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...
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2008
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oai:doaj.org-article:af43775a7c4e45428bfb7a3ddf3d3ba72021-11-25T05:46:33ZMycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production.1553-73661553-737410.1371/journal.ppat.1000081https://doaj.org/article/af43775a7c4e45428bfb7a3ddf3d3ba72008-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18535659/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Mycobacterium 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.Dee N DaoKari SweeneyTsungda HsuSudagar S GurchaIvan P NascimentoIvan P NascimentoDan RoshevskyGurdyal S BesraJohn ChanSteven A PorcelliWilliam R JacobsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 4, Iss 6, p e1000081 (2008) |
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DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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. |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
mycolic acid modification by the mmaa4 gene of m. tuberculosis modulates il-12 production. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2008 |
| url |
https://doaj.org/article/af43775a7c4e45428bfb7a3ddf3d3ba7 |
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