Virus-Infected Alveolar Epithelial Cells Direct Neutrophil Chemotaxis and Inhibit Their Apoptosis

Abstract

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.Keywords: alveolar epithelial cells; neutrophils; rat coronavirus; CXC chemokines; CXCR2Numerous viruses infect the epithelial cells that line the respiratory tract, and increased pathogenesis is associated with the spread of viral infection to the alveoli. Viral antigens or nucleic acids have been found in type I (AT1) and/or type II (AT2) alveolar epithelial cells in autopsy material from fatal infections with severe acute respiratory syndrome-associated coronavirus, respiratory syncytial virus (RSV), and avian (H5N1) and 2009 pandemic (H1N1) influenza A viruses (1-4). These findings have been replicated in animal models that show a correlation between alveolar infection and disease severity (5, 6). Damage to the alveolar surface and respiratory distress during viral infections are often associated with the infiltration of inflammatory cells into the alveoli, yet these responses are necessary to mount effective antiviral immune responses that eliminate the infection. PMNs are recruited to the respiratory tract early during viral infections and can contribute to effective immune responses but also can enhance pathology (7,8). Despite their importance in viral pathogenesis, little is known about the interactions between alveolar epithelial cells and the PMNs that contribute to inflammatory responses to viral infection.In addition to providing a barrier between inhaled air and the host, the epithelium of the respiratory tract actively participates in host defense. For example, Stat1 is required by airway epithelial cells, but not hematopoietic cells, to control Sendai virus infection in mice (9). Although several studies have characterized proinflammatory responses to viral infec...

Lung epithelial cells have virus-specific and shared gene expression responses to infection by diverse respiratory viruses

“…Alveolar epithelial cells have a key role in alerting the immune system to infection by respiratory viruses and shaping immune responses [37, 56, 57]. As viruses from several different families all target respiratory epithelial cells, it is important to understand the similarities and differences in how these cells respond to a diverse set of viruses.…”

Differentiated phenotypes of primary murine alveolar epithelial cells and their susceptibility to infection by respiratory viruses

“…Primary rat alveolar epithelial cells cultured with distinct ATI and ATII phenotypes have been widely used as in vitro models for studies of lung physiology (Gonzalez et al, 2005;Qiao et al, 2003). Limitations of rat model systems include the very few genetic knock-out lines and established models of respiratory viral infections Miura et al, 2007;Rzepka et al, 2012). Based on the availability of well-characterized genetic lines and established models of respiratory viral pathogenesis, it is highly desirable to establish murine ATI and ATII cell models to study virus-host interactions in the differentiated cell types of the alveolar epithelium.…”

“…The pathogenesis of respiratory viral infections is often correlated with an excessive inflammatory response in the lungs. Alveolar epithelial cells express proinflammatory cytokines and chemokines in response to viral infection and may be important in the initiation of these damaging inflammatory responses (Herold et al, 2006;Miura et al, 2007;Rzepka et al, 2012;Tate et al, 2011;Wang et al, 2011). In this study, we compared cytokine expression by murine ATI-like cells infected by MHV-1 or PR8, and IL-1␤ expression by ATI-like and ATII cells infected by MHV-1, PR8, or v2163.…”

Viral Disease

“…The primary target of RCV in the alveoli is the type 1 alveolar epithelial cells (Funk et al, 2009;Miura et al, 2007). Using an in vitro model system, RCV infection induced proinflammatory cytokines and, specifically, CXC chemokines that inhibit polymorphonuclear leukocyte (PMN) apoptosis in type 1-like alveolar epithelia Rzepka et al, 2012). Furthermore, it was shown that RCV-infected rats deficient in PMNs have more severe and prolonged disease, indicating PMNs are required for an effective antiviral response but also contribute the lung pathology (Haick et al, 2014).…”