scholarly journals Brucella suppress STING expression via miR-24 to enhance infection

2020 ◽  
Vol 16 (10) ◽  
pp. e1009020 ◽  
Author(s):  
Mike Khan ◽  
Jerome S. Harms ◽  
Yiping Liu ◽  
Jens Eickhoff ◽  
Jin Wen Tan ◽  
...  
Keyword(s):  
Damage Control ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Dependent Manner ◽  
Chronic Infections ◽  
Type Iv ◽  
Live Bacteria ◽  
The Impact

Brucellosis, caused by a number of Brucella species, remains the most prevalent zoonotic disease worldwide. Brucella establish chronic infections within host macrophages despite triggering cytosolic innate immune sensors, including Stimulator of Interferon Genes (STING), which potentially limit infection. In this study, STING was required for control of chronic Brucella infection in vivo. However, early during infection, Brucella down-regulated STING mRNA and protein. Down-regulation occurred post-transcriptionally, required live bacteria, the Brucella type IV secretion system, and was independent of host IRE1-RNase activity. STING suppression occurred in MyD88-/- macrophages and was not induced by Toll-like receptor agonists or purified Brucella lipopolysaccharide (LPS). Rather, Brucella induced a STING-targeting microRNA, miR-24-2, in a type IV secretion system-dependent manner. Furthermore, STING downregulation was inhibited by miR-24 anti-miRs and in Mirn23a locus-deficient macrophages. Failure to suppress STING expression in Mirn23a-/- macrophages correlated with diminished Brucella replication, and was rescued by exogenous miR-24. Mirn23a-/- mice were also more resistant to splenic colonization one week post infection. Anti-miR-24 potently suppressed replication in wild type, but much less in STING-/- macrophages, suggesting most of the impact of miR-24 induction on replication occurred via STING suppression. In summary, Brucella sabotages cytosolic surveillance by miR-24-dependent suppression of STING expression; post-STING activation “damage control” via targeted STING destruction may enable establishment of chronic infection.

scholarly journals Brucella suppress innate immunity by down-regulating STING expression in macrophages

2020 ◽  
Author(s):  
Mike Khan ◽  
Jerome S. Harms ◽  
Yiping Liu ◽  
Jens Eickhoff ◽  
Jin Wen Tan ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Damage Control ◽  
Bacterial Species ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Innate Immune ◽  
Type Iv Secretion System ◽  
Chronic Infections ◽  
Type Iv ◽  
The Impact

AbstractBrucellosis, caused by Brucella bacteria species, remains the most prevalent zoonotic disease worldwide. Brucella establish chronic infections within host macrophages despite triggering cytosolic innate immune sensors, including Stimulator of Interferon Genes (STING), which potentially limit infection. In this study, STING was required for control of chronic Brucella infection in vivo. However, early during infection, Brucella down-regulated STING mRNA and protein. Down-regulation occurred post-transcriptionally, required live bacteria, the Brucella type IV secretion system, and was independent of host IRE1-RNase activity. Rather, Brucella induced a STING-targeting microRNA, miR-24-2. Furthermore, STING downregulation was inhibited by miR-24 anti-miRs and in mirn23a locus-deficient macrophages. Failure to suppress STING expression in mirn23a−/− macrophages correlated with diminished Brucella replication, and was rescued by exogenous miR-24. Anti-miR-24 potently suppressed replication in wild type, but much less in STING−/− macrophages, suggesting most of the impact of miR-24 induction on replication occurred via STING suppression. In summary, Brucella sabotages innate immunity by miR-24-dependent suppression of STING expression; post-STING activation “damage control” via targeted STING destruction may enable establishment of chronic infection.Author summaryCytosolic pattern recognition receptors, such as the nucleotide-activated STING molecule, play a critical role in the innate immune system by detecting the presence of intracellular invaders. Brucella bacterial species establish chronic infections in macrophages despite initially activating STING. STING does participate in the control of Brucella infection, as mice or cells lacking STING show a higher burden of Brucella infection. However, we have found that early following infection, Brucella upregulates a microRNA, miR-24, that targets the STING messenger RNA, resulting in lower STING levels. Dead bacteria or bacteria lacking a functional type IV secretion system were defective at upregulating miR-24 and STING suppression, suggesting an active bacteria-driven process. Failure to upregulate miR-24 and suppress STING greatly compromised the capacity for Brucella to replicate inside macrophages. Thus, although Brucella initially activate STING during infection, the ensuing STING downregulation serves as a “damage control” mechanism, enabling intracellular infection. Viruses have long been known to target immune sensors such as STING. Our results indicate that intracellular bacterial pathogens also directly target innate immune receptors to enhance their infectious success.

scholarly journals 814 – Helicobacter Pylori Induces Aberrant Lrig1 Stem Cell Activity Within the Stomach in a Cag Type Iv Secretion System-Dependent Manner

2019 ◽  
Vol 156 (6) ◽  
pp. S-171-S-172 ◽  
Author(s):  
Lydia Wroblewski ◽  
Eunyoung Choi ◽  
Christine Petersen ◽  
Alberto Delgado ◽  
M. Blanca Piazuelo ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Stem Cell ◽  
Cell Activity ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Dependent Manner ◽  
Type Iv ◽  
Stem Cell Activity

930 HELICOBACTER PYLORI PROMOTES THE DIFFERENTIATION OF PPAR∂-EXPRESSING EPITHELIAL CELLS FROM LRIG+ STEM CELLS IN A CAG TYPE IV SECRETION SYSTEM-DEPENDENT MANNER

2020 ◽  
Vol 158 (6) ◽  
pp. S-185
Author(s):  
Lydia Wroblewski ◽  
Alberto Delgado ◽  
Maria B. Piazuelo ◽  
Judith Romero-Gallo ◽  
Robert J. Coffey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Dependent Manner ◽  
Type Iv

scholarly journals In Situ Visualization of the pKM101-Encoded Type IV Secretion System Reveals a Highly Symmetric ATPase Energy Center at the Channel Entrance

2021 ◽  
Author(s):  
Pratick Khara ◽  
Peter J. Christie ◽  
Bo Hu
Keyword(s):  
Cell Envelope ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Membrane Complex ◽  
Type Iv ◽  
Inner Membrane Complex ◽  
Cytoplasmic Complex

Bacterial conjugation systems are members of the type IV secretion system (T4SS) superfamily. T4SSs can be classified as ‘minimized’ or ‘expanded’ based on whether assembly requires only a core set of signature subunits or additional system-specific components. The prototypical ‘minimized’ systems mediating Agrobacterium tumefaciens T-DNA transfer and conjugative transfer of plasmids pKM101 and R388 are built from 12 subunits generically named VirB1-VirB11 and VirD4. In this study, we visualized the pKM101-encoded T4SS in the native context of the bacterial cell envelope by in situ cryoelectron tomography (CryoET). The T4SSpKM101 is composed of an outer membrane core complex (OMCC) connected by a thin stalk to an inner membrane complex (IMC). The OMCCexhibits 14-fold symmetry and resembles that of the T4SSR388, a large substructure of which was previously purified and analyzed by negative-stain electron microscopy (nsEM). The IMC of the in situ T4SSpKM101 machine is highly symmetrical and exhibits 6-fold symmetry, dominated by a hexameric collar in the periplasm and a cytoplasmic complex composed of a hexamer of dimers of the VirB4-like TraB ATPase. The IMCclosely resembles equivalent regions of three ‘expanded’ T4SSs previously visualized by in situ CryoET, but strikingly differs from the IMC of the purified T4SSR388 whose cytoplasmic complex instead presents as two side-by-side VirB4 hexamers.  Together, our findings support a unified architectural model for all T4SSs assembled in vivo regardless of their classification as ‘minimized’ or ‘expanded’: the signature VirB4-like ATPases invariably are arranged as central hexamers of dimers at the entrances to the T4SS channels.

scholarly journals In Vivo Structures of the Helicobacter pylori cag Type IV Secretion System

Cell Reports ◽  
2018 ◽  
Vol 23 (3) ◽  
pp. 673-681 ◽  
Author(s):  
Yi-Wei Chang ◽  
Carrie L. Shaffer ◽  
Lee A. Rettberg ◽  
Debnath Ghosal ◽  
Grant J. Jensen
Keyword(s):  
Helicobacter Pylori ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Type Iv

scholarly journals Brucella melitensis Invades Murine Erythrocytes during Infection

2014 ◽  
Vol 82 (9) ◽  
pp. 3927-3938 ◽  
Author(s):  
Marie-Alice Vitry ◽  
Delphine Hanot Mambres ◽  
Michaël Deghelt ◽  
Katrin Hack ◽  
Arnaud Machelart ◽  
...  
Keyword(s):  
Brucella Melitensis ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Bacterial Cells ◽  
Content Type ◽  
Type Iv ◽  
Transmission Electron ◽  
Time Point

ABSTRACTBrucellaspp. are facultative intracellular Gram-negative coccobacilli responsible for brucellosis, a worldwide zoonosis. We observed thatBrucella melitensisis able to persist for several weeks in the blood of intraperitoneally infected mice and that transferred blood at any time point tested is able to induce infection in naive recipient mice. Bacterial persistence in the blood is dramatically impaired by specific antibodies induced followingBrucellavaccination. In contrast toBartonella, the type IV secretion system and flagellar expression are not critically required for the persistence ofBrucellain blood. ImageStream analysis of blood cells showed that following a brief extracellular phase,Brucellais associated mainly with the erythrocytes. Examination by confocal microscopy and transmission electron microscopy formally demonstrated thatB. melitensisis able to invade erythrocytesin vivo. The bacteria do not seem to multiply in erythrocytes and are found free in the cytoplasm. Our results open up new areas for investigation and should serve in the development of novel strategies for the treatment or prophylaxis of brucellosis. Invasion of erythrocytes could potentially protect the bacterial cells from the host's immune response and hamper antibiotic treatment and suggests possibleBrucellatransmission by bloodsucking insects in nature.

scholarly journals Helicobacter pyloriInduces Gastric Epithelial Cell Invasion in a c-Met and Type IV Secretion System-dependent Manner

2006 ◽  
Vol 281 (46) ◽  
pp. 34888-34896 ◽  
Author(s):  
Maria J. Oliveira ◽  
Ana C. Costa ◽  
Angela M. Costa ◽  
Lara Henriques ◽  
Gianpaolo Suriano ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Invasion ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Gastric Epithelial Cell ◽  
Type Iv Secretion System ◽  
Dependent Manner ◽  
Type Iv ◽  
Epithelial Cell Invasion

scholarly journals The Impact of Bartonella VirB/VirD4 Type IV Secretion System Effectors on Eukaryotic Host Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Katja Fromm ◽  
Christoph Dehio
Keyword(s):  
Current Knowledge ◽  
Secretion System ◽  
Effector Proteins ◽  
Type Iv Secretion ◽  
Host Cells ◽  
Type Iv Secretion System ◽  
Type Iv ◽  
Wide Range ◽  
Host Signaling ◽  
The Impact

Bartonella spp. are facultative intracellular pathogens that infect a wide range of mammalian hosts including humans. The VirB/VirD4 type IV secretion system (T4SS) is a key virulence factor utilized to translocate Bartonella effector proteins (Beps) into host cells in order to subvert their functions. Crucial for effector translocation is the C-terminal Bep intracellular delivery (BID) domain that together with a positively charged tail sequence forms a bipartite translocation signal. Multiple BID domains also evolved secondary effector functions within host cells. The majority of Beps possess an N-terminal filamentation induced by cAMP (FIC) domain and a central connecting oligonucleotide binding (OB) fold. FIC domains typically mediate AMPylation or related post-translational modifications of target proteins. Some Beps harbor other functional modules, such as tandem-repeated tyrosine-phosphorylation (EPIYA-related) motifs. Within host cells the EPIYA-related motifs are phosphorylated, which facilitates the interaction with host signaling proteins. In this review, we will summarize our current knowledge on the molecular functions of the different domains present in Beps and highlight examples of Bep-dependent host cell modulation.

scholarly journals AnIn VivoHigh-Throughput Screening Approach Targeting the Type IV Secretion System Component VirB8 Identified Inhibitors ofBrucella abortus2308 Proliferation

2010 ◽  
Vol 79 (3) ◽  
pp. 1033-1043 ◽  
Author(s):  
Athanasios Paschos ◽  
Andreas den Hartigh ◽  
Mark A. Smith ◽  
Vidya L. Atluri ◽  
Durga Sivanesan ◽  
...  
Keyword(s):  
Secretion System ◽  
Bacterial Virulence ◽  
Type Iv Secretion ◽  
Host Cells ◽  
System Component ◽  
Type Iv Secretion System ◽  
Promising Alternative ◽  
Type Iv ◽  
Two Hybrid

ABSTRACTAs bacterial pathogens develop resistance against most currently used antibiotics, novel alternatives for treatment of microbial infectious diseases are urgently needed. Targeting bacterial virulence functions in order to disarm pathogens represents a promising alternative to classical antibiotic therapy. Type IV secretion systems, which are multiprotein complexes in the cell envelope that translocate effectors into host cells, are critical bacterial virulence factors in many pathogens and excellent targets for such “antivirulence” drugs. The VirB8 protein from the mammalian pathogenBrucellawas chosen as a specific target, since it is an essential type IV secretion system component, it participates in multiple protein-protein interactions, and it is essential for the assembly of this translocation machinery. The bacterial two-hybrid system was adapted to assay VirB8 interactions, and a high-throughput screen identified specific small-molecule inhibitors. VirB8 interaction inhibitors also reduced the levels of VirB8 and of other VirB proteins, and many of them inhibitedvirBgene transcription inBrucella abortus2308, suggesting that targeting of the secretion system has complex regulatory effectsin vivo. One compound strongly inhibited the intracellular proliferation ofB. abortus2308 in a J774 macrophage infection model. The results presented here show thatin vivoscreens with the bacterial two-hybrid assay are suited to the identification of inhibitors ofBrucellatype IV secretion system function.

scholarly journals Cytotoxicity of Brucella smooth strains for macrophages is mediated by increased secretion of the type IV secretion system

Microbiology ◽  
2009 ◽  
Vol 155 (10) ◽  
pp. 3392-3402 ◽  
Author(s):  
Zhijun Zhong ◽  
Yufei Wang ◽  
Feng Qiao ◽  
Zhoujia Wang ◽  
Xinying Du ◽  
...  
Keyword(s):  
Cell Density ◽  
Secretion System ◽  
Effector Proteins ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Dependent Manner ◽  
Density Dependent ◽  
Type Iv ◽  
A Cell

Some Brucella rough mutants cause cytotoxicity that resembles oncosis and necrosis in macrophages. This cytotoxicity requires the type IV secretion system (T4SS). In rough mutants, the cell-surface O antigen is shortened and the T4SS structure is thus exposed on the surface. Cytotoxicity effector proteins can therefore be more easily secreted. This enhanced secretion of effector proteins might cause the increased levels of cytotoxicity observed. However, whether this cytotoxicity is unique to the rough mutant and is mediated by overexpression of the T4SS has not been definitively determined. To test this, in the present study, a virB inactivation mutant (BMΔvirB) and an overexpression strain (BM-VIR) of a smooth Brucella melitensis strain (BM) were constructed and their cytotoxicity for macrophages and intracellular survival capability were analysed and compared. Cytotoxicity was detected in macrophages infected with higher concentrations of strains BM or BM-VIR, but not in those infected with BMΔvirB. The quorum sensing signal molecule N-dodecanoyl-dl-homoserine lactone (C12-HSL), a molecule that can inhibit expression of virB, inhibited the cytotoxicity of BM and BM-VIR, but not of BMΔvirB. These results indicated that overexpression of virB is responsible for Brucella cytotoxicity in macrophages. Transcription analysis showed that virB is regulated in a cell-density-dependent manner both in in vitro culture and during macrophage infection. When compared with BM, BM-VIR showed a reduced survival capacity in macrophages and mice, but both strains demonstrated similar resistance to in vitro stress conditions designed to simulate intracellular environments. Taken together, the cytotoxicity of Brucella for macrophages is probably mediated by increased secretion of effector proteins that results from overexpression of virB or an increase in the number of bacterial cells. The observation that both inactivation and overexpression of virB are detrimental for Brucella intracellular survival also indicated that the expression of virB is tightly regulated in a cell-density-dependent manner.

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