Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation

Yongxing Wang; Vikram V. Kulkarni; Jezreel Pantaleón García; Miguel M. Leiva-Juárez; David L. Goldblatt; Fahad Gulraiz; Lisandra Vila Ellis; Jichao Chen; Michael K. Longmire; Sri Ramya Donepudi; Philip L. Lorenzi; Hao Wang; Lee Jun Wong; Michael J. Tuvim; Scott E. Evans

doi:10.1371/journal.ppat.1011138

Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation

Yongxing Wang, Vikram V. Kulkarni, Jezreel Pantaleón García, Miguel M. Leiva-Juárez, David L. Goldblatt, Fahad Gulraiz, Lisandra Vila Ellis, Jichao Chen, Michael K. Longmire, Sri Ramya Donepudi, Philip L. Lorenzi, Hao Wang, Lee Jun Wong, Michael J. Tuvim, Scott E. Evans

Research output: Contribution to journal › Article › peer-review

Abstract

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs’ intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (Δ^Ψm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

Original language	English (US)
Article number	e1011138
Journal	PLoS pathogens
Volume	19
Issue number	9 September
DOIs	https://doi.org/10.1371/journal.ppat.1011138
State	Published - Sep 2023

ASJC Scopus subject areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

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10.1371/journal.ppat.1011138

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Wang, Y., Kulkarni, V. V., García, J. P., Leiva-Juárez, M. M., Goldblatt, D. L., Gulraiz, F., Ellis, L. V., Chen, J., Longmire, M. K., Donepudi, S. R., Lorenzi, P. L., Wang, H., Wong, L. J., Tuvim, M. J., & Evans, S. E. (2023). Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation. PLoS pathogens, 19(9 September), Article e1011138. https://doi.org/10.1371/journal.ppat.1011138

Wang, Y, Kulkarni, VV, García, JP, Leiva-Juárez, MM, Goldblatt, DL, Gulraiz, F, Ellis, LV, Chen, J, Longmire, MK, Donepudi, SR, Lorenzi, PL, Wang, H, Wong, LJ, Tuvim, MJ & Evans, SE 2023, 'Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation', PLoS pathogens, vol. 19, no. 9 September, e1011138. https://doi.org/10.1371/journal.ppat.1011138

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abstract = "Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs{\textquoteright} intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.",

author = "Yongxing Wang and Kulkarni, {Vikram V.} and Garc{\'i}a, {Jezreel Pantale{\'o}n} and Leiva-Ju{\'a}rez, {Miguel M.} and Goldblatt, {David L.} and Fahad Gulraiz and Ellis, {Lisandra Vila} and Jichao Chen and Longmire, {Michael K.} and Donepudi, {Sri Ramya} and Lorenzi, {Philip L.} and Hao Wang and Wong, {Lee Jun} and Tuvim, {Michael J.} and Evans, {Scott E.}",

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doi = "10.1371/journal.ppat.1011138",

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AU - Ellis, Lisandra Vila

AU - Chen, Jichao

AU - Longmire, Michael K.

AU - Donepudi, Sri Ramya

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AB - Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs’ intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

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Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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