Lower Respiratory Tract Infection Induced by a Genetically Modified Picornavirus in Its Natural Murine Host

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e32061. DOI: 10.1371/journal.pone.0032061
Source: PubMed
Infections with the picornavirus, human rhinovirus (HRV), are a major cause of wheezing illnesses and asthma exacerbations. In developing a murine model of picornaviral airway infection, we noted the absence of murine rhinoviruses and that mice are not natural hosts for HRV. The picornavirus, mengovirus, induces lethal systemic infections in its natural murine hosts, but small genetic differences can profoundly affect picornaviral tropism and virulence. We demonstrate that inhalation of a genetically attenuated mengovirus, vMC(0), induces lower respiratory tract infections in mice. After intranasal vMC(0) inoculation, lung viral titers increased, peaking at 24 h postinoculation with viral shedding persisting for 5 days, whereas HRV-A01a lung viral titers decreased and were undetectable 24 h after intranasal inoculation. Inhalation of vMC(0), but not vehicle or UV-inactivated vMC(0), induced an acute respiratory illness, with body weight loss and lower airway inflammation, characterized by increased numbers of airway neutrophils and lymphocytes and elevated pulmonary expression of neutrophil chemoattractant CXCR2 ligands (CXCL1, CXCL2, CXCL5) and interleukin-17A. Mice inoculated with vMC(0), compared with those inoculated with vehicle or UV-inactivated vMC(0), exhibited increased pulmonary expression of interferon (IFN-α, IFN-β, IFN-λ), viral RNA sensors [toll-like receptor (TLR)3, TLR7, nucleotide-binding oligomerization domain containing 2 (NOD2)], and chemokines associated with HRV infection in humans (CXCL10, CCL2). Inhalation of vMC(0), but not vehicle or UV-inactivated vMC(0), was accompanied by increased airway fluid myeloperoxidase levels, an indicator of neutrophil activation, increased MUC5B gene expression, and lung edema, a sign of infection-related lung injury. Consistent with experimental HRV inoculations of nonallergic, nonasthmatic human subjects, there were no effects on airway hyperresponsiveness after inhalation of vMC(0) by healthy mice. This novel murine model of picornaviral airway infection and inflammation should be useful for defining mechanisms of HRV pathogenesis in humans.

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    • "Of note, no exacerbations were observed in mice chronically challenged with house dust mite and then challenged with RV1B [79]. Because of these issues, an attenuated mengovirus, which is a natural mouse pathogen of the same family (Picornaviridae) as RV, has been suggested as an alternative for the study of disease pathogenesis in rodent hosts [77]. There are also several reports of models of an exacerbation of asthma based on challenging mice with the human pneumovirus pathogen RSV. "
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