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Posttranscriptional Inhibition of Gene Expression by Mycobacterium tuberculosis Offsets Transcriptional Synergism with IFN- and Posttranscriptional Up-Regulation by IFN-¹

Yaming Qiao^*, Savita Prabhakar^*, Antony Canova^*, Yoshihiko Hoshino, Michael Weiden and Richard Pine^2,*

^* Public Health Research Institute and Public Health Research Institute Tuberculosis Center, Newark, NJ 07103; and New York University School of Medicine, Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York, NY 10016

Host defense against Mycobacterium tuberculosis requires the cytokine IFN- and IFN regulatory factor 1 (IRF-1), a transcription factor that is induced to high levels by IFN-. Therefore, we chose to study regulation of IRF-1 expression as a model for effects of M. tuberculosis on response to IFN-. We found that IRF-1 mRNA abundance increased far more than transcription rate in human monocytic THP-1 cells stimulated by IFN-, but less than transcription rate in cells infected by M. tuberculosis. IFN- stimulation of infected cells caused a synergistic increase in IRF-1 transcription, yet IRF-1 mRNA abundance was similar in uninfected and infected cells stimulated by IFN-, as was the IRF-1 protein level. Comparable infection by Mycobacterium bovis bacillus Calmette-Guérin failed to induce IRF-1 expression and had no effect on the response to IFN-. We also examined the kinetics of transcription, the mRNA t_1/2, and the distribution of IRF-1 transcripts among total nuclear RNA, poly(A) nuclear RNA, and poly(A) cytoplasmic RNA pools in cells that were infected by M. tuberculosis and/or stimulated by IFN-. Our data suggest that infection by M. tuberculosis inhibits RNA export from the nucleus. Moreover, the results indicate that regulated entry of nascent transcripts into the pool of total nuclear RNA affects IRF-1 expression and that this process is stimulated by IFN- and inhibited by M. tuberculosis. The ability of infection by M. tuberculosis to limit the increase in IRF-1 mRNA expression that typically follows transcriptional synergism may contribute to the pathogenicity of M. tuberculosis.