Brucella suppress STING expression via miR-24 to enhance infection

Khan, Mike; Harms, Jerome S.; Liu, Yiping; Eickhoff, Jens; Tan, Jin; Hu, Tony; Cai, Fengwei; Guimarães, Erika S.; Oliveira, Sérgio C.; Dahl, Richard; Cheng, Yong; Gutman, Delia; Barber, Glen N.; Splitter, Gary A.; Smith, Judith A.

doi:10.1371/journal.ppat.1009020

Cited by 19 publications

(15 citation statements)

References 67 publications

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“…Many studies have shown Brucella subversion of TLR signaling through proteins such as Tcbp, which leads to decreased proinflammatory cytokine expression [10]. Additionally, Brucella microRNAs can lead to the downregulation of the mRNA and protein expression of innate immune PRRs [34]. These mechanisms likely did not occur in our gDNA studies as there was no inclusion of these immunosuppressive proteins or production of inhibitory microRNAs.…”

Section: Discussionmentioning

confidence: 94%

ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA

et al. 2020

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Brucella abortus is a zoonotic pathogen that causes brucellosis. Because of Brucella’s unique LPS layer and intracellular localization predominately within macrophages, it can often evade immune detection. However, pattern recognition receptors are capable of sensing Brucella pathogen-associated molecular patterns (PAMPS). For example, NOD-like receptors (NLRs) can form a multi-protein inflammasome complex to attenuate Brucella pathogenesis. The inflammasome activates IL-1β and IL-18 to drive immune cell recruitment. Alternatively, inflammasome activation also initiates inflammatory cell death, termed pyroptosis, which augments bacteria clearance. In this report, we assess canonical and non-canonical inflammasome activation following B. abortus infection. We conducted in vivo studies using Asc−/− mice and observed decreased mouse survival, immune cell recruitment, and increased bacteria load. We also conducted studies with Caspase-11−/− mice and did not observe any significant impact on B. abortus pathogenesis. Through mechanistic studies using Asc−/− macrophages, our data suggests that the protective role of ASC may result from the induction of pyroptosis through a gasdermin D-dependent mechanism in macrophages. Additionally, we show that the recognition of Brucella is facilitated by sensing the PAMP gDNA rather than the less immunogenic LPS. Together, these results refine our understanding of the role that inflammasome activation and pyroptosis plays during brucellosis.

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Section: Discussionmentioning

confidence: 94%

ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA

et al. 2020

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“…Huang et al reported miR-24 binding to rat STING mRNA [ 30 ]. Recently Shen et al and Khan et al have also reported this targeting in a liver ischemia model and Brucella infection respectively [ 31 , 32 ]. As anticipated, transfection of synthetic miR-24 caused a reduction of STING protein expression ( Fig 1C ); conversely, transfection of antimiR-24 enhanced STING expression ( Fig 1D ).…”

Section: Resultsmentioning

confidence: 99%

Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis

et al. 2021

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STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3’ untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING’s antiviral action.

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“…with 1 × 10 6 CFU B. abortus strain S2308 and sacrificed at 1, 2 or 3 weeks post infection. To measure Brucella CFU, the spleens extracted from the animals were macerated in 10 ml of sterile saline solution (NaCl 0.9%) using a steel sieve and plated on Brucella broth agar and after 3 days, the number of CFU was counted as described previously (Khan et al, 2020). To measure intracellular multiplication in macrophages, macrophages were plated onto 24‐well plates at the density of 5 × 10 5 cells per well.…”

Section: Methodsmentioning

confidence: 99%

Galectin‐3 regulates proinflammatory cytokine function and favoursBrucella abortuschronic replication in macrophages and mice

Tana

Guimarães

Cerqueira

et al. 2021

Cellular Microbiology

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In this study, we provide evidence that galectin‐3 (Gal‐3) plays an important role in Brucella abortus infection. Our results showed increased Gal‐3 expression and secretion in B. abortus infected macrophages and mice. Additionally, our findings indicate that Gal‐3 is dispensable for Brucella‐containing vacuoles disruption, inflammasome activation and pyroptosis. On the other hand, we observed that Brucella‐induced Gal‐3 expression is crucial for induction of molecules associated to type I IFN signalling pathway, such as IFN‐β: Interferon beta (IFN‐β), C‐X‐C motif chemokine ligand 10 (CXCL10) and guanylate‐binding proteins. Gal‐3 KO macrophages showed reduced bacterial numbers compared to wild‐type cells, suggesting that Gal‐3 facilitates bacterial replication in vitro. Moreover, priming Gal‐3 KO cells with IFN‐β favoured B. abortus survival in macrophages. Additionally, we also observed that Gal‐3 KO mice are more resistant to B. abortus infection and these animals showed elevated production of proinflammatory cytokines when compared to control mice. Finally, we observed an increased recruitment of macrophages, dendritic cells and neutrophils in spleens of Gal‐3 KO mice compared to wild‐type animals. In conclusion, this study demonstrated that Brucella‐induced Gal‐3 is detrimental to host and this molecule is implicated in inhibition of recruitment and activation of immune cells, which promotes B. abortus spread and aggravates the infection. Take Aways Brucella abortus infection upregulates galectin‐3 expression Galectin‐3 regulates guanylate‐binding proteins expression but is not required for Brucella‐containing vacuole disruption Galectin‐3 modulates proinflammatory cytokine production during bacterial infection Galectin‐3 favours Brucella replication

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Brucella suppress STING expression via miR-24 to enhance infection

Cited by 19 publications

References 67 publications

ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA

ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA

Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis

Galectin‐3 regulates proinflammatory cytokine function and favoursBrucella abortuschronic replication in macrophages and mice

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