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Because they are common components of the nasopharyngeal flora that share the potential to cause disease, we investigated the effects of<jats:italic>Haemophilus influenzae<\/jats:italic>and<jats:italic>Streptococcus pneumoniae<\/jats:italic>, alone and in combination, on human respiratory epithelial cells in culture and in a murine model of nasopharyngeal colonization. Exposure of A549 or Detroit 562 epithelial cells to both<jats:italic>S. pneumoniae<\/jats:italic>and<jats:italic>H. influenzae<\/jats:italic>led to a synergistic increase in production of IL-8, the major neutrophil chemokine in the airway, through an NF-\u03baB-dependent mechanism. Likewise, nasal cocolonization of mice caused a synergistic rise in local production of macrophage inflammatory protein 2 in nasal lavage fluid and subsequent recruitment of neutrophils. This synergistic effect depended on production of the pore-forming cytolytic toxin, pneumolysin, by<jats:italic>S. pneumoniae<\/jats:italic>and activation of host p38 mitogen-activated protein kinase. Although both<jats:italic>H. influenzae<\/jats:italic>and<jats:italic>S. pneumoniae<\/jats:italic>have ligands for Toll-like receptors (TLRs) TLR2 and TLR4, synergistic activation was TLR2- and TLR4-independent. Thus, epithelial surfaces are capable of amplifying proinflammatory responses during concurrent stimulation by multiple microbial species. These synergistic responses, demonstrated both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>, may contribute to inflammation of heavily colonized mucosal barriers.<\/jats:p>","DOI":"10.1073\/pnas.0500599102","type":"journal-article","created":{"date-parts":[[2005,2,23]],"date-time":"2005-02-23T04:34:57Z","timestamp":1109133297000},"page":"3429-3434","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":131,"title":["Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces"],"prefix":"10.1073","volume":"102","author":[{"given":"Adam J.","family":"Ratner","sequence":"first","affiliation":[{"name":"Departments of Microbiology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104"}]},{"given":"Elena S.","family":"Lysenko","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104"}]},{"given":"Marina N.","family":"Paul","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104"}]},{"given":"Jeffrey N.","family":"Weiser","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104"}]}],"member":"341","published-online":{"date-parts":[[2005,2,22]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118275"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00121.2003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.12.3770-3783.2001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1560"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400557101"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1089\/107662903764736409"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.8.4430-4440.2000"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/315388"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/341658"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.79.2.137"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2000.01707.x"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011576"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.57.7.2037-2042.1989"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80119-3"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.59.7.2297-2304.1991"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2865"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.2.810"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0435928100"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.11.2091"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.2.850-856.2003"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.10.5523-5530.2003"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107484200"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.4.1882"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006454-199711000-00011"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)83529-2"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.3109\/01902149109063278"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071914"},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1189\/jlb.72.5.847","volume":"72","year":"2002","unstructured":"Hoffmann, E., Dittrich-Breiholz, O., Holtmann, H. & Kracht, M. 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