{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T12:46:09Z","timestamp":1792586769094,"version":"4.5.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2011,1,1]],"date-time":"2011-01-01T00:00:00Z","timestamp":1293840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leishmania major is a protozoan parasite that causes skin ulcerations in cutaneous leishmaniasis. In the mammalian host, the parasite resides in professional phagocytes and has evolved to avoid killing by macrophages. We identified L. major genes encoding inhibitors of serine peptidases (ISPs), which are orthologs of bacterial ecotins, and found that ISP2 inhibits trypsin-fold S1A family peptidases. In this study, we show that L. major mutants deficient in ISP2 and ISP3 (\u0394isp2\/3) trigger higher phagocytosis by macrophages through a combined action of the complement type 3 receptor, TLR4, and unregulated activity of neutrophil elastase (NE), leading to parasite killing. Whereas all three components are required to mediate enhanced parasite uptake, only TLR4 and NE are necessary to promote parasite killing postinfection. We found that the production of superoxide by macrophages in the absence of ISP2 is the main mechanism controlling the intracellular infection. Furthermore, we show that NE modulates macrophage infection in vivo, and that the lack of ISP leads to reduced parasite burdens at later stages of the infection. Our findings support the hypothesis that ISPs function to prevent the activation of TLR4 by NE during the Leishmania\u2013macrophage interaction to promote parasite survival and growth.<\/jats:p>","DOI":"10.4049\/jimmunol.1002175","type":"journal-article","created":{"date-parts":[[2010,11,23]],"date-time":"2010-11-23T05:24:36Z","timestamp":1290489876000},"page":"411-422","source":"Crossref","is-referenced-by-count":46,"title":["<i>Leishmania<\/i> Inhibitor of Serine Peptidase 2 Prevents TLR4 Activation by Neutrophil Elastase Promoting Parasite Survival in Murine Macrophages"],"prefix":"10.1093","volume":"186","author":[{"given":"Marilia S","family":"Faria","sequence":"first","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria , Rio de Janeiro ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia C G","family":"Reis","sequence":"additional","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria , Rio de Janeiro ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo L","family":"Azevedo-Pereira","sequence":"additional","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria , Rio de Janeiro ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley S","family":"Morrison","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow , Glasgow ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy C","family":"Mottram","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow , Glasgow ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula C A","family":"Lima","sequence":"additional","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria , Rio de Janeiro ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,1,1]]},"reference":[{"key":"2025032410572881700_r1","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.ijpara.2007.04.007","article-title":"The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist","volume":"37","author":"Kima","year":"2007","journal-title":"Int. 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