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by Live Virulent Mycobacterium tuberculosis Is Independent of Mature Mycobacterial Lipoproteins but Dependent on TLR21
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* Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, NY 10016;
Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143;
Howard Hughes Medical Institute and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and
Department of Microbiology, New York University School of Medicine, New York, NY 10016
Mycobacterium tuberculosis is a highly successful pathogen that can persist and cause disease despite an immune response. One potential mechanism for resisting elimination is by inhibiting the action of IFN-
. We have previously shown that live M. tuberculosis inhibits selected macrophage responses to IFN-, and that purified M. tuberculosis 19-kDa lipoprotein inhibits induction of selected IFN--responsive genes through a TLR2-dependent pathway, whereas peptidoglycan inhibits responses to IFN- by a TLR2-independent pathway. To determine the relative contribution of lipoproteins to the inhibition of responses to IFN-, we deleted the M. tuberculosis gene (lspA) that encodes lipoprotein signal peptidase. This revealed that M. tuberculosis lipoprotein processing is indispensable for stimulation of TLR2 reporter cells, but that the lspA mutant inhibits macrophage responses to IFN- to the same extent as wild-type bacteria. Macrophages lacking TLR2 are more resistant to inhibition by either strain of M. tuberculosis, suggesting that nonlipoprotein TLR2 agonists contribute to inhibition. Indeed, we found that phosphatidylinositol mannan from M. tuberculosis inhibits macrophage responses to IFN-. M. tuberculosis inhibition of responses to IFN- requires new protein synthesis, indicating that a late effect of innate immune stimulation is the inhibition of responses to IFN-. These results establish that M. tuberculosis possesses multiple mechanisms of inhibiting responses to IFN-.
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