Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production

Dee N. Dao, Kari Sweeney, Tsungda Hsu, Sudagar S. Gurcha, Ivan P. Nascimento, Dan Roshevsky, Gurdyal S. Besra, John Chan, Steven A. Porcelli, William R. Jacobs

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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-α 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 ΔmmaA4 mutant stimulated increased IL-12p40, similar to the increase observed from ΔmmaA4 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.

Original languageEnglish (US)
Article numbere1000081
JournalPLoS Pathogens
Volume4
Issue number6
DOIs
StatePublished - Jun 2008

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Mycolic Acids
Interleukin-12 Subunit p40
Interleukin-12
Tuberculosis
Mycobacterium tuberculosis
Cord Factors
Macrophages
Genes
Virulence
Immune Evasion
Transferases
Libraries
Immune System
Immunity
Oxygen
Cell Line

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Dao, D. N., Sweeney, K., Hsu, T., Gurcha, S. S., Nascimento, I. P., Roshevsky, D., ... Jacobs, W. R. (2008). Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. PLoS Pathogens, 4(6), [e1000081]. https://doi.org/10.1371/journal.ppat.1000081

Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. / Dao, Dee N.; Sweeney, Kari; Hsu, Tsungda; Gurcha, Sudagar S.; Nascimento, Ivan P.; Roshevsky, Dan; Besra, Gurdyal S.; Chan, John; Porcelli, Steven A.; Jacobs, William R.

In: PLoS Pathogens, Vol. 4, No. 6, e1000081, 06.2008.

Research output: Contribution to journalArticle

Dao, DN, Sweeney, K, Hsu, T, Gurcha, SS, Nascimento, IP, Roshevsky, D, Besra, GS, Chan, J, Porcelli, SA & Jacobs, WR 2008, 'Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production', PLoS Pathogens, vol. 4, no. 6, e1000081. https://doi.org/10.1371/journal.ppat.1000081
Dao DN, Sweeney K, Hsu T, Gurcha SS, Nascimento IP, Roshevsky D et al. Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. PLoS Pathogens. 2008 Jun;4(6). e1000081. https://doi.org/10.1371/journal.ppat.1000081
Dao, Dee N. ; Sweeney, Kari ; Hsu, Tsungda ; Gurcha, Sudagar S. ; Nascimento, Ivan P. ; Roshevsky, Dan ; Besra, Gurdyal S. ; Chan, John ; Porcelli, Steven A. ; Jacobs, William R. / Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. In: PLoS Pathogens. 2008 ; Vol. 4, No. 6.
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