{"content"=>"The Key Role of c-Fos for Immune Regulation and Bacterial Dissemination in Infected Macrophage.", "i"=>{"content"=>"Brucella"}} (original) (raw)
Related papers
Interleukin 10 suppresses lysosome-mediated killing of Brucella abortus in cultured macrophages
The Journal of biological chemistry, 2018
Brucella abortus is a Gram-negative zoonotic pathogen for which there is no 100% effective vaccine. Phagosomes in B. abortus-infected cells fail to mature allowing the pathogen to survive and proliferate. Interleukin 10 (IL-10) promotes B. abortus persistence in macrophages by mechanisms that are not fully understood. In this study, we investigated the regulatory role of IL-10 in the immune response to B. abortus infection. B. abortus-infected macrophages were treated with either IL10 siRNA or recombinant IL-10 (rIL-10) and the expression of phagolysosome- or inflammation-related genes was evaluated by qRT-PCR and Western blot. Phagolysosome fusion was monitored by fluorescence microscopy. We found that the synthesis of several membrane-trafficking regulators and lysosomal enzymes was suppressed by IL-10 during infection, resulting in a significant increase in the recruitment of hydrolytic enzymes by Brucella-containing phagosomes (BCPs) when IL-10 signaling was blocked. Moreover, b...
PLoS Pathogens, 2013
Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4 + CD25 + T cells to produce the anti-inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of proinflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25 + CD4 + T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection. Citation: Xavier MN, Winter MG, Spees AM, Nguyen K, Atluri VL, et al. (2013) CD4 + T Cell-derived IL-10 Promotes Brucella abortus Persistence via Modulation of Macrophage Function. PLoS Pathog 9(6): e1003454.
Infection and Immunity, 2011
Our studies showed that smooth virulent B. suis strain 1330 (S1330) prevented programmed cell death of infected macrophages and rough attenuated B. suis strain VTRS1 (a vaccine candidate) induced strong macrophage cell death. To further investigate the mechanism of VTRS1-induced macrophage cell death, microarrays were used to analyze temporal transcriptional responses of murine macrophage-like J774.A1 cells infected with S1330 or VTRS1. In total 17,685 probe sets were significantly regulated based on the effects of strain, time and their interactions. A miniTUBA dynamic Bayesian network analysis predicted that VTRS1-induced macrophage cell death was mediated by a proinflammatory gene (the tumor necrosis factor alpha [TNF-␣] gene), an NF-B pathway gene (the IB-␣ gene), the caspase-2 gene, and several other genes. VTRS1 induced significantly higher levels of transcription of 40 proinflammatory genes than S1330. A Mann-Whitney U test confirmed the proinflammatory response in VTRS1-infected macrophages. Increased production of TNF-␣ and interleukin 1 (IL-1) were also detected in the supernatants in VTRS1-infected macrophage cell culture. Hyperphosphorylation of IB-␣ was observed in macrophages infected with VTRS1 but not S1330. The important roles of TNF-␣ and IB-␣ in VTRS1-induced macrophage cell death were further confirmed by individual inhibition studies. VTRS1induced macrophage cell death was significantly inhibited by a caspase-2 inhibitor but not a caspase-1 inhibitor. The role of caspase-2 in regulating the programmed cell death of VTRS1-infected macrophages was confirmed in another study using caspase-2-knockout mice. In summary, VTRS1 induces a proinflammatory, caspase-2-and NF-B-mediated macrophage cell death. This unique cell death differs from apoptosis, which is not proinflammatory. It is also different from classical pyroptosis, which is caspase-1 mediated.
Immunological pathways of macrophage response to Brucella ovis infection
Innate Immunity
As the molecular mechanisms of Brucella ovis pathogenicity are not completely clear, we have applied a transcriptome approach to identify the differentially expressed genes (DEGs) in RAW264.7 macrophage infected with B. ovis. The DEGs related to immune pathway were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) functional enrichment analysis. Quantitative real-time PCR (qRT-PCR) was performed to validate the transcriptome sequencing data. In total, we identified 337 up-regulated and 264 down-regulated DEGs in B. ovis-infected group versus mock group. Top 20 pathways were enriched by KEGG analysis and 20 GO by functional enrichment analysis in DEGs involved in the molecular function, cellular component, and biological process and so on, which revealed multiple immunological pathways in RAW264.7 macrophage cells in response to B. ovis infection, including inflammatory response, immune system process, immune response, cytokine activity, chemotaxis, ...
The role of innate immune signals in immunity to Brucella abortus
Frontiers in Cellular and Infection Microbiology, 2012
Innate immunity serves as the first line of defense against infectious agents such as intracellular bacteria. The innate immune platform includes Toll-like receptors (TLRs), retinoid acid-inducible gene-I-like receptors and other cytosolic nucleic acid sensors, nucleotide-binding and oligomerization domain-like receptors, adaptors, kinases and other signaling molecules that are required to elicit effective responses against different pathogens. Our research group has been using the Gram-negative bacteria Brucella abortus as a model of pathogen. We have demonstrated that B. abortus triggers MAPK and NF-κB signaling pathways in macrophages in a MyD88 and IRAK-4-dependent manner. Furthermore, we claimed that so far TLR9 is the most important single TLR during Brucella infection. The identification of host receptors that recognize pathogen-derived nucleic acids has revealed an essential role for nucleic acid sensing in the triggering of immunity to intracellular pathogens. Besides TLRs, herein we describe recent advances in NOD1, NOD2, and type I IFN receptors in innate immune pathways during B. abortus infection.
Brucella suppress innate immunity by down-regulating STING expression in macrophages
Brucellosis, 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 replicatio...
Cellular & molecular immunology, 2014
Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-α, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-κB in macrophages. In addition, continuous exposure (>24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-γ-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4(+) T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2(...
Regulation of cytokine gene expression during Brucella abortus infection
Scientific Research and Essays, 2013
Toll-like receptors (TLR) play a key role in antimicrobial host defense. Bacterial cell wall components and lipopolysaccharide (LPS) are recognized by macrophages via TLR, resulting in activation of professional antigen-presenting cells, initiation of acquired immune responses and further elimination of the invasive bacteria. TLR2 and TLR4 have been shown to recognize bacterial components. TLR2 is required for signaling by numerous ligands from gram-negative and gram-positive bacteria such as lipoteichoic acids, peptidoglycan and lipoproteins. In contrast, TLR4 fails to confer responsiveness to gram-positive bacteria and their components, but it is the main LPS signaling receptor. LPS is a major constituent of the outer membrane of gram-negative bacteria, such as Brucella, and is known to activate neutrophils, monocytes, macrophages, and other cell types to up-regulate expression of adhesion molecules and produce a number of pro-and anti-inflammatory cytokines. This study demonstrates that the attenuated strain Brucella abortus RB51 can stimulate cells through TLR4 and MyD88, resulting in NF-κ κ κ κB activation. The virulent strain B. abortus 2308 can also stimulate the cells by a MyD88-dependent pathway without involving either TLR4 or TLR2. It also induced NF-κ κ κ κB activation and nuclear translocation, suggesting that B. abortus RB51 induces activation of the proinflammatory response by a TLR4-dependent pathway with the subsequent NF-κ κ κ κB activation and nuclear translocation; nevertheless, the 2308 strain induced NF-κ κ κ κB nuclear translocation that was activated by an alternative pathway, different from that induced by TLR.
The key roles of toll-like receptor (TLR) for intracellular survival of Brucella
Journal of Preventive Veterinary Medicine, 2013
Brucella spp. are facultative intracellular pathogens that have the ability to survive and multiply in professional and nonprofessional phagocytes and cause abortion in domestic animals and undulant fever in humans. Brucella species can survive in a variety of cells, including macrophages and their virulence and chronic infections are thought to be due to their ability to avoid the killing mechanisms within macrophages. Inhibition of phagosome-lysosome fusion has been proposed as a mechanism for intracellular survival of Brucella in professional and nonprofessional phagocytes. Toll-like receptors (TLRs) are part of a skillful system for detection of invasion by microbial pathogens. Recognition of microbial components by TLRs triggers signaling pathways that promote expression of genes and regulate innate immune responses. Recent studies for the interaction between TLRs-Brucella have indicated the importance of control of Brucella infection. Here, we review selected aspects of TLRs-Brucella interaction, which may be helpful to understanding the mechanism of Brucella pathogenesis.