{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:16:57Z","timestamp":1768511817390,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,25]]},"group-title":"Microbiology","reference-count":89,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                  (\n                  <jats:italic>Sp<\/jats:italic>\n                  ), a leading cause of community-acquired pneumonia, can spread from the lung into the bloodstream to cause septicemia and meningitis, with a concomitant three-fold increase in mortality. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread. The major\n                  <jats:italic>Sp<\/jats:italic>\n                  virulence factor, pneumolysin (PLY), triggers acute inflammation by stimulating the 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway in epithelial cells. This pathway is required for systemic spread in a mouse pneumonia model and produces a number of bioactive lipids, including hepoxilin A3 (HXA\n                  <jats:sub>3<\/jats:sub>\n                  ), a hydroxy epoxide PMN chemoattractant that has been hypothesized to facilitate breach of mucosal barriers. To understand how 12-LOX-dependent inflammation promotes dissemination during\n                  <jats:italic>Sp<\/jats:italic>\n                  lung infection and dissemination, we utilized bronchial stem cell-derived air-liquid interface (ALI) cultures that lack this enzyme to show that HXA\n                  <jats:sub>3<\/jats:sub>\n                  methyl ester (HXA\n                  <jats:sub>3<\/jats:sub>\n                  -ME) is sufficient to promote basolateral-to-apical PMN transmigration, monolayer disruption, and concomitant\n                  <jats:italic>Sp<\/jats:italic>\n                  barrier breach. In contrast, PMN transmigration in response to the non-eicosanoid chemoattractant fMLP did not lead to epithelial disruption or bacterial translocation. Correspondingly, HXA\n                  <jats:sub>3<\/jats:sub>\n                  -ME but not fMLP increased release of neutrophil elastase (NE) from\n                  <jats:italic>Sp<\/jats:italic>\n                  -infected PMNs. Pharmacologic blockade of NE secretion or activity diminished epithelial barrier disruption and bacteremia after pulmonary challenge of mice. Thus, HXA\n                  <jats:sub>3<\/jats:sub>\n                  promotes barrier disrupting PMN transmigration and NE release, pathological events that can be targeted to curtail systemic disease following pneumococcal pneumonia.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    (\n                    <jats:italic>Sp<\/jats:italic>\n                    ), a leading cause of pneumonia, can spread from the lung into the bloodstream to cause systemic disease. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that limit pathologic host immune responses to\n                    <jats:italic>Sp<\/jats:italic>\n                    . Excessive polymorphonuclear leukocyte (PMN) infiltration into\n                    <jats:italic>Sp<\/jats:italic>\n                    -infected airways promotes systemic disease. Using stem cell-derived respiratory cultures that reflect\n                    <jats:italic>bona fide<\/jats:italic>\n                    lung epithelium, we identified the eicosanoid hepoxilin A3 as a critical pulmonary PMN chemoattractant that is sufficient to drive PMN-mediated epithelial damage by inducing the release of neutrophil elastase. Inhibition of the release or activity of this protease in mice limited epithelial barrier disruption and bacterial dissemination, suggesting a new host-directed treatment for\n                    <jats:italic>Sp<\/jats:italic>\n                    lung infection.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.25.600637","type":"posted-content","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T23:50:10Z","timestamp":1719359410000},"source":"Crossref","is-referenced-by-count":0,"title":["Blocking HXA\n                  <sub>3<\/sub>\n                  -mediated neutrophil elastase release during\n                  <i>S. pneumoniae<\/i>\n                  lung infection limits pulmonary epithelial barrier disruption and bacteremia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4572-8663","authenticated-orcid":false,"given":"Shuying","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1093-2576","authenticated-orcid":false,"given":"Shumin","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Romanos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L.","family":"Reedy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8892-8695","authenticated-orcid":false,"given":"Michael K.","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-9565","authenticated-orcid":false,"given":"Jatin M.","family":"Vyas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-6672","authenticated-orcid":false,"given":"Joan","family":"Mecsas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Mou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Leong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024062708250800000_2024.06.25.600637v1.1","doi-asserted-by":"crossref","unstructured":"Henriques-Normark B , Tuomanen EI . 2013. 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