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Updated: May 27, 2025
Modeling Tuberculosis in Mycobacterium marinum Infected Adult Zebrafish
Published on: October 8, 2018
Necrosis drives susceptibility to Mycobacterium tuberculosis in PolgD257A mutator mice
C J Mabry1, C G Weindel1, L W Stranahan2
1Department of Microbial Pathogenesis and Immunology, Texas A&M Health, College of Medicine, Bryan, Texas, USA.
Abstract:
The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity, and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma potentiate susceptibility to Mtb infection in mice. PolgD257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection time point, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected PolgD257A mice, and PolgD257A mutator macrophages are hypersusceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.
Insights
Mitochondrial DNA polymerase gamma mutations increase susceptibility to tuberculosis (TB) in mice by impairing early immune responses and promoting lung necrosis. This highlights the importance of mitochondrial health in fighting TB infection.
Area of Science:
- Immunology
- Genetics
- Mitochondrial Biology
Background:
- The genetic basis for varied outcomes in Mycobacterium tuberculosis (Mtb) infections remains unclear.
- Mitochondrial dysfunction is linked to increased severity of mycobacterial diseases, with some mitochondrial gene mutations causing susceptibility.
Purpose of the Study:
- To investigate the role of mitochondrial DNA (mtDNA) polymerase gamma (Polg) mutations in susceptibility to Mtb infection.
- To elucidate the mechanisms by which Polg mutations affect the host immune response to Mtb.
Main Methods:
- Utilized Polg D257A mutator mice with mtDNA mutations.
- Assessed bacterial burden, immune cell populations (macrophages, neutrophils), and tissue damage (necrosis) in the lungs post-Mtb infection.
- Performed ex vivo analysis of macrophage susceptibility to necroptosis.
Main Results:
- Polg D257A mice exhibited higher bacterial loads and impaired innate immunity, characterized by reduced M1 macrophages and increased neutrophils.
- Mtb-infected Polg D257A mice showed enhanced lung necrosis.
- Macrophages from Polg D257A mice were more prone to necroptosis when stimulated.
Conclusions:
- mtDNA mutations, specifically in Polg, contribute to increased susceptibility to Mtb infection.
- mtDNA mutations promote necrosis during Mtb infection, underscoring the need for mitochondrial homeostasis for effective immune responses.
