{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:00:10Z","timestamp":1760122810204,"version":"3.40.5"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T00:00:00Z","timestamp":1545177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSTO","award":["CB3948"],"award-info":[{"award-number":["CB3948"]}]},{"name":"US USAMRIID project","award":["1324392"],"award-info":[{"award-number":["1324392"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Burkholderia mallei<\/jats:italic> (<jats:italic>B. mallei<\/jats:italic>) and <jats:italic>Burkholderia pseudomallei<\/jats:italic> (<jats:italic>B. pseudomallei<\/jats:italic>), causative agents of glanders and melioidosis, respectively, are invasive intracellular pathogens that actively multiply in phagocytic and non\u2010phagocytic cells. Activation of cell\u2010autonomous autophagy mechanism eliminate intracellular pathogens in which p62 a cytosolic cargo protein is selectively degraded, and an accumulation of this marker occurs if autophagy is deficient. Recurrent, relapsed and reinfection of <jats:italic>B. pseudomallei<\/jats:italic> in melioidosis patients in endemic area indicative of lack of complete of clearance and persistence of the pathogen. Reasoning that abundance in the levels of p62 may provide an indication of the intracellular infection, we sought to examine whether increase in intracellular p62 and bacterial burden with <jats:italic>Burkholderia<\/jats:italic> infection are linked to autophagy deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we investigated cell culture and mouse models of disease to identify an association between autophagy biomarkers (p62\/NBR1) accumulation and intracellular persistence of <jats:italic>B. mallei<\/jats:italic> and <jats:italic>B. pseudomallei<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate, that elevated levels of intracellular p62\/NBR1 correlated with bacterial persistence, while pre\u2010treatment with a pharmacological inducer of autophagy, rapamycin, reduced both intracellular p62, and bacterial survival. Our results showed an elevated p62 levels (2\u20105 fold) in spleen and liver cells of <jats:italic>Burkholderia<\/jats:italic>\u2010infected BALB\/c mice, as well as in spleen cells of <jats:italic>Burkholderia<\/jats:italic>\u2010infected C57BL\/6 mice, suggesting that an increase in p62\/NBR1 was due to an autophagy deficiency. Similar to p62, cytosolic LC3\u2010I levels were also elevated, while the characteristic conversion to the autophagosome\u2010associated membrane bound form LC3\u2010II was low in spleens of the infected mice further supporting the conclusion that autophagy was deficient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, our results suggest that an increase in intracellular p62\/NBR1 may be a potential host cell biomarker of <jats:italic>B. mallei<\/jats:italic> or <jats:italic>B. pseudomallei<\/jats:italic> infections, and identifying autophagy manipulation may potentially aid to therapeutic approach for complete clearance of the pathogen.<\/jats:p><\/jats:sec>","DOI":"10.1002\/iid3.239","type":"journal-article","created":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T07:09:02Z","timestamp":1545289742000},"page":"7-21","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["An increase in intracellular p62\/NBR1 and persistence of <i>Burkholderia mallei<\/i> and <i>B. pseudomallei<\/i> in infected mice linked to autophagy deficiency"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4345-0373","authenticated-orcid":false,"given":"Kamal U.","family":"Saikh","sequence":"first","affiliation":[{"name":"Department of Immunology Army Medical Research Institute of Infectious Diseases Frederick Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L.","family":"Dankmeyer","sequence":"additional","affiliation":[{"name":"Department of Bacteriology Army Medical Research Institute of Infectious Diseases Frederick Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiankun","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pathology Army Medical Research Institute of Infectious Diseases Frederick Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert G.","family":"Ulrich","sequence":"additional","affiliation":[{"name":"Department of Immunology Army Medical Research Institute of Infectious Diseases Frederick Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Amemiya","sequence":"additional","affiliation":[{"name":"Department of Bacteriology Army Medical Research Institute of Infectious Diseases Frederick Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,12,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3273"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1099\/00222615-31-2-109"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1128\/iai.64.3.782-790.1996","article-title":"Intracellular survival pseudomonas pseudomallei","volume":"64","author":"Jones AL","year":"1996","journal-title":"Infect Immun"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(57)90382-0"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/bst022088s"},{"key":"e_1_2_10_7_1","first-page":"35","article-title":"An ultrastructural study of the phagocytosis of Burkholderia pseudomelli","volume":"94","author":"Harley VS","year":"1998","journal-title":"Microbios"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-015-0395-7"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2012.82"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.27.061406.093749"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro865"},{"key":"e_1_2_10_12_1","first-page":"159","article-title":"Eating oneself and uninvited guests: autophagy\u2010related pathways in cellular defense","volume":"120","author":"Levine B","year":"2005","journal-title":"Cell"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.01.020"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1800"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13540"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6246"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017852"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2012.00120"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200107263450404"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2015.07.004"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02420-14"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2007.04.017"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.09.021"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2014.11.009"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.1997.0179"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1083\/jcb.200507002","article-title":"P62\/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin\u2010induced cell death","volume":"17","author":"Bj\u00f8rk\u00f8y G","year":"2005","journal-title":"J Cell Biol"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(08)03612-4"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.87"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6745028"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-017-0172-4"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.27344"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12122"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2013.1531"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17256"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1086\/520223"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0035-9203(00)90333-X"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.10.025"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.411728"}],"container-title":["Immunity, Inflammation and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fiid3.239","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/iid3.239","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/iid3.239","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/iid3.239","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T16:34:55Z","timestamp":1694363695000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/iid3.239"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,19]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,3]]}},"alternative-id":["10.1002\/iid3.239"],"URL":"https:\/\/doi.org\/10.1002\/iid3.239","archive":["Portico"],"relation":{},"ISSN":["2050-4527","2050-4527"],"issn-type":[{"type":"print","value":"2050-4527"},{"type":"electronic","value":"2050-4527"}],"subject":[],"published":{"date-parts":[[2018,12,19]]},"assertion":[{"value":"2018-06-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}