Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology.

Polymorphonuclear neutrophils (PMN) infiltrate the respiratory tract early after viral infection and can contribute to both host defence and pathology. Coronaviruses are important causes of respiratory tract infections, ranging from mild to severe depending on the viral strain. This study evaluated the role of PMN during a non-fatal pulmonary coronavirus infection in the natural host. Rat coronavirus (RCoV) causes respiratory disease in adult rats, characterized by an early PMN response, viral replication and inflammatory lesions in the lungs, mild weight loss and effective resolution of infection. To determine their role during RCoV infection, PMN were depleted and the effects on disease progression, viral replication, inflammatory response and lung pathology were analysed. Compared with RCoV infection in control animals, PMN-depleted rats had worsened disease with weight loss, clinical signs, mortality and prolonged pulmonary viral replication. PMN-depleted animals had fewer macrophages and lymphocytes in the respiratory tract, corresponding to lower chemokine levels. Combined with in vitro experiments showing that PMN express cytokines and chemokines in response to RCoV-infected alveolar epithelial cells, these findings support a role for PMN in eliciting an inflammatory response to RCoV infection. Despite their critical role in the protection from severe disease, the presence of PMN was correlated with haemorrhagic lesions, epithelial barrier permeability and cellular inflammation in the lungs. This study demonstrated that while PMN are required for an effective antiviral response, they also contribute to lung pathology during RCoV infection.

Virus-infected alveolar epithelial cells direct neutrophil chemotaxis and inhibit their apoptosis.

The alveolar epithelium is a critical target for pulmonary viruses and can produce proinflammatory cytokines and chemokines upon viral infection. However, the molecular interactions between virus-infected alveolar epithelial cells and inflammatory cells, including polymorphonuclear leukocytes (PMNs), have not been thoroughly characterized. Rat coronavirus (RCoV) is used as a model to study the immune response to viral infection in the lung of the natural host. We have developed an in vitro model to characterize the response of PMNs to RCoV-infected type I-like alveolar epithelial (AT1) cells, the primary target for RCoV infection in the alveoli. Multiple CXC chemokines that signal through CXCR2 were required for PMN chemotaxis toward medium from RCoV-infected AT1-like cells (RCoV-AT1). Furthermore, RCoV-AT1 inhibited spontaneous PMN apoptosis, including activation of effector caspase 3 and initiator caspases 8 and 9. Use of a selective inhibitor of CXCR2, SB265610, demonstrated that CXCR2 signaling was required for RCoV-AT1-mediated inhibition of PMN apoptosis. These data suggest that CXC chemokines produced by RCoV-infected AT1-like cells inhibit PMN apoptosis during infection. These studies provide new insight into the molecular mechanisms whereby alveolar epithelial cells direct the functions of PMNs during viral infection of the lung.