Mycolic Acid Modification by the mmaA4 Gene of M. tuberculosis Modulates IL-12 Production

PLoS Pathogens

Sudagar S. Gurcha¹  Kari Sweeney¹  William R. Jacobs Jr.¹  Tsungda Hsu²  Ivan P. Nascimento²  John Chan²  Dee N. Dao²  Gurdyal S. Besra³  Dan Roshevsky⁴  Steven A. Porcelli⁴ 

[1] Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America;Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America;Instituto Butantan, Biotecnologia Molecular IV, São Paulo, São Paulo, Brazil;School of Biosciences, The University of Birmingham, Edgbaston, United Kingdom

关键词: Mycobacterium tuberculosis;    Macrophages;    Cytokines;    Dendritic cells;    Transposable elements;    Immune response;    Immunity;    Lipids;   

DOI  :  10.1371/journal.ppat.1000081

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY