Lower Respiratory Tract Infection Induced by
a Genetically Modified Picornavirus in Its Natural
Louis A. Rosenthal1*, Renee J. Szakaly1, Svetlana P. Amineva2, Yina Xing1, Marchel R. Hill3,
Ann C. Palmenberg3, James E. Gern2, Ronald L. Sorkness1,2,4
1Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America, 2Department of Pediatrics,
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America, 3Institute for Molecular Virology, University of Wisconsin-
Madison, Madison, Wisconsin, United States of America, 4School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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, vMC0, induces lower respiratory tract infections in mice. After intranasal vMC0
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 vMC0, but not
vehicle or UV-inactivated vMC0, 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 vMC0,
compared with those inoculated with vehicle or UV-inactivated vMC0, exhibited increased pulmonary expression of
interferon (IFN-a, IFN-b, IFN-l), 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 vMC0, but not
vehicle or UV-inactivated vMC0, 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 vMC0by healthy mice. This novel murine model of picornaviral airway infection and
inflammation should be useful for defining mechanisms of HRV pathogenesis in humans.
Citation: Rosenthal LA, Szakaly RJ, Amineva SP, Xing Y, Hill MR, et al. (2012) Lower Respiratory Tract Infection Induced by a Genetically Modified Picornavirus in Its
Natural Murine Host. PLoS ONE 7(2): e32061. doi:10.1371/journal.pone.0032061
Editor: Paulo Lee Ho, Instituto Butantan, Brazil
Received July 19, 2011; Accepted January 23, 2012; Published February 15, 2012
Copyright: ? 2012 Rosenthal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by National Institutes of Health (http://www.nih.gov/) grant U19 AI070503 to LAR, ACP, and JEG. The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Infections with the picornavirus, human rhinovirus (HRV), are
the most frequent cause of the common cold. However, HRV
infections, which usually cause self-limiting upper respiratory tract
illnesses, are also the leading cause of virus-induced asthma
exacerbations , and HRV wheezing illnesses in the first few
years of life are associated with increased risk for the development
of childhood asthma [2–4]. The mechanisms by which a common
cold virus can induce asthma exacerbations and contribute to the
development of persistent lower airway sequelae in susceptible
children remain to be elucidated [5,6].
There is considerable evidence that HRV can infect the lower
respiratory tract [7–14] and that HRV infection stimulates the
production of proinflammatory chemokines and cytokines by
lower airway epithelial cells . Neutrophils are the main first-
line inflammatory cells recruited to the airways during HRV
infections [16–18], and this neutrophilic inflammatory response
has been associated with asthma symptoms and airway dysfunc-
tion [19–22]. However, the relationship between neutrophilic
airway inflammation and HRV-induced airway disease is still
largely undefined. The eventual outcome of HRV infection, a
relatively uneventful upper respiratory tract illness versus a more
severe lower respiratory tract illness, might be related to the
balance between detrimental and beneficial effects of the
neutrophilic inflammatory response in the airways, which might
be influenced by host, viral, developmental, and environmental
factors. The development of useful small animal models of
picornavirus-induced neutrophilic airway inflammation could
facilitate mechanistic studies to address these issues.
There are no known murine rhinoviruses, which has signifi-
cantly hampered the investigation of the mechanisms governing
the inflammatory responses to HRV infection and the subsequent
development of airway sequelae. Experimental models using either
minor receptor group HRV in wild-type mice or major receptor
group HRV in mice that are transgenic for human intercellular
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adhesion molecule-1 (ICAM-1; CD54), the receptor for major
group HRV, have been developed recently [23–28]. A limitation
of these useful models is that HRV titers exhibit a steep decline
after inoculation of normal mice [23–26]. The development of
rodent models in which picornavirus replication persists for several
days in the airways of unmanipulated hosts, as in experimental and
clinical HRV infections, could facilitate investigation of the
relationships between viral replication and the development of
airway inflammation and dysfunction. For this reason, we have
explored the use of a murine picornavirus, which replicates
efficiently in its natural hosts, to model picornavirus-induced
Mice are the natural hosts for mengovirus, a picornavirus whose
wild-type form causes infections that are more similar to systemic
poliovirus infections than to HRV-induced airway infections .
The mengovirus genome has a poly(C) tract in the distal region of
its 59 untranslated region, which has been shown to be an
important virulence determinant that inhibits host type I
interferon (IFN) responses [30–34]. Investigation of a mengovirus
mutant, vMC0, in which the poly(C) tract had been deleted
showed that vMC0induces robust type I IFN responses and that
vMC0inoculation by intracerebral or intraperitoneal routes results
in self-limited infections rather than the often lethal, systemic
infections induced by wild-type mengovirus [30–34]. Wild-type
mengovirus efficiently replicates in both epithelial and macro-
phage lineage cells; however, vMC0, like HRV, replicates well in
epithelial cells but poorly in macrophage lineage cells [34,35].
These similarities between vMC0and HRV led us to hypothesize
that vMC0could produce a respiratory tract infection in rodents
akin to HRV infections in humans. Using rats, were able to
demonstrate that inoculation of vMC0 by an inhalation route
could induce infection of the lower airways and neutrophilic
airway inflammation . An effective HRV infection model has
not been established in rats. Therefore, vMC0should be useful for
investigating picornavirus-induced airway infections in rats, and
studies to explore the effects of vMC0infection in an established
rat model of allergic airway inflammation are underway.
However, the much wider range of mutant strains and genetic
tools available in the mouse also made it highly desirable to
develop a robust murine model of vMC0-induced airway infection.
In this paper, we demonstrate that inhalation of the genetically
attenuated mengovirus, vMC0, induces an acute lower respiratory
tract illness in mice, which is characterized by replication and
persistent shedding of virus and neutrophilic airway inflammation
with evidence of neutrophil activation and lung injury. This novel
murine model of picornavirus-induced lower respiratory tract
infection and inflammation should be useful for investigating
mechanisms of HRV pathogenesis in humans.
Viral replication and persistent viral shedding in the
lungs after inhalation of attenuated mengovirus, vMC0
After an intranasal inoculation of 106plaque-forming units
(PFU) of attenuated mengovirus, vMC0, a median of 5.46103PFU
were detected in whole lung homogenates from mice at 0.1 h
postinoculation, with viral titers remaining relatively stable at 1
Figure 1. Differences between attenuated mengovirus and
HRV in the kinetics of lung viral titers. Mice received intranasal
inoculations of 106PFU of attenuated mengovirus, vMC0[A (n=7 mice
per group), B (n=6 mice per group)], or 56106PFU of HRV-A01a (C;
n=4 mice per group). Lungs were harvested at the indicated times, and
viral titers in lung homogenates were determined by plaque assays.
Data are the total amount of virus present in the lung homogenates
(virus concentrations were multiplied by lung homogenate volumes).
No virus was detected in lungs from vehicle-inoculated mice. Data are
presented as box plots. For one HRV-A01a-inoculated mouse at 3 h
postinoculation, a value of 1 PFU was assigned for graphing purposes
because virus was undetectable. ND, not detectable.
Picornavirus-Induced Airway Infection in Mice
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