFN-gamma, IL-5, or IL-13 in bronchoalveolar lavage fluid. However, levels of both IL-4 and CCL3 (macrophage inflammatory protein-1alpha) in bronchoalveolar lavage fluid were markedly diminished in PVM Ag-vaccinated, PVM-infected eosinophil-deficient mice when compared with wild-type controls.

SUBMITTER: Percopo CM

PROVIDER: S-EPMC2754814 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Pulmonary eosinophils and their role in immunopathologic responses to formalin-inactivated pneumonia virus of mice.

Percopo Caroline M CM Qiu Zhijun Z Phipps Simon S Foster Paul S PS Domachowske Joseph B JB Rosenberg Helene F HF

Journal of immunology (Baltimore, Md. : 1950) 20090701 1

Enhanced disease is the term used to describe the aberrant Th2-skewed responses to naturally acquired human respiratory syncytial virus (hRSV) infection observed in individuals vaccinated with formalin-inactivated viral Ags. Here we explore this paradigm with pneumonia virus of mice (PVM), a pathogen that faithfully reproduces features of severe hRSV infection in a rodent host. We demonstrate that PVM infection in mice vaccinated with formalin-inactivated Ags from PVM-infected cells (PVM Ags) yi ...[more]

PMID: 19542471

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Project description:UnlabelledAntibodies against the fusion (F) protein of respiratory syncytial virus (RSV) play an important role in the protective immune response to this important respiratory virus. Little is known, however, about antibody levels against multiple F-specific epitopes induced by infection or after vaccination against RSV, while this is important to guide the evaluation of (novel) vaccines. In this study, we analyzed antibody levels against RSV proteins and F-specific epitopes in human sera and in sera of vaccinated and experimentally infected cotton rats and the correlation thereof with virus neutralization. Analysis of human sera revealed substantial diversity in antibody levels against F-, G (attachment)-, and F-specific epitopes between individuals. The highest correlation with virus neutralization was observed for antibodies recognizing prefusion-specific antigenic site Ø. Nevertheless, our results indicate that high levels of antibodies targeting other parts of the F protein can also mediate a potent antiviral antibody response. In agreement, sera of experimentally infected cotton rats contained high neutralizing activity despite lacking antigenic site Ø-specific antibodies. Strikingly, vaccination with formalin-inactivated RSV (FI-RSV) exclusively resulted in the induction of poorly neutralizing antibodies against postfusion-specific antigenic site I, although antigenic sites I, II, and IV were efficiently displayed in FI-RSV. The apparent immunodominance of antigenic site I in FI-RSV likely explains the low levels of neutralizing antibodies upon vaccination and challenge and may play a role in the vaccination-induced enhancement of disease observed with such preparations.ImportanceRSV is an importance cause of hospitalization of infants. The development of a vaccine against RSV has been hampered by the disastrous results obtained with FI-RSV vaccine preparations in the 1960s that resulted in vaccination-induced enhancement of disease. To get a better understanding of the antibody repertoire induced after infection or after vaccination against RSV, we investigated antibody levels against fusion (F) protein, attachment (G) protein, and F-specific epitopes in human and animal sera. The results indicate the importance of prefusion-specific antigenic site Ø antibodies as well as of antibodies targeting other epitopes in virus neutralization. However, vaccination of cotton rats with FI-RSV specifically resulted in the induction of weakly neutralizing, antigenic site I-specific antibodies, which may play a role in the enhancement of disease observed after vaccination with such preparations.

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Pulmonary eosinophils and their role in immunopathologic responses to formalin-inactivated pneumonia virus of mice.

Publications

Pulmonary eosinophils and their role in immunopathologic responses to formalin-inactivated pneumonia virus of mice.

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