Mechanisms of Airway Inflammation in A Murine Model of Picornavirus Infection

University Of Wisconsin-Madison, Madison WI

Investigators

Linked publications & trials

Abstract

Rhinoviruses, which are members of the picornavirus family, trigger neutrophilic host inflammatory[unreadable] responses and are a major cause of asthma exacerbations. Rhinovirus-induced lower airway neutrophilic[unreadable] inflammation may initiate airway injury. However, neutrophils may also participate in the resolution of[unreadable] rhinovirus infections. The chemokine receptor CXCR2 and its ligands, e.g., interleukin-8, appear to be key[unreadable] factors in neutrophilic host responses to rhinovirus infection (Projects I and III). Rhinovirus research lacks a[unreadable] useful rodent model. There are no known rodent rhinoviruses, but mice are natural hosts for mengovirus, a[unreadable] picornavirus whose wild-type form causes systemic infections. In preliminary studies, inoculation of mice with[unreadable] attenuated mengoviruses (which were developed by Project V) via a respiratory route induced lower airway[unreadable] infection, neutrophilic inflammation, and expression of CXCR2 ligands, MCP-1 (monocyte chemoattractant[unreadable] protein-1; a CCR2 ligand that may indirectly regulate neutrophil function) (Project II), and interferon. These[unreadable] data closely mimic observations in human airways during rhinovirus-induced colds, demonstrating this[unreadable] model's relevance. The central hypotheses of this project are that replication-dependent release of CXCR2[unreadable] ligands is critically important for picornavirus-induced lower airway neutrophilic inflammation and that, in the[unreadable] host response to lower airway picornavirus infection, low levels of neutrophil recruitment may be beneficial[unreadable] (i.e., enhance resolution of the viral infection), whereas high levels of neutrophil recruitment may be[unreadable] detrimental (i.e., mediate airway injury). To test these hypotheses: (1) Mechanisms mediating picornavirus-induced[unreadable] lower airway neutrophilic inflammation will be determined by inoculating mice with attenuated[unreadable] mengovirus, and determining the effects on outcomes of infection, including neutrophil recruitment, mucus[unreadable] production, and the production and cell source of CXCR2 ligands [KC, LIX (lipopolysaccharide-induced CXC[unreadable] chemokine), and MIP-2 (macrophage-inflammatory protein-2)]. (2) The role of neutrophils in mediating[unreadable] detrimental and/or beneficial host responses to lower airway infection with attenuated mengovirus will be[unreadable] determined by comparing neutrophil-depleted and control mice with regard to the outcomes of infection. (3)[unreadable] Using the comprehensive and unique set of reagents available for the study of murine immunology, the roles[unreadable] of CXCR2 and its ligands in mediating detrimental and/or beneficial neutrophil-dependent host responses to[unreadable] lower airway infection will be determined by comparing relevant knockout mice, mice treated with[unreadable] neutralizing anti-chemokine antibodies, and control mice with regard to the outcomes of infection.[unreadable] Relevance: Rhinovirus-induced colds are a major cause of asthma exacerbations. The absence of a rodent[unreadable] model of rhinovirus infection has hindered asthma research. By filling this gap, this unique mouse model[unreadable] should provide novel insights into human rhinovirus-induced airway inflammation and asthma exacerbations.[unreadable]