scholarly journals Mycobacterial surface-associated ESX-1 virulence factors play a role in mycobacterial adherence and invasion into lung epithelial cells

2020 ◽  
Author(s):  
Yanqing Bao ◽  
Qi Zhang ◽  
Lin Wang ◽  
Javier Aguilera ◽  
Salvador Vazquez Reyes ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Gene Knockout ◽  
Tween 80 ◽  
Cytolytic Activity ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Bacterial Surface ◽  
Surface Receptors ◽  
Neutral Ph ◽  
Lung Epithelial

AbstractEsxA has long been recognized as an important virulence factor of Mycobacterium tuberculosis (Mtb) that plays an essential role in Mtb cytosolic translocation by penetrating phagosomal membranes with its acidic pH-dependent membrane permeabilizing activity (MPA). Since the reported cytolytic activity of EsxA at neutral pH is controversial, in the present study we have obtained direct evidence that it is the residual ASB-14, a detergent used in EsxA purification, but not EsxA that causes cytolysis at neutral pH. Besides, we have also found that the exogenously added EsxA was internalized into lung epithelial cells (WI-26) and inserted into the host membranes, and these processes could be blocked by cytochalasin D and bafilomycin A. This indicates that EsxA is bound by host surface receptors and internalized into acidic endosomal compartments. This observation has intrigued us to investigate the role of EsxA in mycobacterial adherence and invasion in host cells. Interestingly, compared to the Mycobacterium marinum (Mm) wild type strain, the Mm strain with deletion of the esxBA operon (MmΔEsxA:B) had a lower adherence but a higher invasion in WI-26 cells. More interestingly, either inducible knockdown of EsxAB or removal of the bacterial surface-associated EsxAB by Tween-80 exhibited opposite results compared to gene knockout. Finally, the surface-associated EsxA is correlated to mycobacterial virulence. Together, the present study has shown for the first time that EsxA is internalized into the host cells and inserts into the host membranes, and mycobacterial surface-associated EsxAB plays an important role in mycobacterial adherence and invasion in host cells, which warrants further investigation.

scholarly journals Membrane Insertion of Mycobacterium tuberculosis EsxA in Cultured Lung Epithelial Cells

2020 ◽  
Author(s):  
Qi Zhang ◽  
Javier Aguilera ◽  
Salvador Vazquez Reyes ◽  
Jianjun Sun
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Epithelial Cells ◽  
Cytolytic Activity ◽  
Current Data ◽  
Lung Epithelial Cells ◽  
Neutral Ph ◽  
Subcellular Compartments ◽  
Lung Epithelial ◽  
Important Virulence Factor ◽  
First Time

AbstractEsxA has long been recognized as an important virulence factor of Mycobacterium tuberculosis (Mtb) that plays an essential role in Mtb cytosolic translocation presumably by penetrating phagosomal membranes with its acidic pH-dependent membrane permeabilizing activity (MPA). However, current data suggest that the observed cytolytic activity of EsxA at neutral pH is due to contamination of ASB-14, a detergent used in EsxA protein purification, and the role of EsxA MPA in Mtb cytosolic translocation is also questionable. Here, we have obtained evidence that it is ASB-14, not EsxA that causes cytolysis at neutral pH. Quantitative liquid chromatography and mass spectrometry showed that even after gel filtration, dialysis, or passing through detergent removal column, the remaining ASB-14 in the EsxA protein solution was still at a concentration enough to kill cultured lung epithelial cells. When treated with trypsin or proteinase K, the digested EsxA protein solution with ASB-14 was still cytotoxic. Interestingly, however, we have found that the exogenously added EsxA is endocytosed into lung epithelial cells and inserts into the host membranes within acidic subcellular compartments, which can be blocked by cytochalasin D and bafilomycin A. It is for the first time EsxA is found to insert into the host membranes within acidic subcellular compartments.ImportanceEsxA has long been recognized as an important virulence factor of Mycobacterium tuberculosis (Mtb) that plays an essential role in Mtb virulence. However, current data regarding to its role in Mtb virulence are controversial. Here, we have obtained evidence showing that the cytolytic activity of EsxA at neutral pH is due to contamination of ASB-14, a detergent used in EsxA preparation. Moreover, it is for the first time we have found that EsxA protein is endocytosed into lung epithelial cells and inserts into the host membranes within acidic subcellular compartments, implicating an important role of the acidic pH-dependent membrane permeabilizing activity of EsxA in Mtb virulence.

scholarly journals Host DNA Repair Proteins in Response toPseudomonas aeruginosain Lung Epithelial Cells and in Mice

2010 ◽  
Vol 79 (1) ◽  
pp. 75-87 ◽  
Author(s):  
Min Wu ◽  
Huang Huang ◽  
Weidong Zhang ◽  
Shibichakravarthy Kannan ◽  
Andrew Weaver ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Epithelial Cells ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Myeloperoxidase Activity ◽  
Gram Negative ◽  
Lung Epithelial ◽  
Dna Repair Proteins

ABSTRACTAlthough DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacteriumPseudomonas aeruginosasignificantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection withP. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate thatP. aeruginosainfection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response toP. aeruginosainfection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections.

scholarly journals Peroxisome Proliferator-Activated Receptors Mediate Host Cell Proinflammatory Responses to Pseudomonas aeruginosa Autoinducer

2008 ◽  
Vol 190 (13) ◽  
pp. 4408-4415 ◽  
Author(s):  
Aruna Jahoor ◽  
Rashila Patel ◽  
Amanda Bryan ◽  
Catherine Do ◽  
Jay Krier ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Transcriptional Activity ◽  
Expression Patterns ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Pparγ Agonist ◽  
Lung Epithelial

ABSTRACT The pathogenic bacterium Pseudomonas aeruginosa utilizes the 3-oxododecanoyl homoserine lactone (3OC12-HSL) autoinducer as a signaling molecule to coordinate the expression of virulence genes through quorum sensing. 3OC12-HSL also affects responses in host cells, including the upregulation of genes encoding inflammatory cytokines. This proinflammatory response may exacerbate underlying disease during P. aeruginosa infections. The specific mechanism(s) through which 3OC12-HSL influences host responses is unclear, and no mammalian receptors for 3OC12-HSL have been identified to date. Here, we report that 3OC12-HSL increases mRNA levels for a common panel of proinflammatory genes in murine fibroblasts and human lung epithelial cells. To identify putative 3OC12-HSL receptors, we examined the expression patterns of a panel of nuclear hormone receptors in these two cell lines and determined that both peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) and PPARγ were expressed. 3OC12-HSL functioned as an agonist of PPARβ/δ transcriptional activity and an antagonist of PPARγ transcriptional activity and inhibited the DNA binding ability of PPARγ. The proinflammatory effect of 3OC12-HSL in lung epithelial cells was blocked by the PPARγ agonist rosiglitazone, suggesting that 3OC12-HSL and rosiglitazone are mutually antagonistic negative and positive regulators of PPARγ activity, respectively. These data identify PPARβ/δ and PPARγ as putative mammalian 3OC12-HSL receptors and suggest that PPARγ agonists may be employed as anti-inflammatory therapeutics for P. aeruginosa infections.

scholarly journals The Novel Fibrinogen-Binding Protein FbsB Promotes Streptococcus agalactiae Invasion into Epithelial Cells

2004 ◽  
Vol 72 (6) ◽  
pp. 3495-3504 ◽  
Author(s):  
Heike Gutekunst ◽  
Bernhard J. Eikmanns ◽  
Dieter J. Reinscheid
Keyword(s):  
Epithelial Cells ◽  
Streptococcus Agalactiae ◽  
Deletion Mutant ◽  
Binding Protein ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Bacterial Invasion ◽  
Fibrinogen Binding ◽  
Lung Epithelial

ABSTRACT Streptococcus agalactiae is a major cause of bacterial sepsis and meningitis in human newborns. The interaction of S. agalactiae with host proteins and the entry into host cells thereby represent important virulence traits of these bacteria. The present report describes the identification of the fbsB gene, encoding a novel fibrinogen-binding protein that plays a crucial role in the invasion of S. agalactiae into human cells. In Western blots and enzyme-linked immunosorbent assay (ELISA) experiments, the FbsB protein was demonstrated to interact with soluble and immobilized fibrinogen. Binding studies showed the N-terminal 388 residues of FbsB and the Aα-subunit of human fibrinogen to recognize each other. By reverse transcription (RT)-PCR, the fbsB gene was shown to be cotranscribed with the gbs0851 gene in S. agalactiae. Deletion of the fbsB gene in the genome of S. agalactiae did not influence the binding of the bacteria to fibrinogen, suggesting that FbsB does not participate in the attachment of S. agalactiae to fibrinogen. In tissue culture experiments, however, the fbsB deletion mutant was severely impaired in its invasion into lung epithelial cells. Bacterial invasion could be reestablished by introducing the fbsB gene on a shuttle plasmid into the fbsB deletion mutant. Furthermore, treatment of lung epithelial cells with FbsB fusion protein blocked S. agalactiae invasion of epithelial cells in a dose-dependent fashion. These results suggest an important role of the FbsB protein in the overall process of host cell entry by S. agalactiae.

scholarly journals Francisella tularensis Invasion of Lung Epithelial Cells

2008 ◽  
Vol 76 (7) ◽  
pp. 2833-2842 ◽  
Author(s):  
Robin R. Craven ◽  
Joshua D. Hall ◽  
James R. Fuller ◽  
Sharon Taft-Benz ◽  
Thomas H. Kawula
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Francisella Tularensis ◽  
Bacterial Pathogen ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Epithelial Cell Line ◽  
Bacterial Surface ◽  
Lung Epithelial

ABSTRACT Francisella tularensis, a gram-negative facultative intracellular bacterial pathogen, causes disseminating infections in humans and other mammalian hosts. Macrophages and other monocytes have long been considered the primary site of F. tularensis replication in infected animals. However, recently it was reported that F. tularensis also invades and replicates within alveolar epithelial cells following inhalation in a mouse model of tularemia. TC-1 cells, a mouse lung epithelial cell line, were used to study the process of F. tularensis invasion and intracellular trafficking within nonphagocytic cells. Live and paraformaldehyde-fixed F. tularensis live vaccine strain organisms associated with, and were internalized by, TC-1 cells at similar frequencies and with indistinguishable differences in kinetics. Inhibitors of microfilament and microtubule activity resulted in significantly decreased F. tularensis invasion, as did inhibitors of phosphatidylinositol 3-kinase and tyrosine kinase activity. Collectively, these results suggest that F. tularensis epithelial cell invasion is mediated by a preformed ligand on the bacterial surface and driven entirely by host cell processes. Once internalized, F. tularensis-containing endosomes associated with early endosome antigen 1 (EEA1) followed by lysosome-associated membrane protein 1 (LAMP-1), with peak coassociation frequencies occurring at 30 and 120 min postinoculation, respectively. By 2 h postinoculation, 70.0% (± 5.5%) of intracellular bacteria were accessible to antibody delivered to the cytoplasm, indicating vacuolar breakdown and escape into the cytoplasm.

scholarly journals 969. GRP78 and Integrin β1/α3 Play Disparate Roles in Epithelium Invasion During Mucormycosis

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S37-S37
Author(s):  
Abdullah Alqarihi ◽  
Teclegiorgis Gebremariam ◽  
Sondus Alkhazraji ◽  
Priya Uppuluri ◽  
John E Edwards ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Host Cell ◽  
Cell Injury ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Β1 Integrin ◽  
Dependent Manner ◽  
Cell Receptors ◽  
Lung Epithelial

Abstract Background Mucormycosis is a lethal fungal infection caused by Mucorales. Inhalation is the major route of entry resulting in rhino-orbital or pulmonary infections. Nasal and lung epithelial cells are among the first cells that encounter inhaled spores. We sought to identify the nasal and lung epithelial cell receptors interacting with Rhizopus during tissue invasion. Methods R. delemar-induced nasal (CCL30) or lung epithelial (A549) cell invasion was studied using Uvetix dye, while host cell injury was determined by 51Cr-release assay. Epithelial cell receptors were isolated by affinity purification of biotinylated host cell membrane proteins and then identified by LC-MS. Blocking antibodies were used to confirm the role of the receptor in the invasion/injury assays. For survival studies, ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on day-2, +3, and +8. Mice were infected with 2.5 × 105R. delemar spores intratracheally, and then treated with a single dose of 100 μg (i.p.) anti-β1 integrin antibody. Placebo mice received 100 µg of isotype-matching IgG. Results R. delemar invades and damages both cells in a time-dependent manner. Nasal Grp78 and alveolar β1α3 integrin were isolated as putative receptors. Polyclonal antibodies targeting Grp78 or β1 integrin blocked R. delemar-mediated endocytosis of nasal and lung cells by ~70%. Also, anti-Grp78 and anti-β1 integrin antibodies blocked R. delemar-induced nasal and lung cell injury by ~60% (P < 0.001). Elevated glucose, iron, or BHB increased the expression of nasal Grp78 by 2- to 6-fold which resulted in enhanced R. delemar-mediated invasion and injury of host cells, while having no effect on β1α3 integrin expression. Finally, β1 antibodies protected mice from mucormycosis with median survival time of 16 days for treated mice versus 11 days for placebo and an overall survival of 30% versus 0% for placebo mice (P = 0.0006). Conclusion The upregulation of Grp78 on nasal epithelial cells in response to physiological elevated concentrations of glucose, iron, and BHB and subsequent enhanced invasion likely to provide insights into why diabetics in ketoacidosis are infected with the rhino-orbital mucormycosis rather than pulmonary disease. Our studies also provide a foundation for therapeutic interventions against mucormycosis. Disclosures All authors: No reported disclosures.

scholarly journals Pulmonary pathology of COVID-19

2020 ◽  
Vol 7 (3) ◽  
pp. 79-83
Author(s):  
Attapon Cheepsattayakorn ◽  
Ruangrong Cheepsattayakorn
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Role Playing ◽  
Lymphoid Cells ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Spike Protein ◽  
Main Mode ◽  
Apical Side ◽  
Lung Epithelial

Currently, animal-to-human transmission of SARS-CoV-2 (COVID-19) has not yet been confirmed, whereas the main mode of transmission is human-to-human. Droplets are the main route of human-to-human transmission, whereas aerosols could be another route in addition to stool-based transmission. Currently, no evidence is available to indicate intrauterine vertical transmission of SARS-CoV-2 (COVID-19) in pregnant women. In the host, the life cycle of coronavirus consists of 5 steps: 1) attachment, 2) penetration, 3) biosynthesis, 4) maturation, and 5) release. Once viruses bind to host receptors (attachment), they enter host cells, particularly type II pneumocytes via endocytosis or membrane fusion (penetration). Once viral contents are released inside the host cells, viral RNA enters the host’s nucleus for replication and making viral proteins (biosynthesis). New viral particles are produced (maturation) and released. Spike protein of coronaviruses which determines the diversity of coronaviruses and host tropism is composed of a transmembrane trimetric glycoprotein protruding from the viral surface. Structural and functional studies demonstrated that the spike protein the of coronaviruses can bind to angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV. ACE2 expression is high in lung (high expression on lung epithelial cells), heart, ileum, and kidney. The lungs of severe COVID-19 patients demonstrate infiltration of a large number of inflammatory cells. Due to high ACE2 expression on the apical side of lung epithelial cells in the alveolar space, SARS-CoV-2 (COVID-19) can enter and destroy lung epithelial cells. Significant ACE2 expression on innate lymphoid cells (ILC)2, ILC3, and endothelial cells is also demonstrated. Pulmonary endothelial cells represent one third of the lung cells. Endothelial function includes promotion of anti-aggregation, fibrinolysis, and vasodilatation. Due to a significant role playing in thrombotic regulation, hypercoagulable profiles that are demonstrated in severe COVID-19 patients likely suggest significant endothelial injury. Pulmonary thrombosis and embolism accompanying elevation of d-dimer and fibrinogen levels have been demonstrated in severe COVID-19. In conclusion, whether these histopathological lesions are direct consequences of sepsis, SARS-CoV-2 (C)OVID-19), and /or multiple organ failure is difficult to conclude. Further studies on understanding the roles of ILC1, ILC2, ILC3, including the difference in response to SARS-CoV-2 (COVID-19) infection between children and adults are urgently needed to develop efficient targeted therapies.

scholarly journals Association and Virulence Gene Expression Vary among Serotype III Group B Streptococcus Isolates following Exposure to Decidual and Lung Epithelial Cells

2014 ◽  
Vol 82 (11) ◽  
pp. 4587-4595 ◽  
Author(s):  
Michelle L. Korir ◽  
David Knupp ◽  
Kathryn LeMerise ◽  
Erica Boldenow ◽  
Rita Loch-Caruso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Virulence Genes ◽  
Virulence Gene ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Virulence Gene Expression ◽  
Decidual Cells ◽  
Lung Epithelial ◽  
Group B

ABSTRACTGroup BStreptococcus(GBS) causes severe disease in neonates, the elderly, and immunocompromised individuals. GBS species are highly diverse and can be classified by serotype and multilocus sequence typing. Sequence type 17 (ST-17) strains cause invasive neonatal disease more frequently than strains of other STs. Attachment and invasion of host cells are key steps in GBS pathogenesis. We investigated whether four serotype III strains representing ST-17 (two strains), ST-19, and ST-23 differ in their abilities to attach to and invade both decidual cells and lung epithelial cells. Virulence gene expression following host cell association and exposure to amnion cells was also tested. The ST-17 strains differed in their abilities to attach to and invade decidual cells, whereas there were no differences with lung epithelial cells. The ST-19 and ST-23 strains, however, attached to and invaded decidual cells less than both ST-17 strains. Although the ST-23 strain attached to lung epithelial cells better than ST-17 and -19 strains, none of the strains effectively invaded the lung epithelial cells. Notably, the association with host cells resulted in the differential expression of several virulence genes relative to basal expression levels. Similar expression patterns of some genes were observed regardless of cell type used. Collectively, these results show that GBS strains differ in their abilities to attach to distinct host cell types and express key virulence genes that are relevant to the disease process. Enhancing our understanding of pathogenic mechanisms could aid in the identification of novel therapeutic targets or vaccine candidates that could potentially decrease morbidity and mortality associated with neonatal infections.

scholarly journals Pseudomonas Quinolone Signal Induces Oxidative Stress and Inhibits Heme Oxygenase-1 Expression in Lung Epithelial Cells

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Maher Y. Abdalla ◽  
Traci Hoke ◽  
Javier Seravalli ◽  
Barbara L. Switzer ◽  
Melissa Bavitz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Flow Cytometry ◽  
Epithelial Cells ◽  
Heme Oxygenase ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Heme Oxygenase 1 ◽  
Ros Production ◽  
Content Type ◽  
Lung Epithelial

ABSTRACT Pseudomonas aeruginosa causes lung infections in patients with cystic fibrosis (CF). The Pseudomonas quinolone signal (PQS) compound is a secreted P. aeruginosa virulence factor that contributes to the pathogenicity of P. aeruginosa. We were able to detect PQS in sputum samples from CF patients infected with P. aeruginosa but not in samples from uninfected patients. We then tested the hypothesis that PQS induces oxidative stress in host cells by determining the ability of PQS to induce the production of reactive oxygen species (ROS) in lung epithelial cells (A549 and primary normal human bronchial epithelial [NHBE]) cells and macrophages (J774A.1 and THP-1). ROS production induced by PQS was detected with fluorescent probes (dichlorodihydrofluorescein diacetate, dihydroethidium, and MitoSOX Red) in conjunction with confocal microscopy and flow cytometry. PQS induced ROS production in lung epithelial (A549 and NHBE) cells and macrophages (J774A.1 and THP-1 cells). NHBE cells were sensitive to PQS concentrations as low as 500 ng/ml. PQS significantly induced early apoptosis (P < 0.05, n = 6) in lung epithelial cells, as measured by annexin/propidium iodide detection by flow cytometry. However, no change in apoptosis upon PQS treatment was seen in J774A.1 cells. Heme oxygenase-1 (HO-1) protein is an antioxidant enzyme usually induced by oxidative stress. Interestingly, incubation with PQS significantly reduced HO-1 and NrF2 expression in A549 and NHBE cells but increased HO-1 expression in J774A.1 cells (P < 0.05, n = 3), as determined by immunoblotting and densitometry. These PQS effects on host cells could play an important role in the pathogenicity of P. aeruginosa infections.

scholarly journals Roles of Chaperone/Usher Pathways of Yersinia pestis in a Murine Model of Plague and Adhesion to Host Cells

2012 ◽  
Vol 80 (10) ◽  
pp. 3490-3500 ◽  
Author(s):  
Matthew Hatkoff ◽  
Lisa M. Runco ◽  
Celine Pujol ◽  
Indralatha Jayatilaka ◽  
Martha B. Furie ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Yersinia Pestis ◽  
Pathogenic Bacteria ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Cell Binding ◽  
Content Type ◽  
Infection Models ◽  
Virulence Attenuation ◽  
Lung Epithelial

ABSTRACTYersinia pestisand many other Gram-negative pathogenic bacteria use the chaperone/usher (CU) pathway to assemble virulence-associated surface fibers termed pili or fimbriae.Y. pestishas two well-characterized CU pathways: thecafgenes coding for the F1 capsule and thepsagenes coding for the pH 6 antigen. TheY. pestisgenome contains additional CU pathways that are capable of assembling pilus fibers, but the roles of these pathways in the pathogenesis of plague are not understood. We constructed deletion mutations in the usher genes for six of the additionalY. pestisCU pathways. The wild-type (WT) and usher deletion strains were compared in the murine bubonic (subcutaneous) and pneumonic (intranasal) plague infection models.Y. pestisstrains containing deletions in CU pathwaysy0348-0352,y1858-1862, andy1869-1873were attenuated for virulence compared to the WT strain by the intranasal, but not subcutaneous, routes of infection, suggesting specific roles for these pathways during pneumonic plague. We examined binding of theY. pestisWT and usher deletion strains to A549 human lung epithelial cells, HEp-2 human cervical epithelial cells, and primary human and murine macrophages.Y. pestisCU pathwaysy0348-0352andy1858-1862were found to contribute to adhesion to all host cells tested, whereas pathwayy1869-1873was specific for binding to macrophages. The correlation between the virulence attenuation and host cell binding phenotypes of the usher deletion mutants identifies three of the additional CU pathways ofY. pestisas mediating interactions with host cells that are important for the pathogenesis of plague.

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