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1.
Cell ; 184(16): 4154-4167.e12, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34324837

RESUMEN

Environmental light cycles entrain circadian feeding behaviors in animals that produce rhythms in exposure to foodborne bacteria. Here, we show that the intestinal microbiota generates diurnal rhythms in innate immunity that synchronize with feeding rhythms to anticipate microbial exposure. Rhythmic expression of antimicrobial proteins was driven by daily rhythms in epithelial attachment by segmented filamentous bacteria (SFB), members of the mouse intestinal microbiota. Rhythmic SFB attachment was driven by the circadian clock through control of feeding rhythms. Mechanistically, rhythmic SFB attachment activated an immunological circuit involving group 3 innate lymphoid cells. This circuit triggered oscillations in epithelial STAT3 expression and activation that produced rhythmic antimicrobial protein expression and caused resistance to Salmonella Typhimurium infection to vary across the day-night cycle. Thus, host feeding rhythms synchronize with the microbiota to promote rhythms in intestinal innate immunity that anticipate exogenous microbial exposure.


Asunto(s)
Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Microbioma Gastrointestinal , Inmunidad Innata , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Adhesión Bacteriana , Adhesión Celular , Células Epiteliales/microbiología , Conducta Alimentaria , Intestino Delgado/microbiología , Intestino Delgado/ultraestructura , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Muramidasa/metabolismo , Proteínas Asociadas a Pancreatitis/metabolismo , Factor de Transcripción STAT3/metabolismo , Salmonelosis Animal/microbiología , Transducción de Señal
2.
Cell ; 183(3): 650-665.e15, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-33031742

RESUMEN

Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.


Asunto(s)
Endocannabinoides/metabolismo , Enterobacteriaceae/patogenicidad , Animales , Ácidos Araquidónicos/química , Ácidos Araquidónicos/metabolismo , Adhesión Bacteriana , Proteínas Bacterianas/metabolismo , Sistemas de Secreción Bacterianos/metabolismo , Citrobacter rodentium/patogenicidad , Colon/microbiología , Colon/patología , Endocannabinoides/química , Infecciones por Enterobacteriaceae/microbiología , Femenino , Microbioma Gastrointestinal , Glicéridos/química , Glicéridos/metabolismo , Células HeLa , Interacciones Huésped-Patógeno , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monoacilglicerol Lipasas/metabolismo , Salmonella/patogenicidad , Virulencia
3.
Cell ; 177(3): 683-696.e18, 2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-30929902

RESUMEN

Microbiota and intestinal epithelium restrict pathogen growth by rapid nutrient consumption. We investigated how pathogens circumvent this obstacle to colonize the host. Utilizing enteropathogenic E. coli (EPEC), we show that host-attached bacteria obtain nutrients from infected host cell in a process we termed host nutrient extraction (HNE). We identified an inner-membrane protein complex, henceforth termed CORE, as necessary and sufficient for HNE. The CORE is a key component of the EPEC injectisome, however, here we show that it supports the formation of an alternative structure, composed of membranous nanotubes, protruding from the EPEC surface to directly contact the host. The injectisome and flagellum are evolutionarily related, both containing conserved COREs. Remarkably, CORE complexes of diverse ancestries, including distant flagellar COREs, could rescue HNE capacity of EPEC lacking its native CORE. Our results support the notion that HNE is a widespread virulence strategy, enabling pathogens to thrive in competitive niches.


Asunto(s)
Escherichia coli Enteropatógena/patogenicidad , Proteínas de Escherichia coli/metabolismo , Nutrientes/metabolismo , Aminoácidos/metabolismo , Adhesión Bacteriana/fisiología , Escherichia coli Enteropatógena/crecimiento & desarrollo , Escherichia coli Enteropatógena/metabolismo , Fluoresceínas/metabolismo , Células HeLa , Humanos , Proteínas de la Membrana/metabolismo , Microscopía Electrónica de Rastreo , Microscopía Fluorescente
4.
Cell ; 174(1): 143-155.e16, 2018 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-29779947

RESUMEN

Neisseria meningitidis, a bacterium responsible for meningitis and septicemia, proliferates and eventually fills the lumen of blood capillaries with multicellular aggregates. The impact of this aggregation process and its specific properties are unknown. We first show that aggregative properties are necessary for efficient infection and study their underlying physical mechanisms. Micropipette aspiration and single-cell tracking unravel unique features of an atypical fluidized phase, with single-cell diffusion exceeding that of isolated cells. A quantitative description of the bacterial pair interactions combined with active matter physics-based modeling show that this behavior relies on type IV pili active dynamics that mediate alternating phases of bacteria fast mutual approach, contact, and release. These peculiar fluid properties proved necessary to adjust to the geometry of capillaries upon bacterial proliferation. Intermittent attractive forces thus generate a fluidized phase that allows for efficient colonization of the blood capillary network during infection.


Asunto(s)
Adhesión Bacteriana/fisiología , Capilares/microbiología , Fimbrias Bacterianas/fisiología , Neisseria meningitidis/patogenicidad , Animales , Carga Bacteriana , Capilares/patología , Endotelio/metabolismo , Endotelio/microbiología , Endotelio/patología , Femenino , Proteínas Fimbrias/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones SCID , Microscopía Confocal , Neisseria meningitidis/fisiología , Trasplante de Piel , Tensión Superficial , Imagen de Lapso de Tiempo , Trasplante Heterólogo
5.
Cell ; 161(5): 988-997, 2015 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-26000479

RESUMEN

In the wild, bacteria are predominantly associated with surfaces as opposed to existing as free-swimming, isolated organisms. They are thus subject to surface-specific mechanics, including hydrodynamic forces, adhesive forces, the rheology of their surroundings, and transport rules that define their encounters with nutrients and signaling molecules. Here, we highlight the effects of mechanics on bacterial behaviors on surfaces at multiple length scales, from single bacteria to the development of multicellular bacterial communities such as biofilms.


Asunto(s)
Escherichia coli/fisiología , Pseudomonas aeruginosa/fisiología , Adhesión Bacteriana , Biopelículas , Transporte Biológico , Fenómenos Biomecánicos , Escherichia coli/citología , Locomoción , Pseudomonas aeruginosa/citología
6.
Cell ; 163(2): 273-4, 2015 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-26451476

RESUMEN

Gut bacteria are known to affect immune cell development, but most intestinal lymphocytes have no direct contact with luminal bacteria. Two studies by Atarashi et al. and Sano et al. shed light on how bacterial adhesion can cue intestinal epithelial cells to direct differentiation of gut T cells.


Asunto(s)
Adhesión Bacteriana , Citrobacter rodentium/fisiología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli O157/fisiología , Microbioma Gastrointestinal , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Intestinos/inmunología , Receptores de Interleucina/metabolismo , Proteína Amiloide A Sérica/metabolismo , Células Th17/inmunología , Animales , Humanos
7.
Cell ; 163(2): 367-80, 2015 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-26411289

RESUMEN

Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.


Asunto(s)
Adhesión Bacteriana , Citrobacter rodentium/fisiología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli O157/fisiología , Mucosa Intestinal/inmunología , Células Th17/inmunología , Animales , Infecciones Bacterianas/inmunología , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Células Epiteliales/ultraestructura , Heces/microbiología , Humanos , Inmunoglobulina A/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Microscopía Electrónica de Rastreo , Ratas , Ratas Endogámicas F344 , Especificidad de la Especie
8.
Nature ; 618(7966): 733-739, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37344647

RESUMEN

Control of adhesion is a striking feature of living matter that is of particular interest regarding technological translation1-3. We discovered that entropic repulsion caused by interfacial orientational fluctuations of cholesterol layers restricts protein adsorption and bacterial adhesion. Moreover, we found that intrinsically adhesive wax ester layers become similarly antibioadhesive when containing small quantities (under 10 wt%) of cholesterol. Wetting, adsorption and adhesion experiments, as well as atomistic simulations, showed that repulsive characteristics depend on the specific molecular structure of cholesterol that encodes a finely balanced fluctuating reorientation at the interface of unconstrained supramolecular assemblies: layers of cholesterol analogues differing only in minute molecular variations showed markedly different interfacial mobility and no antiadhesive effects. Also, orientationally fixed cholesterol layers did not resist bioadhesion. Our insights provide a conceptually new physicochemical perspective on biointerfaces and may guide future material design in regulation of adhesion.


Asunto(s)
Adhesión Bacteriana , Colesterol , Entropía , Proteínas , Adsorción , Proteínas/química , Humectabilidad , Colesterol/química
9.
Immunity ; 48(6): 1070-1072, 2018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29924970

RESUMEN

Shigella pathogenesis has confounded researchers for years because of its narrow host selectivity and extraordinary infectious capability. In this issue of Immunity, Xu et al. (2018) identify a cunning mechanism whereby Shigella hijacks human α-defensin 5 to enhance its adhesion and subsequent invasion.


Asunto(s)
Adhesión Bacteriana , Disentería Bacilar , Humanos , Shigella , alfa-Defensinas
10.
Immunity ; 48(6): 1233-1244.e6, 2018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29858013

RESUMEN

Shigella is a Gram-negative bacterium that causes bacillary dysentery worldwide. It invades the intestinal epithelium to elicit intense inflammation and tissue damage, yet the underlying mechanisms of its host selectivity and low infectious inoculum remain perplexing. Here, we report that Shigella co-opts human α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, to enhance its adhesion to and invasion of mucosal tissues. HD5 promoted Shigella infection in vitro in a structure-dependent manner. Shigella, commonly devoid of an effective host-adhesion apparatus, preferentially targeted HD5 to augment its ability to colonize the intestinal epithelium through interactions with multiple bacterial membrane proteins. HD5 exacerbated infectivity and Shigella-induced pathology in a culture of human colorectal tissues and three animal models. Our findings illuminate how Shigella exploits innate immunity by turning HD5 into a virulence factor for infection, unveiling a mechanism of action for this highly proficient human pathogen.


Asunto(s)
Adhesión Bacteriana/fisiología , Disentería Bacilar/inmunología , Interacciones Huésped-Patógeno/fisiología , Shigella/patogenicidad , alfa-Defensinas , Animales , Humanos
11.
Immunity ; 49(1): 151-163.e5, 2018 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-29980437

RESUMEN

The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX3CR1+ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.


Asunto(s)
Receptor 1 de Quimiocinas CX3C/metabolismo , Microbioma Gastrointestinal/inmunología , Mucosa Intestinal/inmunología , Sistema Mononuclear Fagocítico/inmunología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Animales , Presentación de Antígeno , Adhesión Bacteriana/inmunología , Modelos Animales de Enfermedad , Femenino , Homeostasis , Tolerancia Inmunológica , Inmunidad Mucosa , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones , Células RAW 264.7
12.
Proc Natl Acad Sci U S A ; 121(17): e2315361121, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38621130

RESUMEN

Biofilms inhabit a range of environments, such as dental plaques or soil micropores, often characterized by noneven surfaces. However, the impact of surface irregularities on the population dynamics of biofilms remains elusive, as most experiments are conducted on flat surfaces. Here, we show that the shape of the surface on which a biofilm grows influences genetic drift and selection within the biofilm. We culture Escherichia coli biofilms in microwells with a corrugated bottom surface and observe the emergence of clonal sectors whose size corresponds to that of the corrugations, despite no physical barrier separating different areas of the biofilm. The sectors are remarkably stable and do not invade each other; we attribute this stability to the characteristics of the velocity field within the biofilm, which hinders mixing and clonal expansion. A microscopically detailed computer model fully reproduces these findings and highlights the role of mechanical interactions such as adhesion and friction in microbial evolution. The model also predicts clonal expansion to be limited even for clones with a significant growth advantage-a finding which we confirm experimentally using a mixture of antibiotic-sensitive and antibiotic-resistant mutants in the presence of sublethal concentrations of the antibiotic rifampicin. The strong suppression of selection contrasts sharply with the behavior seen in range expansion experiments in bacterial colonies grown on agar. Our results show that biofilm population dynamics can be affected by patterning the surface and demonstrate how a better understanding of the physics of bacterial growth can be used to control microbial evolution.


Asunto(s)
Antibacterianos , Biopelículas , Bacterias , Rifampin/farmacología , Escherichia coli/genética , Adhesión Bacteriana
13.
PLoS Pathog ; 20(9): e1012241, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39283948

RESUMEN

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of cases of infectious diarrhea annually, predominantly in children from low-middle income regions. Notably, in children, as well as volunteers challenged with ETEC, diarrheal severity is significantly increased in blood group A (bgA) individuals. EtpA, is a secreted glycoprotein adhesin that functions as a blood group A lectin to promote critical interactions between ETEC and blood group A glycans on intestinal epithelia for effective bacterial adhesion and toxin delivery. EtpA is highly immunogenic resulting in robust antibody responses following natural infection and experimental challenge of volunteers with ETEC. To understand how EtpA directs ETEC-blood group A interactions and stimulates adaptive immunity, we mutated EtpA, mapped its glycosylation by mass-spectrometry (MS), isolated polyclonal (pAbs) and monoclonal antibodies (mAbs) from vaccinated mice and ETEC-infected volunteers, and determined structures of antibody-EtpA complexes by cryo-electron microscopy. Both bgA and mAbs that inhibited EtpA-bgA interactions and ETEC adhesion, bound to the C-terminal repeat domain highlighting this region as crucial for ETEC pathogen-host interaction. MS analysis uncovered extensive and heterogeneous N-linked glycosylation of EtpA and cryo-EM structures revealed that mAbs directly engage these unique glycan containing epitopes. Finally, electron microscopy-based polyclonal epitope mapping revealed antibodies targeting numerous distinct epitopes on N and C-terminal domains, suggesting that EtpA vaccination generates responses against neutralizing and decoy regions of the molecule. Collectively, we anticipate that these data will inform our general understanding of pathogen-host glycan interactions and adaptive immunity relevant to rational vaccine subunit design.


Asunto(s)
Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Polisacáridos , Escherichia coli Enterotoxigénica/inmunología , Ratones , Animales , Polisacáridos/inmunología , Polisacáridos/metabolismo , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Humanos , Proteínas de Escherichia coli/inmunología , Glicosilación , Adhesinas de Escherichia coli/inmunología , Adhesinas de Escherichia coli/metabolismo , Anticuerpos Antibacterianos/inmunología , Adhesión Bacteriana/inmunología , Glicoproteínas de Membrana
14.
PLoS Pathog ; 20(9): e1012358, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39312573

RESUMEN

Bacterial biofilm formation and attachment to hosts are mediated by carbohydrate-binding lectins, exopolysaccharides, and their interactions in the extracellular matrix (ECM). During tomato infection Ralstonia pseudosolanacearum (Rps) GMI1000 highly expresses three lectins: LecM, LecF, and LecX. The latter two are uncharacterized. We evaluated the roles in bacterial wilt disease of LecF, a fucose-binding lectin, LecX, a xylose-binding lectin, and the Rps exopolysaccharide EPS I. Interestingly, single and double lectin mutants attached to tomato roots better and formed more biofilm under static conditions in vitro. Consistent with this finding, static bacterial aggregation was suppressed by heterologous expression of lecFGMI1000 and lecXGMI1000 in other Ralstonia strains that naturally lack these lectins. Crude ECM from a ΔlecF/X double mutant was more adhesive than the wild-type ECM, and LecF and LecX increased Rps attachment to ECM. The enhanced adhesiveness of the ΔlecF/X ECM could explain the double mutant's hyper-attachment in static conditions. Unexpectedly, mutating lectins decreased Rps attachment and biofilm viscosity under shear stress, which this pathogen experiences in plant xylem. LecF, LecX, and EPS I were all essential for biofilm development in xylem fluid flowing through cellulose-coated microfluidic channels. These results suggest that under shear stress, LecF and LecX increase Rps attachment by interacting with the ECM and plant cell wall components like cellulose. In static conditions such as on root surfaces and in clogged xylem vessels, the same lectins suppress attachment to facilitate pathogen dispersal. Thus, Rps lectins have a dual biological function that depends on the physical environment.


Asunto(s)
Biopelículas , Lectinas , Enfermedades de las Plantas , Polisacáridos Bacterianos , Ralstonia , Solanum lycopersicum , Biopelículas/crecimiento & desarrollo , Ralstonia/metabolismo , Ralstonia/fisiología , Solanum lycopersicum/microbiología , Solanum lycopersicum/metabolismo , Lectinas/metabolismo , Lectinas/genética , Polisacáridos Bacterianos/metabolismo , Enfermedades de las Plantas/microbiología , Adhesión Bacteriana/fisiología , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Raíces de Plantas/microbiología
15.
PLoS Pathog ; 20(9): e1012513, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39264911

RESUMEN

Porcine circovirus type 2 (PCV2) often causes disease through coinfection with other bacterial pathogens, including Glaesserella parasuis (G. parasuis), which causes high morbidity and mortality, but the role played by PCV2 and bacterial and host factors contributing to this process have not been defined. Bacterial attachment is assumed to occur via specific receptor-ligand interactions between adhesins on the bacterial cell and host proteins adsorbed to the implant surface. Mass spectrometry (MS) analysis of PCV2-infected swine tracheal epithelial cells (STEC) revealed that the expression of Extracellular matrix protein (ECM) Fibronectin (Fn) increased significantly on the infected cells surface. Importantly, efficient G. parasuis serotype 4 (GPS4) adherence to STECs was imparted by interactions with Fn. Furthermore, abrogation of adherence was gained by genetic knockout of Fn, Fn and Integrin ß1 antibody blocking. Fn is frequently exploited as a receptor for bacterial pathogens. To explore the GPS4 adhesin that interacts with Fn, recombinant Fn N-terminal type I and type II domains were incubated with GPS4, and the interacting proteins were pulled down for MS analysis. Here, we show that rare lipoprotein A (RlpA) directly interacts with host Fibronectin mediating GPS4 adhesion. Finally, we found that PCV2-induced Fibronectin expression and adherence of GPS4 were prevented significantly by TGF-ß signaling pathway inhibitor SB431542. Our data suggest the RlpA-Fn interaction to be a potentially promising novel therapeutic target to combat PCV2 and GPS4 coinfection.


Asunto(s)
Circovirus , Fibronectinas , Haemophilus parasuis , Enfermedades de los Porcinos , Tráquea , Animales , Porcinos , Fibronectinas/metabolismo , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/microbiología , Enfermedades de los Porcinos/metabolismo , Haemophilus parasuis/metabolismo , Circovirus/metabolismo , Circovirus/patogenicidad , Tráquea/virología , Tráquea/microbiología , Tráquea/metabolismo , Infecciones por Haemophilus/microbiología , Infecciones por Haemophilus/virología , Infecciones por Haemophilus/metabolismo , Adhesión Bacteriana , Serogrupo , Coinfección/virología , Coinfección/microbiología , Infecciones por Pasteurellaceae/veterinaria , Infecciones por Pasteurellaceae/virología , Infecciones por Pasteurellaceae/microbiología , Infecciones por Pasteurellaceae/metabolismo
16.
PLoS Pathog ; 20(10): e1012451, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39405360

RESUMEN

The ability of the attaching and effacing pathogens enterohaemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium to overcome colonisation resistance is reliant on a type 3 secretion system used to intimately attach to the colonic epithelium. This crucial virulence factor is encoded on a pathogenicity island known as the Locus of Enterocyte Effacement (LEE) but its expression is regulated by several core-genome encoded transcription factors. Here, we unveil that the core transcription factor PdhR, traditionally known as a regulator of central metabolism in response to cellular pyruvate levels, is a key activator of the LEE. Through genetic and molecular analyses, we demonstrate that PdhR directly binds to a specific motif within the LEE master regulatory region, thus activating type 3 secretion directly and enhancing host cell adhesion. Deletion of pdhR in EHEC significantly impacted the transcription of hundreds of genes, with pathogenesis and protein secretion emerging as the most affected functional categories. Furthermore, in vivo studies using C. rodentium, a murine model for EHEC infection, revealed that PdhR is essential for effective host colonization and maximal LEE expression within the host. Our findings provide new insights into the complex regulatory networks governing bacterial pathogenesis. This research highlights the intricate relationship between virulence and metabolic processes in attaching and effacing pathogens, demonstrating how core transcriptional regulators can be co-opted to control virulence factor expression in tandem with the cell's essential metabolic circuitry.


Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae , Escherichia coli Enterohemorrágica , Regulación Bacteriana de la Expresión Génica , Factores de Virulencia , Citrobacter rodentium/genética , Citrobacter rodentium/patogenicidad , Animales , Ratones , Escherichia coli Enterohemorrágica/patogenicidad , Escherichia coli Enterohemorrágica/genética , Escherichia coli Enterohemorrágica/metabolismo , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/genética , Humanos , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/metabolismo , Carbono/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Adhesión Bacteriana , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética
17.
Bioessays ; 46(11): e2400160, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39301984

RESUMEN

The actin cytoskeleton is a key cellular structure subverted by pathogens to infect and survive in or on host cells. Several pathogenic strains of Escherichia coli, such as enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), developed a unique mechanism to remodel the actin cytoskeleton that involves the assembly of actin filament-rich pedestals beneath the bacterial attachment sites. Actin pedestal assembly is driven by bacterial effectors injected into the host cells, and this structure is important for EPEC and EHEC colonization. While the interplay between bacterial effectors and the actin polymerization machinery of host cells is well-understood, how other mechanisms of actin filament remodelling regulate pedestal assembly and bacterial attachment are poorly investigated. This review discusses the gaps in our understanding of the complexity of the actin cytoskeletal remodelling during EPEC and EHEC infection. We describe possible roles of actin depolymerizing, crosslinking and motor proteins in pedestal dynamics, and bacterial interactions with the host cells. We also discuss the biological significance of pedestal assembly for bacterial infection.


Asunto(s)
Citoesqueleto de Actina , Escherichia coli Enterohemorrágica , Escherichia coli Enteropatógena , Interacciones Huésped-Patógeno , Humanos , Escherichia coli Enteropatógena/patogenicidad , Escherichia coli Enteropatógena/metabolismo , Escherichia coli Enterohemorrágica/patogenicidad , Escherichia coli Enterohemorrágica/metabolismo , Citoesqueleto de Actina/metabolismo , Interacciones Huésped-Patógeno/fisiología , Animales , Adhesión Bacteriana/fisiología , Citoesqueleto/metabolismo , Actinas/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo
18.
Proc Natl Acad Sci U S A ; 120(41): e2307718120, 2023 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-37788310

RESUMEN

Fluid flow is thought to prevent bacterial adhesion, but some bacteria use adhesins with catch bond properties to enhance adhesion under high shear forces. However, many studies on bacterial adhesion either neglect the influence of shear force or use shear forces that are not typically found in natural systems. In this study, we use microfluidics and single-cell imaging to examine how the human pathogen Pseudomonas aeruginosa interacts with surfaces when exposed to shear forces typically found in the human body (0.1 pN to 10 pN). Through cell tracking, we demonstrate that the angle between the cell and the surface predicts if a cell will depart the surface. We discover that at lower shear forces, type IV pilus retraction tilts cells away from the surface, promoting surface departure. Conversely, we show that higher shear forces counterintuitively enhance adhesion by counteracting type IV pilus retraction-dependent cell tilting. Thus, our results reveal that P. aeruginosa exhibits behavior reminiscent of a catch bond, without having a specific adhesin that is enhanced by force. Instead, P. aeruginosa couples type IV pilus dynamics and cell geometry to tune adhesion to its mechanical environment, which likely provides a benefit in dynamic host environments.


Asunto(s)
Fimbrias Bacterianas , Pseudomonas aeruginosa , Humanos , Pseudomonas aeruginosa/metabolismo , Fimbrias Bacterianas/metabolismo , Adhesinas Bacterianas/metabolismo , Adhesión Bacteriana , Fenómenos Físicos , Proteínas Fimbrias/metabolismo
19.
Mol Microbiol ; 122(2): 255-270, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-39030901

RESUMEN

The flagellar MS-ring, uniquely constituted by FliF, is essential for flagellar biogenesis and functionality in several bacteria. The aim of this study was to dissect the role of FliF in the Gram-positive and peritrichously flagellated Bacillus cereus. We demonstrate that fliF forms an operon with the upstream gene fliE. In silico analysis of B. cereus ATCC 14579 FliF identifies functional domains and amino acid residues that are essential for protein functioning. The analysis of a ΔfliF mutant of B. cereus, constructed in this study using an in frame markerless gene replacement method, reveals that the mutant is unexpectedly able to assemble flagella, although in reduced amounts compared to the parental strain. Nevertheless, motility is completely abolished by fliF deletion. FliF deprivation causes the production of submerged biofilms and affects the ability of B. cereus to adhere to gastrointestinal mucins. We additionally show that the fliF deletion does not compromise the secretion of the three components of hemolysin BL, a toxin secreted through the flagellar type III secretion system. Overall, our findings highlight the important role of B. cereus FliF in flagella-related functions, being the protein required for complete flagellation, motility, mucin adhesion, and pellicle biofilms.


Asunto(s)
Bacillus cereus , Proteínas Bacterianas , Biopelículas , Flagelos , Operón , Bacillus cereus/metabolismo , Bacillus cereus/genética , Flagelos/metabolismo , Flagelos/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Biopelículas/crecimiento & desarrollo , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Adhesión Bacteriana , Regulación Bacteriana de la Expresión Génica , Eliminación de Gen , Proteínas de la Membrana
20.
Mol Microbiol ; 121(5): 833-849, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38308563

RESUMEN

The nosocomial bacterium Acinetobacter baumannii is protected from antibiotic treatment by acquiring antibiotic resistances and by forming biofilms. Cell attachment, one of the first steps in biofilm formation, is normally induced by environmental metabolites. We hypothesized that vanillic acid (VA), the oxidized form of vanillin and a widely available metabolite, may play a role in A. baumannii cell attachment. We first discovered that A. baumannii actively breaks down VA through the evolutionarily conserved vanABKP genes. These genes are under the control of the repressor VanR, which we show binds directly to VanR binding sites within the vanABKP genes bidirectional promoter. VA in turn counteracts VanR inhibition. We identified a VanR binding site and searched for it throughout the genome, especially in pili encoding promoter genes. We found a VanR binding site in the pilus encoding csu operon promoter and showed that VanR binds specifically to it. As expected, a strain lacking VanR overproduces Csu pili and makes robust biofilms. Our study uncovers the role that VA plays in facilitating the attachment of A. baumannii cells to surfaces, a crucial step in biofilm formation. These findings provide valuable insights into a previously obscure catabolic pathway with significant clinical implications.


Asunto(s)
Acinetobacter baumannii , Adhesión Bacteriana , Proteínas Bacterianas , Biopelículas , Fimbrias Bacterianas , Regulación Bacteriana de la Expresión Génica , Regiones Promotoras Genéticas , Ácido Vanílico , Acinetobacter baumannii/metabolismo , Acinetobacter baumannii/genética , Acinetobacter baumannii/efectos de los fármacos , Ácido Vanílico/metabolismo , Ácido Vanílico/farmacología , Biopelículas/crecimiento & desarrollo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Fimbrias Bacterianas/metabolismo , Fimbrias Bacterianas/genética , Operón , Sitios de Unión , Benzaldehídos/metabolismo , Benzaldehídos/farmacología
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