Streptococcal modulation of cellular invasion via TGF-1 signaling

Streptococcal modulation of cellular invasion via TGF-1 signaling. of adherence was gained by chemical inhibition or genetic knockout of GP96 as well as addition of RGD peptide, an inhibitor of integrin-ligand interactions. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the Creatine epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in T relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract. was identified as the predominant pathogen in more than 95% of all fatal cases (4). Despite development of effective vaccines and potent antibacterial agents, during the 2009 H1N1 pandemic, bacterial pneumonia was a complication in one-quarter to one-half of severe and fatal cases (5). The underlying mechanism of the viral-bacterial synergy leading to disease progression has remained elusive, thus hampering production of effective prophylactic and therapeutic intervention options. Nasopharyngeal pneumococcal colonization is a major predisposing factor related to viral upper respiratory tract infections such as influenza (6, 7). A preceding influenza virus infection can induce excess pneumococcal acquisition and carriage in the nasopharynx, which in turn promotes bacterial dissemination to the lungs. Although respiratory epithelium provides a physical barrier against most human pathogens, the influenza virus can replicate in epithelial cells, leading to direct damage of airway epithelium (8, 9). Virus-induced epithelial damage and exfoliation provide increased receptor availability for bacteria, resulting in establishment of bacterial colonization and onset of invasive diseases. For example, the influenza virus neuraminidase cleaves sialic acid glycoconjugates on airway epithelial cells as well as mucins, which facilitates not only bacterial adherence to cryptic receptors but Creatine also their proliferation in the upper respiratory tract (10). Among bacterial receptors appearing on cell surfaces during influenza virus infection, platelet-activating factor receptor (PAFR) gained attention as a possible therapeutic target (11). Extracellular PAFR binds to phosphorylcholine embedded in the cell walls of numerous respiratory bacterial pathogens, which subsequently accelerates lung bacterial burden and bacteremia and increases mortality risk. However, previous studies have found that genetic knockout or pharmacological inhibition of PAFR had no effect on the susceptibility of mice to secondary bacterial pneumonia, implicating multifaceted mechanisms related to the synergism between influenza viruses and bacterial pathogens (12, 13). A dual viral-bacterial infection causes dysfunction of the epithelial-endothelial barrier and, consequently, exudation of fluids, erythrocytes, and leukocytes into alveolar spaces, leading to gas exchange impairment Creatine and severe respiratory insufficiency. Indeed, pulmonary edema and hemorrhage are commonly found in autopsy examinations (4). The physical barrier function of airway epithelium is provided by four types of cell-cell junctions: tight, adherens, and gap junctions, and desmosomes. Influenza virus-induced disruption of the pulmonary barrier is associated with a loss of integrity of claudin-4, a tight junctional protein (14). Moreover, interaction between the PDZ-binding motif Creatine of the avian influenza virus NS1 protein and the PDZ domain present in tight junctional proteins has been shown to destabilize epithelial junctional integrity (15). Although it is generally accepted that viral-induced epithelial cell damage allows for bacterial invasiveness, the molecular mechanisms involved in dysfunction of the alveolar epithelial barrier followed by bacterial dissemination remain largely unknown. In the present study, novel findings showing that glycoprotein 96 (GP96), a host chaperone protein, is involved in the exacerbation of bacterial pneumonia following influenza A virus (IAV) infection are presented. Interactions Creatine of pneumococci with extracellular GP96 and integrins, whose surface expressions are mediated by the chaperone activity of GP96, were found to promote pneumococcal adherence to IAV-infected epithelial cells. Also, inhibition of GP96 rendered IAV-infected cells as well as tested mice less susceptible to infection. Accordingly, GP96 is considered to be a potential target for therapeutic strategies for treating patients with superinfection. Furthermore, to the best of our knowledge, the present results.