{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:14:21Z","timestamp":1792710861283,"version":"4.5.0"},"reference-count":53,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000774","name":"DOD | Defense Threat Reduction Agency","doi-asserted-by":"publisher","award":["CBCALL12-THRB1-1-0270"],"award-info":[{"award-number":["CBCALL12-THRB1-1-0270"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:named-content content-type=\"genus-species\">Burkholderia mallei<\/jats:named-content>\n                    and\n                    <jats:named-content content-type=\"genus-species\">B. pseudomallei<\/jats:named-content>\n                    cause glanders and melioidosis, respectively, in humans and animals. A hallmark of pathogenesis is the formation of granulomas containing multinucleated giant cells (MNGCs) and cell death. These processes depend on type 6 secretion system 1 (T6SS-1), which is required for virulence in animals. We examined the cell biology of MNGC formation and cell death. We found that chloroquine diphosphate (CLQ), an antimalarial drug, inhibits\n                    <jats:named-content content-type=\"genus-species\">Burkholderia<\/jats:named-content>\n                    growth, phagosomal escape, and subsequent MNGC formation. This depends on CLQ's ability to neutralize the acid pH because other alkalinizing compounds similarly inhibit escape and MNGC formation. CLQ inhibits bacterial virulence protein expression because T6SS-1 and some effectors of type 3 secretion system 3 (T3SS-3), which is also required for virulence, are expressed at acid pH. We show that acid pH upregulates the expression of Hcp1 of T6SS-1 and TssM, a protein coregulated with T6SS-1. Finally, we demonstrate that CLQ treatment of\n                    <jats:named-content content-type=\"genus-species\">Burkholderia<\/jats:named-content>\n                    -infected Madagascar hissing cockroaches (HCs) increases their survival. This study highlights the multiple mechanisms by which CLQ inhibits growth and virulence and suggests that CLQ be further tested and considered, in conjunction with antibiotic use, for the treatment of diseases caused by\n                    <jats:named-content content-type=\"genus-species\">Burkholderia<\/jats:named-content>\n                    .\n                  <\/jats:p>","DOI":"10.1128\/iai.00586-16","type":"journal-article","created":{"date-parts":[[2016,10,31]],"date-time":"2016-10-31T21:12:21Z","timestamp":1477948341000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["pH Alkalinization by Chloroquine Suppresses Pathogenic Burkholderia Type 6 Secretion System 1 and Multinucleated Giant Cells"],"prefix":"10.1128","volume":"85","author":[{"given":"Jennifer","family":"Chua","sequence":"first","affiliation":[{"name":"Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Senft","sequence":"additional","affiliation":[{"name":"Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Lockett","sequence":"additional","affiliation":[{"name":"Optical Microscopy and Analysis Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Brett","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary N.","family":"Burtnick","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"DeShazer","sequence":"additional","affiliation":[{"name":"Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur M.","family":"Friedlander","sequence":"additional","affiliation":[{"name":"Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA"},{"name":"Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.112408.134030"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.2.383-416.2005"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0403302101"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/497382"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1099\/00207713-48-1-317"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01585-06"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/517253"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.37.6.1906-1912.1999"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.7.4172-4187.2004"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.carres.2011.12.011"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-51-7-539"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0035-9203(08)70028-2"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00626-08"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049745"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2011.00170"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6246"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12275-013-2557-3"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1107183108"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01218-10"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05734.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.9.4.352"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.1995.tb00620.x"},{"key":"e_1_3_3_24_2","first-page":"223","article-title":"A case of septicemic glanders in the human subject","volume":"9","author":"Coleman W","year":"1903","unstructured":"Coleman W Ewing J . 1903. 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