The Stimulated Innate Resistance Event in Bordetella pertussis Infection Is Dependent on Reactive Oxygen Species Production

ABSTRACTThe exacerbated induction of innate immune responses in airways can abrogate diverse lung infections by a phenomenon known as stimulated innate resistance (StIR). We recently demonstrated that the enhancement of innate response activation can efficiently impairBordetella pertussiscolonization in a Toll-like receptor 4 (TLR4)-dependent manner. The aim of this work was to further characterize the effect of lipopolysaccharide (LPS) on StIR and to identify the mechanisms that mediate this process. Our results showed that bacterial infection was completely abrogated in treated mice when the LPS ofB. pertussis(1 μg) was added before (48 h or 24 h), after (24 h), or simultaneously with theB. pertussischallenge (107CFU). Moreover, we detected that LPS completely cleared bacterial infection as soon as 2 h posttreatment. This timing suggests that the observed StIR phenomenon should be mediated by fast-acting antimicrobial mechanisms. Although neutrophil recruitment was already evident at this time point, depletion assays using an anti-GR1 antibody showed thatB. pertussisclearance was achieved even in the absence of neutrophils. To evaluate the possible role of free radicals in StIR, we performed animal assays using the antioxidantN-acetyl cysteine (NAC), which is known to inactivate oxidant species. NAC administration blocked theB. pertussisclearance induced by LPS. Nitrite concentrations were also increased in the LPS-treated mice; however, the inhibition of nitric oxide synthetases did not suppress the LPS-induced bacterial clearance. Taken together, our results show that reactive oxygen species (ROS) play an essential role in the TLR4-dependent innate clearance ofB. pertussis.

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Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production

International Immunology ◽

10.1093/intimm/dxt067 ◽

2013 ◽

Vol 26 (4) ◽

pp. 209-220 ◽

Cited By ~ 31

Author(s):

Akihiro Kimura ◽

Hiromi Abe ◽

Sanae Tsuruta ◽

Sayuri Chiba ◽

Yoshiaki Fujii-Kuriyama ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Bacterial Infection ◽

Aryl Hydrocarbon Receptor ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Oxygen Species ◽

Aryl Hydrocarbon ◽

Species Production

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Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species

Eukaryotic Cell ◽

10.1128/ec.00290-12 ◽

2012 ◽

Vol 12 (1) ◽

pp. 91-100 ◽

Cited By ~ 40

Author(s):

Claudia Jiménez-López ◽

John R. Collette ◽

Kimberly M. Brothers ◽

Kelly M. Shepardson ◽

Robert A. Cramer ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Candida Albicans ◽

Amino Acid ◽

Reactive Oxygen ◽

Single Amino Acid ◽

Dependent Manner ◽

Oxygen Species ◽

Biosynthetic Genes ◽

Content Type

ABSTRACTThe interaction ofCandida albicanswith phagocytes of the host's innate immune system is highly dynamic, and its outcome directly impacts the progression of infection. While the switch to hyphal growth within the macrophage is the most obvious physiological response, much of the genetic response reflects nutrient starvation: translational repression and induction of alternative carbon metabolism. Changes in amino acid metabolism are not seen, with the striking exception of arginine biosynthesis, which is upregulated in its entirety during coculture with macrophages. Using single-cell reporters, we showed here that arginine biosynthetic genes are induced specifically in phagocytosed cells. This induction is lower in magnitude than during arginine starvationin vitroand is driven not by an arginine deficiency within the phagocyte but instead by exposure to reactive oxygen species (ROS). Curiously, these genes are induced in a narrow window of sublethal ROS concentrations.C. albicanscells phagocytosed by primary macrophages deficient in thegp91phoxsubunit of the phagocyte oxidase do not express theARGpathway, indicating that the induction is dependent on the phagocyte oxidative burst.C. albicans argpathway mutants are retarded in germ tube and hypha formation within macrophages but are not notably more sensitive to ROS. We also find that theARGpathway is regulated not by the general amino acid control response but by transcriptional regulators similar to theSaccharomyces cerevisiaeArgR complex. In summary, phagocytosis induces this single amino acid biosynthetic pathway in an ROS-dependent manner.

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Manganese Oxide Biomineralization Provides Protection against Nitrite Toxicity in a Cell-Density-Dependent Manner

Applied and Environmental Microbiology ◽

10.1128/aem.02129-18 ◽

2018 ◽

Vol 85 (2) ◽

Cited By ~ 2

Author(s):

Christian Zerfaß ◽

Joseph A. Christie-Oleza ◽

Orkun S. Soyer

Keyword(s):

Reactive Oxygen Species ◽

Manganese Oxide ◽

Model Organism ◽

Reactive Oxygen ◽

Laboratory Culture ◽

Inoculum Size ◽

Dependent Manner ◽

Oxygen Species ◽

Content Type ◽

Nitrite Toxicity

ABSTRACTManganese biomineralization is a widespread process among bacteria and fungi. To date, there is no conclusive experimental evidence for how and if this process impacts microbial fitness in the environment. Here, we show how a model organism for manganese oxidation is growth inhibited by nitrite, and that this inhibition is mitigated in the presence of manganese. We show that such manganese-mediated mitigation of nitrite inhibition is dependent on the culture inoculum size, and that manganese oxide (MnOX) forms granular precipitates in the culture, rather than sheaths around individual cells. We provide evidence that MnOXprotection involves both its ability to catalyze nitrite oxidation into (nontoxic) nitrate under physiological conditions and its potential role in influencing processes involving reactive oxygen species (ROS). Taken together, these results demonstrate improved microbial fitness through MnOXdeposition in an ecological setting, i.e., mitigation of nitrite toxicity, and point to a key role of MnOXin handling stresses arising from ROS.IMPORTANCEWe present here a direct fitness benefit (i.e., growth advantage) for manganese oxide biomineralization activity inRoseobactersp. strain AzwK-3b, a model organism used to study this process. We find that strain AzwK-3b in a laboratory culture experiment is growth inhibited by nitrite in manganese-free cultures, while the inhibition is considerably relieved by manganese supplementation and manganese oxide (MnOX) formation. We show that biogenic MnOXinteracts directly with nitrite and possibly with reactive oxygen species and find that its beneficial effects are established through formation of dispersed MnOXgranules in a manner dependent on the population size. These experiments raise the possibility that manganese biomineralization could confer protection against nitrite toxicity to a population of cells. They open up new avenues of interrogating this process in other species and provide possible routes to their biotechnological applications, including in metal recovery, biomaterials production, and synthetic community engineering.

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Acceleration of Phagocytosis in Human Neutrophils Incubated with Gabexate Mesilate

Journal of International Medical Research ◽

10.1177/030006059402200507 ◽

1994 ◽

Vol 22 (5) ◽

pp. 292-295 ◽

Cited By ~ 8

Author(s):

K Mikawa ◽

H Akamatsu ◽

N Maekawa ◽

K Nishina ◽

H Obara ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Human Neutrophils ◽

Dependent Manner ◽

Oxygen Species ◽

Gabexate Mesilate ◽

Micro Organisms ◽

Species Production

It has recently been shown that gabexate mesilate inhibited human neutrophil functions including chemotaxis and reactive oxygen species production. In the present study, the effects of gabexate mesilate on phagocytosis by human neutrophils in vitro were investigated. Gabexate mesilate significantly enhanced neutrophil phagocytosis in a dose-dependent manner. This characteristic of gabexate mesilate may facilitate protection against infecting micro-organisms, although the inhibition of reactive oxygen species production by neutrophils may be a disadvantage for host-defense against infection.

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Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01876-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1521-1529 ◽

Cited By ~ 23

Author(s):

Juliana K. Ariffin ◽

Kaustav das Gupta ◽

Ronan Kapetanovic ◽

Abishek Iyer ◽

Robert C. Reid ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Histone Deacetylase Inhibitors ◽

Reactive Oxygen ◽

Oxygen Species ◽

Bacterial Clearance ◽

Mitochondrial Reactive Oxygen Species ◽

Bacterial Challenge ◽

Content Type ◽

Human Macrophages ◽

Species Production

Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge withSalmonella entericaserovar Typhimurium orEscherichia coliresults in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellularS. Typhimurium andE. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.

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Reactive Oxygen Species Production Is a Major Factor Directing the Postantibiotic Effect of Fluoroquinolones in Streptococcus pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 4

Author(s):

M. T. García ◽

M. V. Valenzuela ◽

M. J. Ferrándiz ◽

A. G. de la Campa

Keyword(s):

Reactive Oxygen Species ◽

Streptococcus Pneumoniae ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Oxygen Species ◽

Postantibiotic Effect ◽

Content Type ◽

Chromosome Fragmentation ◽

Drug Removal ◽

Species Production

ABSTRACT We studied the molecular mechanisms involved in the postantibiotic effect of the fluoroquinolones levofloxacin and moxifloxacin in Streptococcus pneumoniae. Wild-type strain R6 had postantibiotic effects of 2.05 ± 0.10 h (mean ± standard deviation [SD]) and 3.23 ± 0.45 h at 2.5× and 10× MIC of levofloxacin, respectively. Moxifloxacin exhibited lower effects of 0.87 ± 0.1 and 2.41 ± 0.29 h at 2.5× and 10× MIC, respectively. Fluoroquinolone-induced chromosome fragmentation was measured at equivalent postantibiotic effects for levofloxacin (2.5× MIC) and moxifloxacin (10× MIC). After 2 h of drug removal, reductions were approximately 7-fold for levofloxacin and 3-fold for moxifloxacin, without further decreases at later times. Variations in reactive oxygen species production were detected after 4 to 6 h of drug withdrawals, with decreases ≥400-fold for levofloxacin and ≥800-fold for moxifloxacin at 6 h. In accordance, after 4 to 6 h of drug withdrawal, the levofloxacin-induced upregulation of the fatCDEB operon, introducing iron in the bacteria, decreased up to 2- to 3-fold, and the moxifloxacin-induced upregulation of several genes involved in the production of pyruvate was reduced 3- to 7-fold. In accordance, lower postantibiotic effects (up to 1 h) were observed in strain R6 ΔspxB, lacking the main enzyme involved in oxygen peroxide production, than in R6. Although no change in the recovery of chromosome fragmentation was observed between R6 and R6 ΔspxB, 3.5 × 103-fold lower reactive oxygen species production was observed in R6 ΔspxB, without changes after drug removal. These results show that reactive oxygen species are the main factors directing the postantibiotic effect of levofloxacin and moxifloxacin in S. pneumoniae.

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Ubiquitination of Listeria Virulence Factor InlC Contributes to the Host Response to Infection

mBio ◽

10.1128/mbio.02778-19 ◽

2019 ◽

Vol 10 (6) ◽

Cited By ~ 1

Author(s):

Edith Gouin ◽

Damien Balestrino ◽

Orhan Rasid ◽

Marie-Anne Nahori ◽

Véronique Villiers ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Immune Response ◽

Listeria Monocytogenes ◽

Host Response ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Oxygen Species ◽

Pathogenic Potential ◽

Content Type ◽

Species Production

ABSTRACT Listeria monocytogenes is a pathogenic bacterium causing potentially fatal foodborne infections in humans and animals. While the mechanisms used by Listeria to manipulate its host have been thoroughly characterized, how the host controls bacterial virulence factors remains to be extensively deciphered. Here, we found that the secreted Listeria virulence protein InlC is monoubiquitinated by the host cell machinery on K224, restricting infection. We show that the ubiquitinated form of InlC interacts with the intracellular alarmin S100A9, resulting in its stabilization and in increased reactive oxygen species production by neutrophils in infected mice. Collectively, our results suggest that posttranslational modification of InlC exacerbates the host response upon Listeria infection. IMPORTANCE The pathogenic potential of Listeria monocytogenes relies on the production of an arsenal of virulence determinants that have been extensively characterized, including surface and secreted proteins of the internalin family. We have previously shown that the Listeria secreted internalin InlC interacts with IκB kinase α to interfere with the host immune response (E. Gouin, M. Adib-Conquy, D. Balestrino, M.-A. Nahori, et al., Proc Natl Acad Sci USA, 107:17333–17338, 2010, https://doi.org/10.1073/pnas.1007765107). In the present work, we report that InlC is monoubiquitinated on K224 upon infection of cells and provide evidence that ubiquitinated InlC interacts with and stabilizes the alarmin S100A9, which is a critical regulator of the immune response and inflammatory processes. Additionally, we show that ubiquitination of InlC causes an increase in reactive oxygen species production by neutrophils in mice and restricts Listeria infection. These findings are the first to identify a posttranscriptional modification of an internalin contributing to host defense.

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