Bacterial Subversion of Host Innate Immune Pathways

Baxt, Leigh A.; Garza-Mayers, Anna Cristina; Goldberg, Marcia B.

doi:10.1126/science.1235771

Cited by 182 publications

(158 citation statements)

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“…In plants, the immune response is also mediated by oxidized products of fatty acids, derived from linoleic (18:2 ratio) and linolenic (18:3 ratio) acids in this case (60). Therefore, it is tempting to speculate that Ohr might subvert host immune pathways by some still unknown mechanisms (65). Remarkably, P. aeruginosa contains endogenous enzymatic systems capable of oxidizing unsaturated fatty acids (especially oleic acid) to hydroperoxide and hydroxide derivatives, whose biological function is still elusive (66,67).…”

Section: Discussionmentioning

confidence: 99%

Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite

Alegria

Meireles

Cussiol

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Organic hydroperoxide resistance (Ohr) enzymes are unique Cysbased, lipoyl-dependent peroxidases. Here, we investigated the involvement of Ohr in bacterial responses toward distinct hydroperoxides. In silico results indicated that fatty acid (but not cholesterol) hydroperoxides docked well into the active site of Ohr from Xylella fastidiosa and were efficiently reduced by the recombinant enzyme as assessed by a lipoamide-lipoamide dehydrogenase-coupled assay. Indeed, the rate constants between Ohr and several fatty acid hydroperoxides were in the 10 7 -10 8 M −1 ·s −1 range as determined by a competition assay developed here. Reduction of peroxynitrite by Ohr was also determined to be in the order of 10 7 M −1 ·s −1 at pH 7.4 through two independent competition assays. A similar trend was observed when studying the sensitivities of a Δohr mutant of Pseudomonas aeruginosa toward different hydroperoxides. Fatty acid hydroperoxides, which are readily solubilized by bacterial surfactants, killed the Δohr strain most efficiently. In contrast, both wild-type and mutant strains deficient for peroxiredoxins and glutathione peroxidases were equally sensitive to fatty acid hydroperoxides. Ohr also appeared to play a central role in the peroxynitrite response, because the Δohr mutant was more sensitive than wild type to 3-morpholinosydnonimine hydrochloride (SIN-1 , a peroxynitrite generator). In the case of H 2 O 2 insult, cells treated with 3-amino-1,2,4-triazole (a catalase inhibitor) were the most sensitive. Furthermore, fatty acid hydroperoxide and SIN-1 both induced Ohr expression in the wildtype strain. In conclusion, Ohr plays a central role in modulating the levels of fatty acid hydroperoxides and peroxynitrite, both of which are involved in host-pathogen interactions.hydroperoxides | thiols | Cys-based peroxidase | pathogenic bacteria | Pseudomonas aeruginosa

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Section: Discussionmentioning

confidence: 99%

Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite

Alegria

Meireles

Cussiol

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, some bacteria produce enzymes that digest mucus to penetrate the protective layer, and many bacteria secrete proteases that can disrupt protective peptides and proteins produced by the host (Baxt et al 2013). Second, the rapid inflammatory responses associated with microbial infections are associated with pattern recognition receptors of the innate immune system, rather than passive defence systems.…”

Section: Innate Immunitymentioning

confidence: 99%

Innate immunity and inflammation of the bovine female reproductive tract in health and disease

Sheldon¹,

Cronin²,

Healey³

et al. 2014

Reproduction

128

100

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Mammalian reproductive physiology and the development of viviparity co-evolved with inflammation and immunity over millennia. Many inflammatory mediators contribute to paracrine and endocrine signalling, and the maintenance of tissue homeostasis in the female reproductive tract. However, inflammation is also a feature of microbial infections of the reproductive tract. Bacteria and viruses commonly cause endometritis, perturb ovarian follicle development and suppress the endocrine activity of the hypothalamus and pituitary in cattle. Innate immunity is an evolutionary ancient system that orchestrates host cell inflammatory responses aimed at eliminating pathogens and repairing damaged tissue. Pattern recognition receptors on host cells bind pathogen-associated molecular patterns and damage-associated molecular patterns, leading to the activation of intracellular MAPK and NFkB signalling pathways and the release of inflammatory mediators. Inflammatory mediators typically include the interleukin cytokines IL1b and IL6, chemokines such as IL8, interferons and prostaglandins. This review outlines the mechanisms of inflammation and innate immunity in the bovine female reproductive tract during health and disease condition.

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“…6 For instance, adherent invasive Escherichia coli upregulates levels of MIR30C and MIR130A to reduce expression of ATG5 and ATG16L1 and inhibit autophagy. 14 Our study clearly shows that inhibition of autophagy is mediated by directly targeting ATG10 that results in blocking the conversion from MAP1LC3B-I to MAP1LC3B-II, potentially explaining the impaired autophagic clearance of B. pseudomallei.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5] Autophagy, as one of the earliest defense responses encountered by intracellular pathogens, is a process that engulfs and delivers intracellular bacteria for lysosomal degradation. [6][7] However, the battle between the human host and the infecting pathogens is continuously evolving. Preliminary evidence has indicated that several pathogens, such as Shigella, Salmonella, Mycobacteria, and influenza A virus, have evolved mechanisms that evade the autophagic response.…”

Section: Introductionmentioning

confidence: 99%

Burkholderia pseudomallei survival in lung epithelial cells benefits from miRNA-mediated suppression of ATG10

Yao

Zhu

et al. 2015

Autophagy

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(2015) Burkholderiapseudomallei survival in lung epithelial cells benefits from miRNA-mediated suppression of ATG10, Autophagy, 11:8, 1293-1307, DOI: 10.1080/15548627.2015 Keywords: ATG10, autophagy, Burkholderia pseudomallei, DNA methylation, MIR4458, MIR4667-5p, MIR4668-5pAbbreviations: 3-MA, 3-methyladenine; 3 0 UTR, 3 0 -untranslated region; 5-Aza-CdR, 5-aza-2 0 -deoxycytidine; ACTB, actin, b; ATG4C, autophagy-related 4C, cysteine peptidase; ATG5, autophagy-related 5; ATG10, autophagy-related 10; ATG12, autophagyrelated 12; B. pseudomallei, Burkholderia pseudomallei; CFU, colony forming unit; CQ, chloroquine; DNMT1, DNA (cytosine-5-)-methyltransferase 1; DRAM2, DNA-damage regulated autophagy modulator 2; MAP1LC3B, microtubule-associated protein 1 light chain 3 b; miRNAs, microRNAs; MOI, multiplicity of infection; MSP, methylation-specific PCR; PBS, phosphate-buffered saline; p.i., postinfection; Rapa, rapamycin; siRNA, small interfering RNA; SQSTM1, sequestosome 1; TEM, transmission electron microscopy.Burkholderia pseudomallei is the causative agent of melioidosis, a disease with high mortality, which is prevalent in tropical regions of the world. A recent study shows that B. pseudomallei can survive inside mammalian cells because of its ability to actively evade cell autophagy. However, the underlying mechanisms remain unclear. In the present study, based on microarray screening, we found that ATG10 was downregulated following B. pseudomallei infection in A549 human lung epithelial cells. Forced expression of ATG10 accelerated the elimination of intracellular B. pseudomallei by enhancing the process of autophagy. Moreover, MIR4458, MIR4667-5p, and MIR4668-5p were found, by microarray screening, to be upregulated in response to B. pseudomallei infection. These 3 novel miRNAs, MIR4458, MIR4667-5p, and MIR4668-5p, targeted to the 3 0 -untranslated region of ATG10 in different time-course and spatial manners. Upregulation of these miRNAs reduced the level of ATG10 and inhibited autophagy, leading to increasing survival rate of intracellular B. pseudomallei. Furthermore, the increase of these miRNAs was correlated with the reduced promoter methylation status in A549 cells in response to B. pseudomallei infection. Our results reveal that 3 novel miRNAs regulate autophagymediated elimination of B. pseudomallei by targeting ATG10, and provide potential targets for clinical treatment.

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Bacterial Subversion of Host Innate Immune Pathways

Cited by 182 publications

References 50 publications

Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite

Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite

Innate immunity and inflammation of the bovine female reproductive tract in health and disease

Burkholderia pseudomallei survival in lung epithelial cells benefits from miRNA-mediated suppression of ATG10

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