Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity
Several virulence lipids populate the outer cell wall of pathogenic mycobacteria. Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids, plays important roles in both defending against host antimicrobial programs and in evading these programs altogether. Immediately follo...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/60648 |
| _version_ | 1828221790136041472 |
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| author | CJ Cambier Steven M Banik Joseph A Buonomo Carolyn R Bertozzi |
| author_facet | CJ Cambier Steven M Banik Joseph A Buonomo Carolyn R Bertozzi |
| author_sort | CJ Cambier |
| collection | DOAJ |
| description | Several virulence lipids populate the outer cell wall of pathogenic mycobacteria. Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids, plays important roles in both defending against host antimicrobial programs and in evading these programs altogether. Immediately following infection, mycobacteria rely on PDIM to evade Myd88-dependent recruitment of microbicidal monocytes which can clear infection. To circumvent the limitations in using genetics to understand virulence lipids, we developed a chemical approach to track PDIM during Mycobacterium marinum infection of zebrafish. We found that PDIM's methyl-branched lipid tails enabled it to spread into host epithelial membranes to prevent immune activation. Additionally, PDIM’s affinity for cholesterol promoted this phenotype; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread. |
| first_indexed | 2024-04-12T16:46:17Z |
| format | Article |
| id | doaj.art-a662bef3e1b8482093eb39659e5a9059 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:46:17Z |
| publishDate | 2020-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a662bef3e1b8482093eb39659e5a90592022-12-22T03:24:35ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.60648Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivityCJ Cambier0https://orcid.org/0000-0002-0300-7377Steven M Banik1https://orcid.org/0000-0001-7070-3404Joseph A Buonomo2Carolyn R Bertozzi3https://orcid.org/0000-0003-4482-2754Department of Chemistry, Stanford University, Stanford, United StatesDepartment of Chemistry, Stanford University, Stanford, United StatesDepartment of Chemistry, Stanford University, Stanford, United StatesDepartment of Chemistry, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United StatesSeveral virulence lipids populate the outer cell wall of pathogenic mycobacteria. Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids, plays important roles in both defending against host antimicrobial programs and in evading these programs altogether. Immediately following infection, mycobacteria rely on PDIM to evade Myd88-dependent recruitment of microbicidal monocytes which can clear infection. To circumvent the limitations in using genetics to understand virulence lipids, we developed a chemical approach to track PDIM during Mycobacterium marinum infection of zebrafish. We found that PDIM's methyl-branched lipid tails enabled it to spread into host epithelial membranes to prevent immune activation. Additionally, PDIM’s affinity for cholesterol promoted this phenotype; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread.https://elifesciences.org/articles/60648Mycobacteriabioorthogonal chemistryPDIM |
| spellingShingle | CJ Cambier Steven M Banik Joseph A Buonomo Carolyn R Bertozzi Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity eLife Mycobacteria bioorthogonal chemistry PDIM |
| title | Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity |
| title_full | Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity |
| title_fullStr | Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity |
| title_full_unstemmed | Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity |
| title_short | Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity |
| title_sort | spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity |
| topic | Mycobacteria bioorthogonal chemistry PDIM |
| url | https://elifesciences.org/articles/60648 |
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