Research Article: The Mechanism for Type I Interferon Induction by Mycobacterium tuberculosis is Bacterial Strain-Dependent

Date Published: August 8, 2016

Publisher: Public Library of Science

Author(s): Kirsten E. Wiens, Joel D. Ernst, Thomas R. Hawn.

http://doi.org/10.1371/journal.ppat.1005809

Abstract

Type I interferons (including IFNαβ) are innate cytokines that may contribute to pathogenesis during Mycobacterium tuberculosis (Mtb) infection. To induce IFNβ, Mtb must gain access to the host cytosol and trigger stimulator of interferon genes (STING) signaling. A recently proposed model suggests that Mtb triggers STING signaling through bacterial DNA binding cyclic GMP-AMP synthase (cGAS) in the cytosol. The aim of this study was to test the generalizability of this model using phylogenetically distinct strains of the Mtb complex (MTBC). We infected bone marrow derived macrophages with strains from MTBC Lineages 2, 4 and 6. We found that the Lineage 6 strain induced less IFNβ, and that the Lineage 2 strain induced more IFNβ, than the Lineage 4 strain. The strains did not differ in their access to the host cytosol and IFNβ induction by each strain required both STING and cGAS. We also found that the three strains shed similar amounts of bacterial DNA. Interestingly, we found that the Lineage 6 strain was associated with less mitochondrial stress and less mitochondrial DNA (mtDNA) in the cytosol compared with the Lineage 4 strain. Treating macrophages with a mitochondria-specific antioxidant reduced cytosolic mtDNA and inhibited IFNβ induction by the Lineage 2 and 4 strains. We also found that the Lineage 2 strain did not induce more mitochondrial stress than the Lineage 4 strain, suggesting that additional pathways contribute to higher IFNβ induction. These results indicate that the mechanism for IFNβ by Mtb is more complex than the established model suggests. We show that mitochondrial dynamics and mtDNA contribute to IFNβ induction by Mtb. Moreover, we show that the contribution of mtDNA to the IFNβ response varies by MTBC strain and that additional mechanisms exist for Mtb to induce IFNβ.

Partial Text

Type I interferons (including IFNαβ) are innate cytokines that are protective during most viral infections, but may be pathogenic during infections with bacteria such as Mycobacterium tuberculosis (Mtb) [1]. Studies have shown that active tuberculosis (TB) is associated with expression of interferon-inducible genes [2, 3], lepromatous Mycobacterium leprae lesions are enriched in IFNαβ-inducible mRNAs [4], and that interleukin-1 confers resistance to Mtb by limiting IFNαβ induction [5]. There is also evidence that IFNαβ is protective in certain contexts [6], and thus it is likely that a balance of this cytokine is required for optimal protection. Given the complex role of IFNαβ signaling during Mtb infection, discovering a model for how Mtb induces IFNβ gene transcription—the first step required for IFNαβ signaling—has been an active and challenging area of research.

In this study we show that the M. tuberculosis complex strain 1182 from Lineage 6 induces less mitochondrial ROS, less mtDNA in the cytosol, and lower IFNβ induction than H37Rv/Lineage 4. Further, we show that reducing mitochondrial ROS during Mtb infection reduces IFNβ induction. Therefore we propose that mitochondrial stress contributes to IFNβ induction by Mtb (Fig 7). We also show that 4334/Lineage 2 induces similar to lower levels of mitochondrial ROS and cytosolic mtDNA than H37Rv/Lineage 4, yet induces higher IFNβ induction. Thus we propose that 4334/Lineage 2 induces additional, unidentified pathways to promote IFNβ induction (Fig 7). Together these results show that the mechanism for IFNβ induction by Mtb is much more complex than the established model suggests.

 

Source:

http://doi.org/10.1371/journal.ppat.1005809

 

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