<i>Brucella</i> Infection Regulates Thioredoxin-Interacting Protein Expression to Facilitate Intracellular Survival by Reducing the Production of Nitric Oxide and Reactive Oxygen Species

Hu, Hai; Tian, Mingxing; Gao, Xiang; Lian, Zhengmin; Yin, Yi; Shi, Wentao; Ding, Chan; Yu, Shuang

doi:10.4049/jimmunol.1801550

Cited by 14 publications

(12 citation statements)

References 68 publications

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“…Investigation of Brucella -mediated RIDD genes provides an avenue for understanding how the pathogen subverts or evades host functions to promote its intracellular lifestyle. For example, Brucella infection downregulates the expression of Txnip , a gene shown in this work to be subject to RIDD control and known to facilitate the intracellular survival of the pathogen ( Hu et al, 2020 ). Cells undergoing ER stress following treatment with UPR inducers (e.g., thapsingargin, Tm) increase TXNIP protein levels and mRNA stability by reducing levels of the TXNIP destabilizing microRNA, miR-17 ( Lerner et al, 2012 ).…”

Section: Discussionmentioning

confidence: 95%

“…Therefore, RIDD might be expected to increase the stability of TXNIP mRNA by attacking the miR-17 that affects TXNIP mRNA stability. However, a recent report demonstrated that in vitro cultivated host cells or mouse tissues infected by BaS2308 display reduced expression levels of TXNIP mRNA and/or protein as well as miR-17 ( Hu et al, 2020 ). Consistent with these results, we found that both TXNIP mRNA and miR-17 were destabilized during Brucella infection.…”

Section: Discussionmentioning

confidence: 99%

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Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Wells

Pandey

et al. 2022

eLife

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The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding BLOS1, a protein that promotes endosome–lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus murine hepatitis virus also subverted the RIDD–BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Wells

Pandey

et al. 2022

eLife

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“…High levels of IL-6 were produced by the splenocytes of immunized and infected mice. It was recently shown that IL-6 is required for the induction of IFN-g and TNF-a by infected splenocytes, in addition to promoting the differentiation of CD8+ T cells, indicating a protective role for IL-6 against B. abortus that parallels the type of Th1 immunity response (109,110). Similarly, significant levels of IL-10 in immunized mice were also detected in spleen cells.…”

Section: Discussionmentioning

confidence: 96%

Epitope-Based Vaccine of a Brucella abortus Putative Small RNA Target Induces Protection and Less Tissue Damage in Mice

et al. 2021

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Brucella spp. are Gram-negative, facultative intracellular bacteria that cause brucellosis in humans and animals. Currently available live attenuated vaccines against brucellosis still have drawbacks. Therefore, subunit vaccines, produced using epitope-based antigens, have the advantage of being safe, cost-effective and efficacious. Here, we identified B. abortus small RNAs expressed during early infection with bone marrow-derived macrophages (BMDMs) and an apolipoprotein N-acyltransferase (Int) was identified as the putative target of the greatest expressed small RNA. Decreased expression of Int was observed during BMDM infection and the protein sequence was evaluated to rationally select a putative immunogenic epitope by immunoinformatic, which was explored as a vaccinal candidate. C57BL/6 mice were immunized and challenged with B. abortus, showing lower recovery in the number of viable bacteria in the liver, spleen, and axillary lymph node and greater production of IgG and fractions when compared to non-vaccinated mice. The vaccinated and infected mice showed the increased expression of TNF-α, IFN-γ, and IL-6 following expression of the anti-inflammatory genes IL-10 and TGF-β in the liver, justifying the reduction in the number and size of the observed granulomas. BMDMs stimulated with splenocyte supernatants from vaccinated and infected mice increase the CD86+ marker, as well as expressing greater amounts of iNOS and the consequent increase in NO production, suggesting an increase in the phagocytic and microbicidal capacity of these cells to eliminate the bacteria.

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“…Regarding Brucella infection, the involvement of NOS2 and NO radicals in inhibiting its intracellular replication in macrophages was likewise demonstrated [47]. Additionally, it was recently demonstrated that the multifunctional molecule thioredoxin-interacting protein (TXNIP) augments NOS2 expression and the production of NO which reduces B. abortus intracellular growth in macrophages [48]. Thus, our results indicate that the enhanced NOS2 expression, NO production and the inflammatory profile promoted by HIF-1α may support the control of B. abortus during the early phase of infection.…”

Section: Discussionmentioning

confidence: 97%

“…Additionally, it was recently demonstrated that the multifunctional molecule thioredoxin-interacting protein (TXNIP) augments NOS2 expression and the production of NO which reduces B . abortus intracellular growth in macrophages [ 48 ]. Thus, our results indicate that the enhanced NOS2 expression, NO production and the inflammatory profile promoted by HIF-1α may support the control of B .…”

Section: Discussionmentioning

confidence: 99%

STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection

et al. 2021

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Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.

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Brucella Infection Regulates Thioredoxin-Interacting Protein Expression to Facilitate Intracellular Survival by Reducing the Production of Nitric Oxide and Reactive Oxygen Species

Cited by 14 publications

References 68 publications

Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Epitope-Based Vaccine of a Brucella abortus Putative Small RNA Target Induces Protection and Less Tissue Damage in Mice

STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection

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