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It is a highly inflammatory Toll-like receptor 2 (TLR2) ligand, and previous<jats:italic>in vivo<\/jats:italic>studies have demonstrated its ability to recapitulate pathological features of pneumonia and meningitis. We report that an actin-dependent pathway is involved in the internalization of the CW by epithelial and endothelial cells, in addition to the previously described platelet-activating factor receptor (PAFr)-dependent uptake pathway. Unlike the PAFr-dependent pathway, which is mediated by clathrin and dynamin and does not lead to signaling, the alternative pathway is sensitive to 5-(<jats:italic>N<\/jats:italic>-ethyl-<jats:italic>N<\/jats:italic>-isopropyl) amiloride (EIPA) and engenders Rac1, Cdc42, and phosphatidylinositol 3-kinase (PI3K) signaling. Upon internalization by this macropinocytosis-like pathway, CW is trafficked to lysosomes. Intracellular CW trafficking is more complex than previously recognized and suggests multiple points of interaction with and without innate immune signaling.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold><jats:italic>Streptococcus pneumoniae<\/jats:italic>is a major human pathogen infecting the respiratory tract and brain. It is an established model organism for understanding how infection injures the host. During infection or bacterial growth, bacteria shed their cell wall (CW) into the host environment and trigger inflammation. A previous study has shown that CW enters and crosses cell barriers by interacting with a receptor on the surfaces of host cells, termed platelet-activating factor receptor (PAFr). In the present study, by using cells that are depleted of PAFr, we identified a second pathway with features of macropinocytosis, which is a receptor-independent fluid uptake mechanism by cells. Each pathway contributes approximately the same amount of cell wall trafficking, but the PAFr pathway is silent, while the new pathway appears to contribute to the host inflammatory response to CW insult.<\/jats:p>","DOI":"10.1128\/mbio.02030-16","type":"journal-article","created":{"date-parts":[[2017,1,4]],"date-time":"2017-01-04T01:10:32Z","timestamp":1483492232000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["Dissecting Bacterial Cell Wall Entry and Signaling in Eukaryotic Cells: an Actin-Dependent Pathway Parallels Platelet-Activating Factor Receptor-Mediated Endocytosis"],"prefix":"10.1128","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7040-8170","authenticated-orcid":false,"given":"Lip Nam","family":"Loh","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2363-1561","authenticated-orcid":false,"given":"Geli","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0349-8716","authenticated-orcid":false,"given":"Elaine I.","family":"Tuomanen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.9.6182"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00022-06"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2087"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.7.1584"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/151.5.859"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1164\/arrd.1987.135.4.869"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4049\/jimmunol.163.1.1","article-title":"Recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2","volume":"163","author":"Yoshimura A","year":"1999","unstructured":"Yoshimura A Lien E Ingalls RR Tuomanen E Dziarski R Golenbock D . 1999. 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