Respiratory Syncytial Virus Up-regulates TLR4 and Sensitizes Airway Epithelial Cells to Endotoxin

Abstract

Airway epithelial cells are unresponsive to endotoxin (lipopolysaccharide (LPS)) exposure under normal conditions. This study demonstrates that respiratory syncytial virus (RSV) infection results in increased sensitivity to this environmental exposure. Infection with RSV results in increased expression of Toll-like receptor (TLR) 4 mRNA, protein, and increased TLR4 membrane localization. This permits significantly enhanced LPS binding to the epithelial monolayer that is blocked by disruption of the Golgi. The increased TLR4 results in an LPS-induced inflammatory response as demonstrated by increased mitogen-activated protein (MAP) kinase activity, IL-8 production, and tumor necrosis factor ␣ production. RSV infection also allowed for tumor necrosis factor ␣ production subsequent to TLR4 cross-linking with an immobilized antibody. These data suggest that RSV infection sensitizes airway epithelium to a subsequent environmental exposure (LPS) by altered expression and membrane localization of TLR4. The increased interaction between airway epithelial cells and LPS has the potential to profoundly alter airway inflammation.The ability of cells to respond to microbial motifs depends on expression of a family of Type I transmembrane receptors, Toll-like receptors (TLRs) 1 (1-9). Recent evidence in intestinal epithelial cells suggests that cells that are in constant contact with pathogenic microbes and other environmental exposures express some of the TLRs at very low levels (10 -12). More particularly, these studies suggest that in intestinal epithelial cells, TLR4 is in low abundance, localized in the Golgi, and not present on the plasma membrane. The airway epithelium is another region that is in constant contact with multiple pathogen-related antigens and other environmental agents. These exposures, with the exception of significant pathogen load or an immunosuppressed host, do not normally elicit an immunological response. A recent study by Tsutsumi-Ishii and Nagaoka (13) suggests that the intestinal epithelial cell lack of TLR4 is also true of airway epithelial cells. They found no surface expression of TLR4 and a lack of LPS responsiveness (13).The relative tolerance to foreign antigens that is demonstrated by normal airway epithelial cells is altered in people with asthma and after RSV infection. Asthma and RSV infection are characterized by non-specific responses to both infectious agents and environmental exposures that include heightened inflammatory responses and hyper-responsive airways. The factors that predispose a particular individual to developing asthma are for the most part unclear. One early exposure that has been linked to the subsequent development of asthma is a severe infection with RSV during the first year of life (14 -16). The correlation is especially clear if the RSV infection results in hospitalization for bronchiolitis and other respiratory complications (15,17).RSV is found ubiquitously in the environment. Serious illness, however, is for the most part found only in very young children an...

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