Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production.
Mycobacterium tuberculosis has evolved many strategies to evade elimination by the host immune system, including the selective repression of macrophage IL-12p40 production. To identify the M. tuberculosis genes responsible for this aspect of immune evasion, we used a macrophage cell line expressing...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-06-01
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| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18535659/?tool=EBI |
| _version_ | 1828949467885207552 |
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| author | Dee N Dao Kari Sweeney Tsungda Hsu Sudagar S Gurcha Ivan P Nascimento Ivan P Nascimento Dan Roshevsky Gurdyal S Besra John Chan Steven A Porcelli William R Jacobs |
| author_facet | Dee N Dao Kari Sweeney Tsungda Hsu Sudagar S Gurcha Ivan P Nascimento Ivan P Nascimento Dan Roshevsky Gurdyal S Besra John Chan Steven A Porcelli William R Jacobs |
| author_sort | Dee N Dao |
| collection | DOAJ |
| description | Mycobacterium tuberculosis has evolved many strategies to evade elimination by the host immune system, including the selective repression of macrophage IL-12p40 production. To identify the M. tuberculosis genes responsible for this aspect of immune evasion, we used a macrophage cell line expressing a reporter for IL-12p40 transcription to screen a transposon library of M. tuberculosis for mutants that lacked this function. This approach led to the identification of the mmaA4 gene, which encodes a methyl transferase required for introducing the distal oxygen-containing modifications of mycolic acids, as a key locus involved in the repression of IL-12p40. Mutants in which mmaA4 (hma) was inactivated stimulated macrophages to produce significantly more IL-12p40 and TNF-alpha than wild-type M. tuberculosis and were attenuated for virulence. This attenuation was not seen in IL-12p40-deficient mice, consistent with a direct linkage between enhanced stimulation of IL-12p40 by the mutant and its reduced virulence. Treatment of macrophages with trehalose dimycolate (TDM) purified from the DeltammaA4 mutant stimulated increased IL-12p40, similar to the increase observed from DeltammaA4 mutant-infected macrophages. In contrast, purified TDM isolated from wild-type M. tuberculosis inhibited production of IL-12p40 by macrophages. These findings strongly suggest that M. tuberculosis has evolved mmaA4-derived mycolic acids, including those incorporated into TDM to manipulate IL-12-mediated immunity and virulence. |
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| format | Article |
| id | doaj.art-af43775a7c4e45428bfb7a3ddf3d3ba7 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-14T06:07:12Z |
| publishDate | 2008-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-af43775a7c4e45428bfb7a3ddf3d3ba72022-12-21T23:14:15ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742008-06-0146e100008110.1371/journal.ppat.1000081Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production.Dee N DaoKari SweeneyTsungda HsuSudagar S GurchaIvan P NascimentoIvan P NascimentoDan RoshevskyGurdyal S BesraJohn ChanSteven A PorcelliWilliam R JacobsMycobacterium tuberculosis has evolved many strategies to evade elimination by the host immune system, including the selective repression of macrophage IL-12p40 production. To identify the M. tuberculosis genes responsible for this aspect of immune evasion, we used a macrophage cell line expressing a reporter for IL-12p40 transcription to screen a transposon library of M. tuberculosis for mutants that lacked this function. This approach led to the identification of the mmaA4 gene, which encodes a methyl transferase required for introducing the distal oxygen-containing modifications of mycolic acids, as a key locus involved in the repression of IL-12p40. Mutants in which mmaA4 (hma) was inactivated stimulated macrophages to produce significantly more IL-12p40 and TNF-alpha than wild-type M. tuberculosis and were attenuated for virulence. This attenuation was not seen in IL-12p40-deficient mice, consistent with a direct linkage between enhanced stimulation of IL-12p40 by the mutant and its reduced virulence. Treatment of macrophages with trehalose dimycolate (TDM) purified from the DeltammaA4 mutant stimulated increased IL-12p40, similar to the increase observed from DeltammaA4 mutant-infected macrophages. In contrast, purified TDM isolated from wild-type M. tuberculosis inhibited production of IL-12p40 by macrophages. These findings strongly suggest that M. tuberculosis has evolved mmaA4-derived mycolic acids, including those incorporated into TDM to manipulate IL-12-mediated immunity and virulence.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18535659/?tool=EBI |
| spellingShingle | Dee N Dao Kari Sweeney Tsungda Hsu Sudagar S Gurcha Ivan P Nascimento Ivan P Nascimento Dan Roshevsky Gurdyal S Besra John Chan Steven A Porcelli William R Jacobs Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. PLoS Pathogens |
| title | Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. |
| title_full | Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. |
| title_fullStr | Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. |
| title_full_unstemmed | Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. |
| title_short | Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. |
| title_sort | mycolic acid modification by the mmaa4 gene of m tuberculosis modulates il 12 production |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18535659/?tool=EBI |
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