Are reactive oxygen species always detrimental to pathogens?

Abstract

Reactive oxygen species (ROS) are deadly weapons used by phagocytes and other cell types, such as lung epithelial cells, against pathogens. ROS can kill pathogens directly by causing oxidative damage to biocompounds or indirectly by stimulating pathogen elimination by various nonoxidative mechanisms, including pattern recognition receptors signaling, autophagy, neutrophil extracellular trap formation, and T-lymphocyte responses. Thus, one should expect that the inhibition of ROS production promote infection. Increasing evidences support that in certain particular infections, antioxidants decrease and prooxidants increase pathogen burden. In this study, we review the classic infections that are controlled by ROS and the cases in which ROS appear as promoters of infection, challenging the paradigm. We discuss the possible mechanisms by which ROS could promote particular infections. These mechanisms are still not completely clear but include the metabolic effects of ROS on pathogen physiology, ROS-induced damage to the immune system, and ROS-induced activation of immune defense mechanisms that are subsequently hijacked by particular pathogens to act against more effective microbicidal mechanisms of the immune system. The effective use of antioxidants as therapeutic agents against certain infections is a realistic possibility that is beginning to be applied against viruses.

FIG. 1.

ROS promote pathogen elimination by oxidative mechanisms. Various ROS produced within the phagosome cause oxidative damage (red arrow) to phagocytosed pathogens. ROS from mitochondria also promote pathogen clearance, but whether this effect is caused by oxidative damage is unknown. TLR signaling and NOX2-derived ROS can trigger mitochondrial ROS. NOX2, NADPH oxidase 2; ROS, reactive oxygen species; TLR, toll-like receptor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

ROS promote pathogen elimination by enzymatic mechanisms. After azurophile granules fuse to the phagosome in neutrophils, superoxide promotes K⁺ influx to compensate for negative charges. K⁺ promotes enzyme release from an anionic matrix (green) inside the phagosome, allowing enzymatic assault of pathogens. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

ROS promote pathogen elimination by autophagy. NOX2-derived superoxide promotes LC3 recruitment to the autophagosome. The recognition of microbes in selective autophagy is mediated by proteins that bind to LC3 in a process called xenoautophagy. The autophagosome then fuses with lysosome, where pathogen undergoes an enzymatic assault. LC3, microtubule associated protein 1A/1B light chain 3. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

High levels of ROS inhibit mTOR. The nutrient sensor mTOR is kept repressed by AMPK stimulation, a process that can be reinforced by ROS production. The inhibition of mTOR can potentially reduce the viral burden by autophagy, cell death of infected reservoirs, or stimulation of CD8 cell memory. AMPK, AMP-activated kinase; mTOR, mammalian target of rapamycin.

FIG. 5.

ROS production promote ETosis, which traps pathogens in chromatin extracellular traps rich in microbicidal proteins. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

ROS production participates in the various mechanisms of cell death that follows the recognition of intracellular pathogens and contributes to eliminating infection reservoirs. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Various PRR signaling pathways use ROS and activate microbicidal mechanisms directly or enhance the expression of proteins involved with microbicidal mechanisms. PRR, pattern recognition receptor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

Excessive ROS generated in sepsis reduces defenses against fungi and bacteria. The depletion of endogenous antioxidant GSH, as well as incubation with hydrogen peroxide, increases signaling by TLR4 ligand lipopolysaccharide (LPS), produces NRF2 activation and then increases the expression of ATF3. The two factors act together to reduce transcription of IL-6. Reduction of IL-6 production decreases defenses against Escherichia coli and Aspergillus fumigatus. ATF, activation transcription factor; GSH, reduced glutathione; NRF2, nuclear factor (erythroid-derived 2)-like 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 9.

ROS interfere with iron metabolism and iron availability to pathogens residing in different tissues and cell compartments. ROS promote hepcidin secretion by activation of the stat3 pathway in hepatocytes and releases iron from ferritin, increasing the labile iron pool and propagating oxidative stress. The presence of ferroportin-1 (Fpn-1) in cellular membrane is inhibited by hepcidin. Some pathogens that reside in cytosol scavenge ferritin for iron, others degrade heme, but some pathogens feed on the labile iron pool. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 10.

ROS inhibit cholesterol efflux by ABC transporters to high-density lipoprotein (HDL) and contribute to foam cell formation, a macrophage phenotype preferred by various infectious agents, such as HIV, Trypanosoma cruzi, and Mycobacterium tuberculosis. Cholesterol efflux prevents foam cell formation and is associated with iron efflux (through ferroportin-1) in a macrophage phenotype, the so-called MHem. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 11.

ROS inactivate cathepsins by oxidizing cysteine residues and thus reduce proteolysis inside the phagosome. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 12.

ROS interfere in (A) DC instruction of Th cells and (B) antigen degradation and presentation by DCs. (A) ROS induce physiological changes in DCs, interfering with its antigen presentation capacity, reducing IL-12 secretion, and turning DCs into Th2 or Th17 instructors. (B) ROS enhance antigen cross-presentation in DCs by consuming H⁺ and increasing phagolysosomal pH, thereby reducing antigenic degradation. DCs, dendritic cells; IL, interleukin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars