Genome degradation promotes Salmonella pathoadaptation by remodeling fimbriae-mediated proinflammatory response
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PROVIDER: S-EPMC10642762 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Project description:Typhoid fever is caused primarily by Salmonella enterica serovar Typhi. Approximately 3% to 5% of individuals infected with S Typhi become chronic carriers with the gallbladder (GB) as the site of persistence, as gallstones within the GB are a platform on which the bacteria form a biofilm. S Typhi is a human-restricted pathogen; therefore, asymptomatic carriers represent a critical reservoir for further spread of disease. To examine the dynamics of the Salmonella biofilm during chronic carriage, the human gallstone (GS) environment was simulated by growing biofilms on cholesterol-coated surfaces in the presence of bile, and the transcriptional profile was determined. Some of the most highly activated genes corresponded to the curli fimbria operon, with the major structural component csgA upregulated >80-fold. The curli protein polymer is a major component of the extracellular matrix (ECM) in Salmonella biofilms. The upregulation of curli fimbriae by human bile was validated through reverse transcription-quantitative PCR (qRT-PCR), microscopy, and Western blotting. Interestingly, this activation appears human specific, as qRT-PCR showed repression of csgA in biofilms grown in mouse or ox bile. Comparative transcriptional studies of the two divergent csg operons suggest an early activation of both operons in minimal medium complemented with glucose that quickly diminishes as the biofilm matures. However, in the presence of human bile, there is a modest activation of both operons that steadily increases as the biofilm matures. Understanding the effect of the GB environment on key biofilm-associated factors can help target antibiofilm therapeutics or other preventative strategies to eradicate chronic carriage.IMPORTANCE Typhoid fever is caused by Salmonella enterica serovar Typhi, and 3% to 5% of patients become chronic gallbladder (GB) carriers (also known as "Typhoid Marys"). We have previously demonstrated a role for Salmonella biofilm formation on gallstones as a primary mechanism of carriage. In this study, we found that the important biofilm extracellular matrix component curli fimbria is induced in an in vitro human GB model system. This induction is specific to human bile and increases as the biofilm matures. We also found that the biofilm and curli regulator CsgD play a key role in this observed induction. This work further enhances our understanding biofilm-mediated chronic carriage and provides a potential target for eliminating persistent GB infection by S Typhi.
| S-EPMC6707929 | biostudies-literature
Project description:Histone biogenesis is tightly controlled at multiple steps to maintain the balance between the amounts of DNA and histone protein during the cell cycle. In particular, translation and degradation of replication-dependent histone mRNAs are coordinately regulated. However, the underlying molecular mechanisms remain elusive. Here, we investigate remodeling of stem-loop binding protein (SLBP)-containing histone mRNPs occurring during the switch from the actively translating mode to the degradation mode. The interaction between a CBP80/20-dependent translation initiation factor (CTIF) and SLBP, which is important for efficient histone mRNA translation, is disrupted upon the inhibition of DNA replication or at the end of S phase. This disruption is mediated by competition between CTIF and UPF1 for SLBP binding. Further characterizations reveal hyperphosphorylation of UPF1 by activated ATR and DNA-dependent protein kinase upon the inhibition of DNA replication interacts with SLBP more strongly, promoting the release of CTIF and eIF3 from SLBP-containing histone mRNP. In addition, hyperphosphorylated UPF1 recruits PNRC2 and SMG5, triggering decapping followed by 5'-to-3' degradation of histone mRNAs. The collective observations suggest that both inhibition of translation and recruitment of mRNA degradation machinery during histone mRNA degradation are tightly coupled and coordinately regulated by UPF1 phosphorylation.
| S-EPMC4132728 | biostudies-literature
Project description:Salmonella enterica serovar Typhimurium is known to cause its virulence by secreting various effector proteins directly into the host cytoplasm via two distinct type III secretion systems (T3SS-1 and T3SS-2). Generally, T3SS-1-delivered effectors help Salmonella Typhimurium in the early phases of infection including invasion and immune modulation of the host cells, whereas T3SS-2 effectors mainly help in the survival of Salmonella Typhimurium within the host cells including maintenance of Salmonella-containing vacuole, replication of the bacteria, and dissemination. Some of the effectors are secreted via both T3SS-1 and T3SS-2, suggesting their role in distinct phases of infection of host cells. SteA is such an effector that is secreted by both T3SS-1 and T3SS-2. It has been shown to control the membrane dynamics of the Salmonella-containing vacuole within the host cells in the late phases of infection. In this manuscript, toward characterizing the T3SS-1 function of SteA, we found that SteA suppresses inflammatory responses of the host by interfering with the nuclear factor kappa B pathway. Our initial observation showed that the mice infected with steA-deleted Salmonella Typhimurium (ΔsteA) died earlier compared to the wild-type bacteria due to heightened immune responses, which indicated that SteA might suppress immune responses. Furthermore, our study revealed that SteA suppresses immune responses in macrophages by interfering with the degradation of IκB, the inhibitor of nuclear factor kappa B. SteA suppresses the ubiquitination and hence degradation of IκB by acting on Cullin-1 of the Skp-1, Cullin-1, F-box (SCF)-E3 ligase complex. Our study revealed that SteA suppresses a key step necessary for E3 ligase activation, i.e., neddylation of Cullin-1 by interfering with dissociation of its inhibitor Cand-1.
| S-EPMC6914705 | biostudies-literature
Project description:BackgroundKey hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (-) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis.MethodsNOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2△hep), Rip2-knockout (Rip2△hep), Lamin A/C-knockout (Lamn△hep) and Rip2/Lamin A/C double-knockout (Rip2/Lamn△hep) mice models of diethylnitrosamine (DEN)/CCl4-induced HCC.ResultsNOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl4-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability.ConclusionsWe reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
| S-EPMC7791875 | biostudies-literature
Project description:Abiotrophia defectiva is a nutritionally variant streptococci that is found in the oral cavity, and it is an etiologic agent of infective endocarditis. We have previously reported the binding activity of A. defectiva to fibronectin and to human umbilical vein endothelial cells (HUVECs). However, the contribution of some adhesion factors on the binding properties has not been well delineated. In this study, we identified DnaK, a chaperon protein, as being one of the binding molecules of A. defectiva to fibronectin. Recombinant DnaK (rDnaK) bound immobilized fibronectin in a concentration-dependent manner, and anti-DnaK antiserum reduced the binding activity of A. defectiva with both fibronectin and HUVECs. Furthermore, DnaK were observed on the cell surfaces via immune-electroscopic analysis with anti-DnaK antiserum. Expression of IL-8, CCL2, ICAM-1, and VCAM-1 was upregulated with the A. defectiva rDnaK treatment in HUVECs. Furthermore, TNF-α secretion of THP-1 macrophages was also upregulated with the rDnaK. We observed these upregulations in rDnaK treated with polymyxin B, but not in the heat-treated rDnaK. The findings show that A. defectiva DnaK functions not only as an adhesin to HUVECs via the binding to fibronectin but also as a proinflammatory agent in the pathogenicity to cause infective endocarditis.
| S-EPMC8395199 | biostudies-literature
Project description:Salmonella enterica is a diverse bacterial pathogen and a primary cause of human and animal infections. While many S. enterica serovars present a broad host-specificity, several specialized pathotypes have been adapted to colonize and cause disease in one or limited numbers of host species. The underlying mechanisms defining Salmonella host-specificity are far from understood. Here, we present genetic analysis, phenotypic characterization and virulence profiling of a monophasic S. enterica serovar Typhimurium strain that was isolated from several wild sparrows in Israel. Whole genome sequencing and complete assembly of its genome demonstrate a unique genetic signature that includes the integration of the BTP1 prophage, loss of the virulence plasmid, pSLT and pseudogene accumulation in multiple T3SS-2 effectors (sseJ, steC, gogB, sseK2, and sseK3), catalase (katE), tetrathionate respiration (ttrB) and several adhesion/ colonization factors (lpfD, fimH, bigA, ratB, siiC and siiE) encoded genes. Correspondingly, this strain demonstrates impaired biofilm formation, intolerance to oxidative stress and compromised intracellular replication within non-phagocytic host cells. Moreover, while this strain showed attenuated pathogenicity in the mouse, it was highly virulent and caused an inflammatory disease in an avian host. Overall, our findings demonstrate a unique phenotypic profile and genetic makeup of an overlooked S. Typhimurium sparrow-associated lineage and present distinct genetic signatures that are likely to contribute to its pathoadaptation to passerine birds.
| S-EPMC8011750 | biostudies-literature
Project description:Sequence data from the past decade has laid bare the significance of horizontal gene transfer in creating genetic diversity in the bacterial world. Regulatory evolution, in which non-coding DNA is mutated to create new regulatory nodes, also contributes to this diversity to allow niche adaptation and the evolution of pathogenesis. To survive in the host environment, Salmonella enterica uses a type III secretion system and effector proteins, which are activated by the SsrA-SsrB two-component system in response to the host environment. To better understand the phenomenon of regulatory evolution in S. enterica, we defined the SsrB regulon and asked how this transcription factor interacts with the cis-regulatory region of target genes. Using ChIP-on-chip, cDNA hybridization, and comparative genomics analyses, we describe the SsrB-dependent regulon of ancestral and horizontally acquired genes. Further, we used a genetic screen and computational analyses integrating experimental data from S. enterica and sequence data from an orthologous regulatory system in the insect endosymbiont, Sodalis glossinidius, to identify the conserved yet flexible palindrome sequence that defines DNA recognition by SsrB. Mutational analysis of a representative promoter validated this palindrome as the minimal architecture needed for regulatory input by SsrB. These data provide a high-resolution map of a regulatory network and the underlying logic enabling pathogen adaptation to a host.
| S-EPMC2837388 | biostudies-literature
Project description:Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan-inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC-based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)-stimulated macrophages and a mouse model. By employing B4 as a molecular probe, evidence is found for a previously explored role of HDAC7 that surpasses its deacetylase function, suggesting broader implications in inflammatory processes. Mechanistic investigations reveal the critical involvement of HDAC7 in the Toll-like receptor 4 (TLR4) signaling pathway by directly interacting with the TNF receptor-associated factor 6 and TGFβ-activated kinase 1 (TRAF6-TAK1) complex, thereby initiating the activation of the downstream mitogen-activated protein kinase/nuclear factor-κB (MAPK/NF-κB) signaling cascade and subsequent gene transcription. This study expands the insight into HDAC7's role within intricate inflammatory networks and highlights its therapeutic potential as a novel target for anti-inflammatory treatments.
| S-EPMC11423193 | biostudies-literature
Project description:The SWI/SNF chromatin remodeling complexes control accessibility of chromatin to transcriptional and coregulatory machineries. Chromatin remodeling plays important roles in normal physiology and diseases, particularly cancer. The ARID1A-containing SWI/SNF complex is commonly mutated and thought to be a key tumor suppressor in hepatocellular carcinoma (HCC), but its regulation in response to oncogenic signals remains poorly understood. mTOR is a conserved central controller of cell growth and an oncogenic driver of HCC. Remarkably, cancer mutations in mTOR and SWI/SNF complex are mutually exclusive in human HCC tumors, suggesting that they share a common oncogenic function. Here, we report that mTOR complex 1 (mTORC1) interact with ARID1A and regulates ubiquitination and proteasomal degradation of ARID1A protein. The mTORC1-ARID1A axis promoted oncogenic chromatin remodeling and YAP-dependent transcription, thereby enhancing liver cancer cell growth in vitro and tumor development in vivo. Conversely, excessive ARID1A expression counteracted AKT-driven liver tumorigenesis in vivo. Moreover, dysregulation of this axis conferred resistance to mTOR-targeted therapies. These findings demonstrate that the ARID1A-SWI/SNF complex is a regulatory target for oncogenic mTOR signaling, which is important for mTORC1-driven hepatocarcinogenesis, with implications for therapeutic interventions in HCC. SIGNIFICANCE: mTOR promotes oncogenic chromatin remodeling by controlling ARID1A degradation, which is important for liver tumorigenesis and response to mTOR- and YAP-targeted therapies in hepatocellular carcinoma.See related commentary by Pease and Fernandez-Zapico, p. 5608.
| S-EPMC8595749 | biostudies-literature
Project description:Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children that resembles developing skeletal muscle. Unlike normal muscle cells, RMS cells fail to differentiate despite expression of the myogenic determination protein MYOD. The TWIST2 transcription factor is frequently overexpressed in fusion-negative RMS (FN-RMS). TWIST2 blocks differentiation by inhibiting MYOD activity in myoblasts, but its role in FN-RMS pathogenesis is incompletely understood. Here, we show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo terminal myogenesis. TWIST2 knockdown also substantially reduces tumor growth in a mouse xenograft model of FN-RMS. Mechanistically, TWIST2 controls H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers SMARCA4 and CHD3 to activate growth-related target genes and repress myogenesis-related target genes. These findings provide insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the potential of suppressing TWIST2-regulated pathways to treat FN-RMS.
| S-EPMC10146891 | biostudies-literature