Document Type

Article

Publication Date

3-11-2025

Publication Title

Infection and immunity

Keywords

Animals, Mycobacterium tuberculosis, Mice, Necrosis, Mutation, Tuberculosis, Macrophages, DNA Polymerase gamma, DNA, Mitochondrial, Lung, Disease Models, Animal, Immunity, Innate, Disease Susceptibility, Mice, Inbred C57BL

JAX Source

Infect Immun. Forthcoming 2025:e0032424.

Volume

93

Issue

3

First Page

0032424

Last Page

0032424

ISSN

1098-5522

PMID

39969190

DOI

https://doi.org/10.1128/iai.00324-24

Grant

Funding was provided by NIH/NIAID to R.O.W. and K.L.P. (R01AI155621), W81XWH-20-1-0150 to A.P.W. from the Office of the Assistant Secretary of Defense and for Health Affairs through the Peer Reviewed Medical Research Programs, NIH/NIAID to C.J.M. (F31AI176795), NIH training grant T32GM135748 to E.L.M., NIH/NIAID to E.L.M. (F31AI176821), NIH/NRSA to J.J.V. (F31AI179168), and the Parkinson’s Foundation Launch Award PF-Launch-938138 (C.G.W.).

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. Immunohis tochemistry 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 homeosta sis in mounting balanced immune responses to Mtb.

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