Whereas TLRs can mediate pathogen recognition and initiate an antiviral response in the tissue parenchyma, recruitment of cells (i.e., inflammation) is necessary for the development of effective innate host defenses and the subsequent development of adaptive immunity. In addition to driving the transcription of the type I interferons, ligation of the Toll-like receptors also stimulates an inflammatory response (Diebold et al., 2004; Pasare and
Medzhitov, 2004).The inflammatory response is initiated to recruit a variety of leukocytes (e.g., macrophages, NK cells, and B and T lymphocytes) from the blood to further control virus replication and to begin initiation of the adaptive immune response that will be considered later. Again, almost coincident with infection of the first cell, Toll-like receptor activation results in the transcription of inflammatory cytokine genes. These include IL-1 and TNF-a (Julkunen et al., 2001; Conn et al., 1995). In turn, these proinflam-matory cytokines amplify and engage additional cells in the response to invading microorganisms.
How do the virus-induced proinflammatory cytokines draw additional cells into the lung and into the regional lymph nodes? Analogous to erecting directional signs on highway exit ramps, the proinflammatory cytokines create reactive endothelium in the vicinity of the infected tissue. In response to IL-1 and TNF, the endothelial cells that line the blood vessels adjacent to the site of viral replication augment their expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (McHale et al., 1999; Streiter et al., 2003). As these molecules are displayed on the circulatory side of the blood vessels, cells that flow by and express the appropriate cognate ligand become tethered to the vessel wall. Once loosely bound to the vessels in the vicinity of viral replication, the inflammatory cells themselves become activated. The same IL-1 and TNF that created the reactive endothelium now drive the expression of chemokine receptors on the surface of the tethered cells (Weber et al., 1999; Rosseau et al., 2000).
The display of chemokine receptors is a critical step in inflammation as the cells that are tethered to the vessel endothelium become competent to leave the circulation. Now, recognition of specific chemokine signals will enable the macrophages and natural killer cells to migrate in a directional manner (i.e., chemotax) toward the site where influenza virus is replicating and causing tissue destruction. Like the proinflammatory cytokines and type I interferons, multiple chemokines are also produced after Toll-like receptor activation by influenza virus. In fact, a chemotactic gradient emanates from the point of infection where virus titers are highest and serves as a beacon to attract macrophages and NK cells (Randolph and Furie, 1995; Nieto et al., 1999). Binding to the newly expressed chemokine receptors on the tethered leukocytes is followed by a rapid rearrangement of the cell's cytoskeleton, thus changing the shape of the cell and enabling it to transmigrate from the bloodstream through the vascular endothelium into the site of inflammation (Hordijk, 2003; Walzer et al., 2005).
Influenza A virus infection results in the secretion of multiple chemokines including Macrophage Inflammatory Protein (MIP)-1a, Macrophage Inflammatory Protein (MIP)-1p, Regulated on Activation, Normal T Expressed or Secreted (RANTES), Monocyte Chemotactic Protein (MCP)-1, Monocyte Chemotactic Protein (MCP)-3, Macrophage Inflammatory Protein (MIP)-3a, and Interferon-y-inducible protein (IP) 10 (Kaufmann et al., 2001; Julkunen et al., 2000). During the first few days after infection, together with the proinflammatory cytokines, these chemokines recruit macrophages and NK cells into the tissue parenchyma where viral replication is taking place. Subsequently, after the adaptive immune response has been activated, many of these same chemokines will function to draw virus-specific T cells into the tissue to resolve the infection (Kaufmann et al., 2001; Debes et al., 2004).
In sum, the initial signals driven by Toll-like receptor activation drive two very important aspects of the immune response to influenza infection. First, the type I interferons attempt to provide local protection through the induction of an antiviral state in the parenchymal cells of the respiratory tract.And second, the proinflammatory cytokines and chemokines send out the alarm signal to recruit cells of the immune system to the site of infection where they will kill virus-infected cells and activate the adaptive immune response.
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