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, TX 77807, 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 (POLG) potentiate susceptibility to Mtb infection in mice. PolgD257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection timepoint, 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 hyper-susceptible 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 (POLG) mutations increase susceptibility to Mycobacterium tuberculosis (Mtb) infection. These mutations impair early immune responses, leading to increased necrosis and severe disease.
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Host genetic factors influence Mycobacterium tuberculosis (Mtb) infection outcomes.
- Mitochondrial dysfunction is linked to increased severity of mycobacterial diseases.
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 mtDNA mutations affect the host immune response to Mtb.
Main Methods:
- Utilized PolgD257A mutator mice with mtDNA mutations.
- Assessed bacterial burden, immune cell populations (macrophages, neutrophils), and lung pathology in infected mice.
- Performed ex vivo analysis of macrophage susceptibility to necroptosis.
Main Results:
- PolgD257A mice exhibited higher bacterial loads and impaired innate immune responses early in Mtb infection.
- Reduced M1 macrophages and excessive neutrophil infiltration were observed in the lungs.
- Mtb-infected PolgD257A mice showed enhanced lung necrosis, and their macrophages were more susceptible to necroptosis.
Conclusions:
- mtDNA mutations in POLG potentiate susceptibility to Mtb infection by impairing early immune responses.
- mtDNA mutations contribute to necrosis during Mtb infection.
- Maintaining mitochondrial homeostasis is crucial for effective immune responses against Mtb.
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