scholarly journals Salmonella persisters undermine host immune defenses during antibiotic treatment

Science ◽  
2018 ◽  
Vol 362 (6419) ◽  
pp. 1156-1160 ◽  
Author(s):  
Daphne A. C. Stapels ◽  
Peter W. S. Hill ◽  
Alexander J. Westermann ◽  
Robert A. Fisher ◽  
Teresa L. Thurston ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Macrophage Polarization ◽  
Physiological State ◽  
Innate Immune Responses ◽  
Macrophage Infection ◽  
Immune Defenses ◽  
Type 3 Secretion System ◽  
Type 3 ◽  
Inflammatory Macrophage

Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.

scholarly journals Interaction of Escherichia coli O157:H7 with Leafy Green Produce

2009 ◽  
Vol 72 (7) ◽  
pp. 1531-1537 ◽  
Author(s):  
JUAN XICOHTENCATL-CORTES ◽  
ETHEL SÁNCHEZ CHACÓN ◽  
ZEUS SALDAÑA ◽  
ENRIQUE FREER ◽  
JORGE A. GIRÓN
Keyword(s):  
Escherichia Coli ◽  
Diarrheal Disease ◽  
Foodborne Pathogen ◽  
Enterohemorrhagic Escherichia Coli ◽  
Animal Products ◽  
Atpase Gene ◽  
Type 3 Secretion System ◽  
Human Infections ◽  
Type 3

Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen responsible for human diarrheal disease. EHEC lives in the intestinal tract of cattle and other farm and wild animals, which may be the source of environmental contamination particularly of agricultural fields. Human infections are associated with consumption of tainted animal products and fresh produce. How the bacteria interact with the plant phyllosphere and withstand industrial decontamination remain to be elucidated. The goals of the present study were to investigate the environmental conditions and surface structures that influence the interaction of EHEC O157:H7 with baby spinach and lettuce leaves in vitro. Independently of the production of Shiga toxin, EHEC O157:H7 colonizes the leaf surface via flagella and the type 3 secretion system (T3SS). Ultrastructural analysis of EHEC-infected leafy greens revealed the presence of flagellated bacteria, and mutation of the fliC flagellin gene in EHEC EDL933 rendered the bacteria significantly less adherent, suggesting the involvement of flagella in the bacteria-leaf interaction. EDL933 mutated in the escN (ATPase) gene associated with the function of the T3SS but not in the eae (intimin adhesin) gene required for adherence to host intestinal cells had significantly reduced adherence compared with that of the parental strain. The data suggest a compelling role of flagella and the T3SS in colonization of leafy green produce. Colonization of salad leaves by EHEC strains may be a strategy that ensures survival of these bacteria in the environment and allows transmission to the human host.

An in vitro test system for compounds that modulate human inflammatory macrophage polarization

2018 ◽  
Vol 833 ◽  
pp. 328-338 ◽  
Author(s):  
Hiromi Shiratori ◽  
Carmen Feinweber ◽  
Sonja Luckhardt ◽  
Nadja Wallner ◽  
Gerd Geisslinger ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Test System ◽  
In Vitro Test ◽  
Vitro Test ◽  
Inflammatory Macrophage

scholarly journals Regulation by ToxR-Like Proteins Converges onvttRBExpression To Control Type 3 Secretion System-Dependent Caco2-BBE Cytotoxicity in Vibrio cholerae

2016 ◽  
Vol 198 (11) ◽  
pp. 1675-1682 ◽  
Author(s):  
Kelly A. Miller ◽  
Madeline K. Sofia ◽  
Jacob W. A. Weaver ◽  
Christopher H. Seward ◽  
Michelle Dziejman
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Vibrio Cholerae ◽  
Secretion System ◽  
Content Type ◽  
Transcriptional Regulatory ◽  
Type 3 Secretion System ◽  
Type 3

ABSTRACTGenes carried on the type 3 secretion system (T3SS) pathogenicity island ofVibrio choleraenon-O1/non-O139 serogroup strain AM-19226 must be precisely regulated in order for bacteria to cause disease. Previously reported results showed that both T3SS function and the presence of bile are required to cause Caco2-BBE cell cytotoxicity during coculture with strain AM-19226. We therefore investigated additional parameters affectingin vitrocell death, including bacterial load and the role of three transmembrane transcriptional regulatory proteins, VttRA, VttRB, and ToxR. VttRAand VttRBare encoded on the horizontally acquired T3SS genomic island, whereas ToxR is encoded on the ancestral chromosome. While strains carrying deletions in any one of the three transcriptional regulatory genes are unable to cause eukaryotic cell death, the results of complementation studies point to a hierarchy of regulatory control that converges onvttRBexpression. The data suggest both that ToxR and VttRAact upstream of VttRBand that modifying the level of eithervttRAorvttRBexpression can strongly influence T3SS gene expression. We therefore propose a model whereby T3SS activity and, hence,in vitrocytotoxicity are ultimately regulated byvttRBexpression.IMPORTANCEIn contrast to O1 and O139 serogroupV. choleraestrains that cause cholera using two main virulence factors (toxin-coregulated pilus [TCP] and cholera toxin [CT]), O39 serogroup strain AM-19226 uses a type 3 secretion system as its principal virulence mechanism. Although the regulatory network governing TCP and CT expression is well understood, the factors influencing T3SS-associated virulence are not. Using anin vitromammalian cell model to investigate the role of three ToxR-like transmembrane transcriptional activators in causing T3SS-dependent cytotoxicity, we found that expression levels and a hierarchical organization were important for promoting T3SS gene expression. Furthermore, our results suggest that horizontally acquired, ToxR-like proteins act in concert with the ancestral ToxR protein to orchestrate T3SS-mediated pathogenicity.

scholarly journals Effect of Protein O-Mannosyltransferase (MSMEG_5447) on M. smegmatis and Its Survival in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Liqiu Jia ◽  
Shanshan Sha ◽  
Shufeng Yang ◽  
Ayaz Taj ◽  
Yufang Ma
Keyword(s):  
Gene Knockout ◽  
Initial Step ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Macrophage Infection ◽  
Host Interaction ◽  
Activation Of Transcription ◽  
Host Innate Immune Response

Protein O-mannosyltransferase (PMT) catalyzes an initial step of protein O-mannosylation of Mycobacterium tuberculosis (Mtb) and plays a crucial role for Mtb survival in the host. To better understand the role of PMT in the host innate immune response during mycobacterial infection, in this study, we utilized Mycobacterium smegmatis pmt (MSMEG_5447) gene knockout strain, ΔM5447, to infect THP-1 cells. Our results revealed that the lack of MSMEG_5447 not only impaired the growth of M. smegmatis in 7H9 medium but also reduced the resistance of M. smegmatis against lysozyme and acidic stress in vitro. Macrophage infection assay showed that ΔM5447 displayed attenuated growth in macrophages at 24 h post-infection. The production of TNF-α and IL-6 and the activation of transcription factor NF-κB were decreased in ΔM5447-infected macrophages, which were further confirmed by transcriptomic analysis. Moreover, ΔM5447 failed to inhibit phagosome–lysosome fusion in macrophages. These findings revealed that PMT played a role in modulating the innate immune responses of the host, which broaden our understanding for functions of protein O-mannosylation in mycobacterium–host interaction.

scholarly journals Melatonin Maintains Macrophage M1 Phenotype to Reverse LPS-stimulated Tumor Immune Tolerance

2020 ◽  
Author(s):  
Yukun Lin ◽  
Mengdi Zhang ◽  
Lin Zhou ◽  
Yuehua Wang ◽  
Mengqi Wang ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Immune Tolerance ◽  
Bacterial Infections ◽  
Macrophage Polarization ◽  
Surface Lipid ◽  
Lps Challenge ◽  
Stat3 Signaling ◽  
M1 Phenotype ◽  
M2 Phenotype

Abstract Background: Lipopolysaccharide (LPS) is a potent trigger of macrophage-mediated inflammation and its repeated stimulation results in immune tolerance. This study is to explore the cellular mechanisms of LPS-mediated tumor immune tolerance and to investigate whether melatonin can reverse this tolerance. Methods: The effect of melatonin and LPS on macrophages was assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The tumor-preventing effect of melatonin and LPS were evaluated in the urethane-induced lung carcinoma model and in the H22 liver cancer allograft model. Immunofluorescence, immunohistochemistry and ELISA were used to examine protein expression. The related targets and pathways of melatonin were predicted by comprehensive bioinformatics, and the clinical association of bacterial infections and survival was evaluated in cancer patients by meta-analysis.Results: In vitro，Raw264.7 macrophages were polarized toward the M1 phenotype by single LPS administration but toward the M2 phenotype by repeated LPS administration. Interestingly, combination treatment with repeated LPS and 10 µM melatonin prevented macrophage polarization toward the M2-like phenotype and exerted lasting antitumor efficacy. In the urethane-induced lung carcinoma model, repeated LPS administration stimulated macrophage polarization toward the M2 phenotype and promoted lung carcinogenesis, which was abrogated by macrophage depletion, while melatonin alone or in combination with repeated LPS challenge restored M1-like macrophages and prevented carcinogenesis. In the H22 liver cancer allograft model, melatonin maintained the macrophage phenotype and promoted the tumor-suppressing effect of repeated LPS challenge. Furthermore, we found that macrophages repeatedly stimulated with LPS had a high level of surface lipid rafts that mediated PI3K/AKT and JAK2/STAT3 signaling and prevented both LPS sensitivity and immune response by self-expression of PD-L1 and surface expression of PD-1 receptor on NK cells, whereas melatonin decreased surface lipid rafts and PI3K/AKT and JAK2/STAT3 signaling. Finally, we conducted a comprehensive bioinformatics analysis of melatonin-relevant targets and pathways involved in M2 macrophage polarization and evaluated the clinical associations of bacterial infections and survival in cancer patients. Conclusions: This study suggests a function of melatonin in regulating macrophage polarization to maintain LPS-stimulated tumor immune surveillance.

scholarly journals LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8

2021 ◽  
Author(s):  
Ryan Allen ◽  
Danielle Michell ◽  
Ashley Cavnar ◽  
Wanying Zhu ◽  
Neil Makhijani ◽  
...  
Keyword(s):  
Small Rnas ◽  
Disease Burden ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesions ◽  
Competitive Antagonism ◽  
Inflammatory Activation ◽  
Macrophage Phenotypes ◽  
Inflammatory Macrophage

Abstract Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the natural factors that instigate this polarization are largely unknown. Here, we demonstrate that microbial small RNAs (msRNA) are enriched on LDL and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the ribonucleic acid sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids (nt-LNA) was found to prevent nLDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.

scholarly journals Human Enteric Defensin 5 Promotes Shigella Infection of Macrophages

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Dan Xu ◽  
Chongbing Liao ◽  
Jiu Xiao ◽  
Kun Fang ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Protective Factor ◽  
Antimicrobial Activities ◽  
The Status ◽  
Host Defense Peptide ◽  
Type 3 Secretion System ◽  
Type 3

ABSTRACT Human α-defensins are 3- to 5-kDa disulfide-bridged peptides with a multitude of antimicrobial activities and immunomodulatory functions. Recent studies show that human enteric α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, aids the highly infectious enteropathogen Shigella in breaching the intestinal epithelium in vitro and in vivo. Whether and how HD5 influences Shigella infection of resident macrophages following its invasion of the intestinal epithelium remain poorly understood. Here, we report that HD5 greatly promoted phagocytosis of Shigella by macrophages by targeting the bacteria to enhance bacterium-to-cell contacts in a structure- and sequence-dependent fashion. Subsequent intracellular multiplication of phagocytosed Shigella led to massive necrotic cell death and release of the bacteria. HD5-promoted phagocytosis of Shigella was independent of the status of the type 3 secretion system. Furthermore, HD5 neither inhibited nor enhanced phagosomal escape of Shigella. Collectively, these findings confirm a potential pathogenic role of HD5 in Shigella infection of not only epithelial cells but also macrophages, illuminating how an enteropathogen exploits a host protective factor for virulence and infection.

scholarly journals Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification

2019 ◽  
Author(s):  
Sherine E. Thomas ◽  
Andrew J. Whitehouse ◽  
Karen Brown ◽  
Juan M. Belardinelli ◽  
Ramanuj Lahiri ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Protein Translation ◽  
Mycobacterium Abscessus ◽  
Trna Modification ◽  
Macrophage Infection ◽  
Reading Frame ◽  
New Class ◽  
Translational Frameshift ◽  
Fragment Library

AbstractTranslational frameshift errors are often deleterious to the synthesis of functional proteins as they lead to the production of truncated or inactive proteins. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and has been identified as a therapeutic target for several bacterial infections. Here we validate TrmD as a target inMycobacterium abscessusand describe the application of a structure-guided fragment-based drug discovery approach for the design of a new class of inhibitors against this enzyme. A fragment library screening followed by structure-guided chemical elaboration of hits led to the development of compounds with potentin vitroTrmD inhibitory activity. Several of these compounds exhibit activity against planktonicM. abscessus and Mycobacterium tuberculosis.The compounds were further active in macrophage infection models againstMycobacterium lepraeandM. abscessussuggesting the potential for novel broad-spectrum mycobacterial drugs.

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