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Host mortality primarily results from sepsis-related complications and associated cytokine release. Lipopolysaccharide (LPS), a major virulence factor and mediator of sepsis, is modified by\n                      <jats:italic toggle=\"yes\">B. pseudomallei<\/jats:italic>\n                      in response to external stimuli. LpxO and PagL are lipid A-modifying proteins encoded by the\n                      <jats:italic toggle=\"yes\">B. pseudomallei<\/jats:italic>\n                      genome to decrease recognition by host defenses. The contribution of\n                      <jats:italic toggle=\"yes\">lpxO<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">pagL-<\/jats:italic>\n                      dependent lipid A modifications to outer membrane permeability and host response has not been clearly demonstrated. Mono-phosphorylated lipid A (MPLA) is known to maintain LPS-specific immunogenicity while reducing endotoxicity and has been used extensively as a vaccine adjuvant. Generation of MPLA can be mediated through LpxE. In this work, a panel of defined lipid A modification strains in\n                      <jats:italic toggle=\"yes\">B. pseudomallei<\/jats:italic>\n                      was generated to study effects on bacterial physiology and cytokine expression in macrophages. Knockout of\n                      <jats:italic toggle=\"yes\">lpxO<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">pagL<\/jats:italic>\n                      resulted in dehydroxylation and penta-acylation of lipid A, respectively, and reduced membrane permeability of\n                      <jats:italic toggle=\"yes\">B. pseudomallei<\/jats:italic>\n                      . Expression of\n                      <jats:italic toggle=\"yes\">lpxE<\/jats:italic>\n                      removed one phosphate group as measured by matrix-assisted laser desorption\/ionization time-of-flight (MALDI-TOF) and caused increased membrane permeability. Outer membrane vesicles (OMVs) from the generated mutants were used to study the immunological effect of lipid A modifications on human monocyte-derived macrophages. Macrophages treated with OMVs isolated from\n                      <jats:italic toggle=\"yes\">lpxE<\/jats:italic>\n                      -expressing strains showed significant increases in gene expression of proinflammatory cytokines tumor necrosis factor and interferon gamma compared to wild-type\n                      <jats:italic toggle=\"yes\">B. pseudomallei<\/jats:italic>\n                      OMVs. These results show the importance of lipid A modifiers LpxO and PagL for\n                      <jats:italic toggle=\"yes\">B. pseudomallei<\/jats:italic>\n                      physiology and highlight the immunostimulatory effect of\n                      <jats:italic toggle=\"yes\">lpxE<\/jats:italic>\n                      -modified OMVs that could enhance OMV vaccine technology targeting melioidosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00602-25","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T15:01:31Z","timestamp":1784732491000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Outer membrane engineering through lipid A modification allows modulation of\n                    <i>Burkholderia pseudomallei<\/i>\n                    membrane permeability and innate immune responsivity"],"prefix":"10.1128","volume":"94","author":[{"given":"Thi Hai Au","family":"La","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01wspgy28","id-type":"ROR","asserted-by":"publisher"}],"name":"Pathogen Analysis and Translational Health Group, School of Life Sciences, University of Hawai\u02bbi at M\u0101noa","place":["Honolulu, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"McMillan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01wspgy28","id-type":"ROR","asserted-by":"publisher"}],"name":"Pathogen Analysis and Translational Health Group, School of Life Sciences, University of Hawai\u02bbi at M\u0101noa","place":["Honolulu, USA"]},{"id":[{"id":"https:\/\/ror.org\/01wspgy28","id-type":"ROR","asserted-by":"publisher"}],"name":"Daniel K. 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