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

Abstract

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-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 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 vMC0 by healthy mice. This novel murine model of picornaviral airway infection and inflammation should be useful for defining mechanisms of HRV pathogenesis in humans.

Induction of an Antiviral State and Attenuated Coxsackievirus Replication in Type III Interferon-Treated Primary Human Pancreatic Islets

“…However, this response may not be limited to the B3 serotype, as a very recent study has demonstrated a similar response in human islets infected with the B5 serotype (30). It still remains to be investigated whether type III IFN is produced by islet cells during a systemic CVB infection, but since this family of IFNs is expressed during in vivo infections with other picornaviruses (10,31), it is likely that type III IFN is also expressed during CVB infection.…”

Neutrophil in viral infections, friend or foe?

“…Inflammation is helpful in controlling viral infection, but it very so often becomes damaging to the host. A balance between beneficial and detrimental effects of the neutrophils initiated inflammatory responses must be maintained (Rosenthal et al, 2009; Rosenthal et al, 2011). Hyper-inflammation has been noted in chronic cases of hepatitis B virus infection in which a large influx of neutrophils causes liver damage (Zhang et al, 2011).…”

Nod2 deficiency impairs inflammatory and epithelial aspects of the cutaneous wound‐healing response

“…Our data reveal novel injury‐induced Nod2 and associated signalling component up‐regulation in several skin cell types. To our knowledge, this is the first report on the skin; however, previous studies have shown Nod2 up‐regulation in the small intestine after ischaemia–reperfusion injury or in mouse lungs after respiratory tract infection . These findings raise the intriguing possibility that induction of Nod2 is a common theme in tissue repair.…”