Pulmonary Eosinophils and Their Role in Immunopathologic Responses to Formalin-Inactivated Pneumonia Virus of Mice

IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased immunoglobulin production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has anti-tumor activity. Here we investigated the role of IL-21 in host-defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4+ T cells. Following infection, Il21r-/- mice exhibited less lung infiltration by neutrophils than did WT mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8+, CD4+, and γδ T-cell numbers were also lower in the lungs of PVM-infected Il21r-/- mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r-/- mice. Strikingly, Il21r-/- mice had enhanced survival following PVM-infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections.

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“…Expression of the PVM SH gene as an indicator of virus burden (29) was greatest at day 6 after inoculation (Fig. 1A) .…”

Section: Resultsmentioning

confidence: 99%

“…PCR reactions to quantitatively detect cytokine and chemokine RNAs used probe sets from Applied Biosystems and the 7900HT Sequence Detection System. Relative levels of PVM SH gene expression (29) were determined by quantitative RT-PCR, with normalization to Rpl7 expression.…”

Section: Methodsmentioning

confidence: 99%

IL-21 Promotes the Pathologic Immune Response to Pneumovirus Infection

Spolski

Wang

Wan

et al. 2012

The Journal of Immunology

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“…Enhanced disease in FI-PVM-vaccinated mice is associated with a Th2-biased response, production of IL-4, IL-5, IL-13, and pulmonary eosinophilia [159]. In contrast, neutrophils predominate in BAL from mice vaccinated with FI-uninfected cell antigen, and Th2 cytokine levels are low.…”

Section: Non-human Pneumovirus Animal Modelsmentioning

confidence: 94%

Animal models of respiratory syncytial virus infection

Taylor

2017

Vaccine

160

150

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“…Eosinophils themselves, depending on factors that we do not yet understand, have antiviral properties in vitro [23][24][25] and can clear virus from infected lung tissue in vivo, 26,27 although not in all circumstances. 56 At the same time, respiratory virus infection is not only a disease of virus replication, because we and others have shown that inflammatory mediators produced locally have a profound effect on the clinical course. 22,57,58 Thus, although eosinophils as targets of virus infection may be releasing a limited number of infectious virions, this might be outweighed by the release of important immunomodulatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6

Dyer

Percopo

Fischer³

et al. 2009

Blood

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Eosinophils are recruited to the lung in response to infection with pneumovirus pathogens and have been associated with both the pathophysiologic sequelae of infection and, more recently, with accelerated virus clearance. Here, we demonstrate that the pneumovirus pathogens, respiratory syncytial virus (RSV) and pneumonia virus of mice (PVM), can infect human and mouse eosinophils, respectively, and that virus infection of eosinophils elicits the release of diseaserelated proinflammatory mediators from eosinophils. RSV replication in human eosinophils results in the release of infectious virions and in the release of the proinflammatory mediator, interleukin-6 (IL-6). PVM replication in cultured bone marrow eosinophils (bmEos) likewise results in release of infectious virions and the proinflammatory mediators IL-6, IP-10, CCL2, and CCL3. In contrast to the findings reported in lung tissue of RSVchallenged mice, PVM replication is accelerated in MyD88 gene-deleted bmEos, whereas release of cytokines is dimin- IntroductionEosinophils are unique proinflammatory leukocytes that are easily recognized but poorly understood. Although eosinophil expansion in the bone marrow and recruitment from the bloodstream to peripheral tissues are prominent findings that are clearly associated with asthma, allergic diseases, and infection with helminthes, there is no full consensus about the physiologic or pathophysiologic roles played by eosinophils in any of these disease states. [1][2][3] Interestingly, among the many points that have emerged from the clinical studies featuring therapeutic administration of antiinterleukin 5 (IL-5) monoclonal antibody (mepolizumab), 4-7 it has become evident that we have a very limited understanding of the subtleties of eosinophil recruitment and function; this limited understanding may relate to a long-standing focus on numbers of eosinophils recruited rather than on the nature, quality, and extent of eosinophil activation.With this in mind, we have focused our studies on the role of eosinophils and of eosinophil activation in acute respiratory virus infections, 8 specifically, infections with respiratory syncytial virus (RSV) and pneumonia virus of mice (PVM), a mouse pneumovirus pathogen that replicates the sequelae of the more severe forms of RSV infection in inbred strains of mice. 9,10 Several converging lines of evidence suggest that eosinophils recruited to the lungs in response to pneumovirus infection may have a direct effect on the outcome of disease. Among these findings, several groups have detected immunoreactive eosinophil degranulation products in bronchial washings of patients with the most severe forms of RSV infection, 11,12 and we and others have reported direct recruitment of eosinophils to the lungs of PVM-infected mice. 13-15 RSV and PVM infections of their respective target cells result in the production of numerous proinflammatory cytokines, including the eosinophil chemoattractants RANTES and macrophage inflammatory protein-1␣/CCL3, [16][17][18][19] and RSV-infected tar...

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Pulmonary Eosinophils and Their Role in Immunopathologic Responses to Formalin-Inactivated Pneumonia Virus of Mice

Cited by 26 publications

References 66 publications

IL-21 Promotes the Pathologic Immune Response to Pneumovirus Infection

IL-21 Promotes the Pathologic Immune Response to Pneumovirus Infection

Animal models of respiratory syncytial virus infection

Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6

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