The Aldehyde Hypothesis: Metabolic Intermediates As Antimicrobial Effectors

Overview

Journal Open Biol

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Apr 13

PMID 35414258

Authors

K Heran Darwin

Sarah A Stanley

Affiliations

Soon will be listed here.

Abstract

There are many reactive intermediates found in metabolic pathways. Could these potentially toxic molecules be exploited for an organism's benefit? We propose that during certain microbial infections, the production of inherently reactive aldehydes by an infected host is a previously unappreciated innate immune defence mechanism. While there has been a significant focus on the effects of aldehydes on mammalian physiology, the idea that they might be exploited or purposefully induced to kill pathogens is new. Given that aldehydes are made as parts of metabolic programmes that accompany immune cell activation by the cytokine interferon-gamma (IFN-γ) during infections, we hypothesize that aldehydes are among the arsenal of IFN-γ-inducible effectors needed for pathogen control.

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References

Safi H, Gopal P, Lingaraju S, Ma S, Levine C, Dartois V . Phase variation in produces transiently heritable drug tolerance. Proc Natl Acad Sci U S A. 2019; 116(39):19665-19674. PMC: 6765255. DOI: 10.1073/pnas.1907631116. View

Ward S, Abomoelak B, Hoye E, Steinberg H, Talaat A . CtpV: a putative copper exporter required for full virulence of Mycobacterium tuberculosis. Mol Microbiol. 2010; 77(5):1096-110. PMC: 2965804. DOI: 10.1111/j.1365-2958.2010.07273.x. View

Pethe K, Sequeira P, Agarwalla S, Rhee K, Kuhen K, Phong W . A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy. Nat Commun. 2010; 1:57. PMC: 3220188. DOI: 10.1038/ncomms1060. View

Park S, Park C, Lee H, Park K, Park B, Cheong H . Functional polymorphism in aldehyde dehydrogenase-2 gene associated with risk of tuberculosis. BMC Med Genet. 2014; 15:40. PMC: 3975138. DOI: 10.1186/1471-2350-15-40. View

Behr M, Kaufmann E, Duffin J, Edelstein P, Ramakrishnan L . Latent Tuberculosis: Two Centuries of Confusion. Am J Respir Crit Care Med. 2021; 204(2):142-148. PMC: 8650795. DOI: 10.1164/rccm.202011-4239PP. View

Merker M, Blin C, Mona S, Duforet-Frebourg N, Lecher S, Willery E . Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage. Nat Genet. 2015; 47(3):242-9. PMC: 11044984. DOI: 10.1038/ng.3195. View

Weiss G, Schaible U . Macrophage defense mechanisms against intracellular bacteria. Immunol Rev. 2015; 264(1):182-203. PMC: 4368383. DOI: 10.1111/imr.12266. View

Rachman H, Kim N, Ulrichs T, Baumann S, Pradl L, Eddine A . Critical role of methylglyoxal and AGE in mycobacteria-induced macrophage apoptosis and activation. PLoS One. 2006; 1:e29. PMC: 1762319. DOI: 10.1371/journal.pone.0000029. View

Escoll P, Song O, Viana F, Steiner B, Lagache T, Olivo-Marin J . Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages. Cell Host Microbe. 2017; 22(3):302-316.e7. DOI: 10.1016/j.chom.2017.07.020. View

10.

Tabakh H, McFarland A, Thomason M, Pollock A, Glover R, Zaver S . 4-Hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen. Elife. 2021; 10. PMC: 8174450. DOI: 10.7554/eLife.59295. View

11.

Maksymiuk C, Balakrishnan A, Bryk R, Rhee K, Nathan C . E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress. Proc Natl Acad Sci U S A. 2015; 112(43):E5834-43. PMC: 4629369. DOI: 10.1073/pnas.1510932112. View

12.

Schmoch T, Uhle F, Siegler B, Fleming T, Morgenstern J, Nawroth P . The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology. Int J Mol Sci. 2017; 18(3). PMC: 5372669. DOI: 10.3390/ijms18030657. View

13.

Ragan E, Kleinman M, Sweigart B, Gnatienko N, Parry C, Horsburgh C . The impact of alcohol use on tuberculosis treatment outcomes: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2020; 24(1):73-82. PMC: 7491444. DOI: 10.5588/ijtld.19.0080. View

14.

Puckett S, Trujillo C, Wang Z, Eoh H, Ioerger T, Krieger I . Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in . Proc Natl Acad Sci U S A. 2017; 114(11):E2225-E2232. PMC: 5358392. DOI: 10.1073/pnas.1617655114. View

15.

Bellerose M, Baek S, Huang C, Moss C, Koh E, Proulx M . Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy. mBio. 2019; 10(4). PMC: 6667613. DOI: 10.1128/mBio.00663-19. View

16.

Prantner D, Nallar S, Richard K, Spiegel D, Collins K, Vogel S . Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response. J Leukoc Biol. 2020; 109(3):605-619. PMC: 7855181. DOI: 10.1002/JLB.3A0520-745RR. View

17.

Hazen S, Hsu F, DAVIGNON A, Heinecke J . Human neutrophils employ myeloperoxidase to convert alpha-amino acids to a battery of reactive aldehydes: a pathway for aldehyde generation at sites of inflammation. Biochemistry. 1998; 37(19):6864-73. DOI: 10.1021/bi972449j. View

18.

Luo H, Wu G, Pakstis A, Tong L, Oota H, Kidd K . Origin and dispersal of atypical aldehyde dehydrogenase ALDH2487Lys. Gene. 2009; 435(1-2):96-103. DOI: 10.1016/j.gene.2008.12.021. View

19.

Deitrich R, Erwin V . Mechanism of the inhibition of aldehyde dehydrogenase in vivo by disulfiram and diethyldithiocarbamate. Mol Pharmacol. 1971; 7(3):301-7. View

20.

MacMicking J, NORTH R, LaCourse R, Mudgett J, Shah S, Nathan C . Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A. 1997; 94(10):5243-8. PMC: 24663. DOI: 10.1073/pnas.94.10.5243. View