scholarly journals Inhibition of Neutrophil Primary Granule Release during Yersinia pestis Pulmonary Infection

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Kara R. Eichelberger ◽  
Grant S. Jones ◽  
William E. Goldman
Keyword(s):  
Yersinia Pestis ◽  
Critical Role ◽  
Immune Defense ◽  
Calcium Flux ◽  
Human Neutrophils ◽  
Pneumonic Plague ◽  
Content Type ◽  
Neutrophil Degranulation ◽  
Primary Granule ◽  
Granule Release

ABSTRACT Inhalation of Yersinia pestis causes primary pneumonic plague, the most severe manifestation of plague that is characterized by a dramatic neutrophil influx to the lungs. Neutrophils are ineffective during primary pneumonic plague, failing to control Y. pestis growth in the airways. However, the mechanisms by which Y. pestis resists neutrophil killing are incompletely understood. Here, we show that Y. pestis inhibits neutrophil degranulation, an important line of host innate immune defense. We observed that neutrophils from the lungs of mice infected intranasally with Y. pestis fail to release primary granules throughout the course of disease. Using a type III secretion system (T3SS) injection reporter strain, we determined that Y. pestis directly inhibits neutrophil granule release by a T3SS-dependent mechanism. Combinatorial mutant analysis revealed that a Y. pestis strain lacking both effectors YopE and YopH did not inhibit primary granule release and is killed by neutrophils both in vivo and in vitro. Similarly, Y. pestis strains injecting only YopE or YopH are able to inhibit the majority of primary granule release from human neutrophils. We determined that YopE and YopH block Rac2 activation and calcium flux, respectively, to inhibit neutrophil primary granule release in isolated human neutrophils. These results demonstrate that Y. pestis coordinates the inhibition of neutrophil primary granule release through the activities of two distinct effectors, and this inhibition promotes Y. pestis survival during primary pneumonic plague. IMPORTANCE Yersinia pestis is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of Y. pestis infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of Yersinia pestis pulmonary infections are incompletely understood. Here, we report that Yersinia pestis inhibits neutrophil degranulation during infection, rendering neutrophils ineffective and allowing unrestricted growth of Y. pestis in the lungs. This coordinated inhibition of granule release not only demonstrates the pathogenic benefit of “silencing” lung neutrophils but also reveals specific host processes and pathways that could be manipulated to reduce the severity of primary pneumonic plague.

Primary granule release from human neutrophils is potentiated by soluble fibrinogen through a mechanism depending on multiple intracellular signaling pathways

2004 ◽  
Vol 287 (5) ◽  
pp. C1264-C1272 ◽  
Author(s):  
Florin Tuluc ◽  
Analia Garcia ◽  
Ovidiu Bredetean ◽  
John Meshki ◽  
Satya P. Kunapuli
Keyword(s):  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Significant Inhibition ◽  
Human Neutrophils ◽  
Mitogen Activated Protein ◽  
Neutrophil Degranulation ◽  
Gf 109203X ◽  
Primary Granule ◽  
Granule Release

N-Formyl-methionyl-leucyl-phenylalanine (fMLP) is a potent activator of neutrophil degranulation. The intracellular signaling mechanisms involved in the potentiating effect of fibrinogen on fMLP-induced primary granule release from human neutrophils were investigated. Fibrinogen caused a significant leftward shift of the concentration-response curve of fMLP-induced elastase release. An antibody against Mac-1 (CD11b/CD18) prevented the potentiating effect of fibrinogen, suggesting that soluble fibrinogen potentiates fMLP-induced degranulating effect by a mechanism mediated by the integrin Mac-1. Fibrinogen enhanced fMLP-induced tyrosine phosphorylation in human neutrophils and markedly enhanced the phosphorylation of mitogen-activated protein kinases (MAPK) caused by fMLP. However, U0126, an inhibitor of p44/42 MAPK activation, or SB-203580, an inhibitor of p38 MAPK, did not alter the effect of fibrinogen on fMLP-induced elastase release. Wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, and genistein, a nonspecific tyrosine kinase inhibitor, strongly inhibited fMLP-induced elastase release both in the presence and in the absence of fibrinogen. An Akt/PKB inhibitor failed to alter the potentiating effect of fibrinogen, suggesting that the effect of fibrinogen is mediated by Akt-independent pathways. Gö6976, an inhibitor of classical PKC isoforms, caused a significant inhibition of fMLP-induced elastase release in the presence or absence of fibrinogen, while nonselective inhibitors of PKC, Ro 31-8220, GF-109203X, and staurosporine, caused potentiation of fMLP-induced elastase release. We conclude that fibrinogen potentiation of primary granule release induced by fMLP is mediated by the integrin CD11b/CD18 through pathways dependent on PI3K and tyrosine kinases, but other regulatory mechanisms may be also involved.

scholarly journals Combined Stimulation of Toll-Like Receptor 5 and NOD1 Strongly Potentiates Activity of NF-κB, Resulting in Enhanced Innate Immune Reactions and Resistance to Salmonella enterica Serovar Typhimurium Infection

2013 ◽  
Vol 81 (10) ◽  
pp. 3855-3864 ◽  
Author(s):  
Amir I. Tukhvatulin ◽  
Ilya I. Gitlin ◽  
Dmitry V. Shcheblyakov ◽  
Natalia M. Artemicheva ◽  
Lyudmila G. Burdelya ◽  
...  
Keyword(s):  
Critical Role ◽  
Immune Defense ◽  
Innate Immune ◽  
Microbial Infection ◽  
Immune Reactions ◽  
Content Type ◽  
Essential Components ◽  
Stimulation Of

ABSTRACTPathogen recognition receptors (PRRs) are essential components of host innate immune systems that detect specific conserved pathogen-associated molecular patterns (PAMPs) presented by microorganisms. Members of two families of PRRs, transmembrane Toll-like receptors (TLRs 1, 2, 4, 5, and 6) and cytosolic NOD receptors (NOD1 and NOD2), are stimulated upon recognition of various bacterial PAMPs. Such stimulation leads to induction of a number of immune defense reactions, mainly triggered via activation of the transcription factor NF-κB. While coordination of responses initiated via different PRRs sensing multiple PAMPS present during an infection makes clear biological sense for the host, such interactions have not been fully characterized. Here, we demonstrate that combined stimulation of NOD1 and TLR5 (as well as other NOD and TLR family members) strongly potentiates activity of NF-κB and induces enhanced levels of innate immune reactions (e.g., cytokine production) bothin vitroandin vivo. Moreover, we show that an increased level of NF-κB activity plays a critical role in formation of downstream responses. In live mice, synergy between these receptors resulting in potentiation of NF-κB activity was organ specific, being most prominent in the gastrointestinal tract. Coordinated activity of NOD1 and TLR5 significantly increased protection of mice against enteroinvasiveSalmonellainfection. Obtained results suggest that cooperation of NOD and TLR receptors is important for effective responses to microbial infectionin vivo.

scholarly journals Combinatorial Viral Vector-Based and Live Attenuated Vaccines without an Adjuvant to Generate Broader Immune Responses to Effectively Combat Pneumonic Plague

mBio ◽  
2021 ◽  
Author(s):  
Paul B. Kilgore ◽  
Jian Sha ◽  
Emily K. Hendrix ◽  
Vladimir L. Motin ◽  
Ashok K. Chopra
Keyword(s):  
Immune Responses ◽  
Yersinia Pestis ◽  
Causative Agent ◽  
Viral Vector ◽  
Human Pathogen ◽  
Pneumonic Plague ◽  
Content Type ◽  
Live Attenuated Vaccines ◽  
Tier 1

Yersinia pestis , the causative agent of plague, is a Tier-1 select agent and a reemerging human pathogen. A 2017 outbreak in Madagascar with >75% of cases being pneumonic and 8.6% causalities emphasized the importance of the disease.

scholarly journals IQGAP1 Is Important for Activation of Caspase-1 in Macrophages and Is Targeted by Yersinia pestis Type III Effector YopM

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Lawton K. Chung ◽  
Naomi H. Philip ◽  
Valentina A. Schmidt ◽  
Antonius Koller ◽  
Till Strowig ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Immune Defense ◽  
Effector Proteins ◽  
Innate Immune ◽  
Scaffolding Protein ◽  
Host Proteins ◽  
Content Type ◽  
Binding Partner ◽  
Caspase 1 ◽  
Binding Partners

ABSTRACTYopM is a leucine-rich repeat (LRR)-containing effector in severalYersiniaspecies, includingYersinia pestisandY. pseudotuberculosis. DifferentYersiniastrains encode distinct YopM isoforms with variable numbers of LRRs but conserved C-terminal tails. A 15-LRR isoform inY. pseudotuberculosisYPIII was recently shown to bind and inhibit caspase-1 via a YLTD motif in LRR 10, and attenuation of YopM−YPIII was reversed in mice lacking caspase-1, indicating that caspase-1 inhibition is a major virulence function of YopMYPIII. To determine if other YopM proteins inhibit caspase-1, we utilizedY. pseudotuberculosisstrains natively expressing a 21-LRR isoform lacking the YLTD motif (YopM32777) or ectopically expressing aY. pestis15-LRR version with a functional (YopMKIM) or inactivated (YopMKIMD271A) YLTD motif. Results of mouse and macrophage infections with these strains showed that YopM32777, YopMKIM, and YopMKIMD271A inhibit caspase-1 activation, indicating that the YLTD motif is dispensable for this activity. Analysis of YopMKIMdeletion variants revealed that LRRs 6 to 15 and the C-terminal tail are required to inhibit caspase-1 activation. YopM32777, YopMKIM, and YopMKIMdeletion variants were purified, and binding partners in macrophage lysates were identified. Caspase-1 bound to YopMKIMbut not YopM32777. Additionally, YopMKIMbound IQGAP1 and the use ofIqgap1−/−macrophages revealed that this scaffolding protein is important for caspase-1 activation upon infection with YopM−Y. pseudotuberculosis. Thus, while multiple YopM isoforms inhibit caspase-1 activation, their variable LRR domains bind different host proteins to perform this function and the LRRs of YopMKIMtarget IQGAP1, a novel regulator of caspase-1, in macrophages.IMPORTANCEActivation of caspase-1, mediated by macromolecular complexes termed inflammasomes, is important for innate immune defense against pathogens. Pathogens can, in turn, subvert caspase-1-dependent responses through the action of effector proteins. For example, theYersiniaeffector YopM inhibits caspase-1 activation by arresting inflammasome formation. This caspase-1 inhibitory activity has been studied in a specific YopM isoform, and in this case, the protein was shown to act as a pseudosubstrate to bind and inhibit caspase-1. DifferentYersiniastrains encode distinct YopM isoforms, many of which lack the pseudosubstrate motif. We studied additional isoforms and found that these YopM proteins inhibit caspase-1 activation independently of a pseudosubstrate motif. We also identified IQGAP1 as a novel binding partner of theYersinia pestisYopMKIMisoform and demonstrated that IQGAP1 is important for caspase-1 activation in macrophages infected withYersinia. Thus, this study reveals new insights into inflammasome regulation duringYersiniainfection.

scholarly journals Filifactor alocis Promotes Neutrophil Degranulation and Chemotactic Activity

2016 ◽  
Vol 84 (12) ◽  
pp. 3423-3433 ◽  
Author(s):  
Cortney L. Armstrong ◽  
Irina Miralda ◽  
Adam C. Neff ◽  
Shifu Tian ◽  
Aruna Vashishta ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Periodontal Pocket ◽  
Human Neutrophils ◽  
Neutrophil Chemotaxis ◽  
Granule Exocytosis ◽  
Content Type ◽  
Innate Defense ◽  
Random Migration ◽  
Neutrophil Degranulation ◽  
Filifactor Alocis

Filifactor alocis is a recently recognized periodontal pathogen; however, little is known regarding its interactions with the immune system. As the first-responder phagocytic cells, neutrophils are recruited in large numbers to the periodontal pocket, where they play a crucial role in the innate defense of the periodontium. Thus, in order to colonize, successful periodontal pathogens must devise means to interfere with neutrophil chemotaxis and activation. In this study, we assessed major neutrophil functions, including degranulation and cell migration, associated with the p38 mitogen-activated protein kinase (MAPK) signaling pathway upon challenge with F. alocis. Under conditions lacking a chemotactic gradient, F. alocis -challenged neutrophils had increased migration compared to uninfected cells, indicating that F. alocis increases chemokinesis in human neutrophils. In addition, neutrophil chemotaxis induced by interleukin-8 was significantly enhanced when cells were challenged with F. alocis , compared to noninfected cells. Similar to live bacteria, heat-killed F. alocis induced both random and directed migration of human neutrophils. The interaction of F. alocis with Toll-like receptor 2 induced granule exocytosis along with a transient ERK1/2 and sustained p38 MAPK activation. Moreover, F. alocis -induced secretory vesicle and specific granule exocytosis were p38 MAPK dependent. Blocking neutrophil degranulation with TAT-SNAP23 fusion protein significantly reduced the chemotactic and random migration induced by F. alocis . Therefore, we propose that induction of random migration by F. alocis will prolong neutrophil traffic time in the gingival tissue, and subsequent degranulation will contribute to tissue damage.

Molecular mechanism of nucleotide-induced primary granule release in human neutrophils: role for the P2Y2receptor

2004 ◽  
Vol 286 (2) ◽  
pp. C264-C271 ◽  
Author(s):  
John Meshki ◽  
Florin Tuluc ◽  
Ovidiu Bredetean ◽  
Zhongren Ding ◽  
Satya P. Kunapuli
Keyword(s):  
Arachidonic Acid ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Extracellular Nucleotides ◽  
Human Neutrophils ◽  
Lipoxygenase Pathway ◽  
Arachidonic Acid Metabolites ◽  
Acid Metabolites ◽  
Primary Granule ◽  
Granule Release

Nucleotides are released during vascular injury from activated platelets and broken cells, which could stimulate human neutrophils. In this study, we characterized the P2Y receptors and investigated the functional effects of extracellular nucleotides on human neutrophils. Pharmacological characterization using selective agonists and pertussis toxin revealed that human neutrophils express only functional P2Y2receptors. However, P2Y2receptor agonists ATP or uridine triphosphate (UTP) caused intracellular Ca2+increases in isolated human neutrophils with an EC50of 1 μM but failed to cause release of primary granules from human neutrophils. ATP and UTP were equally potent in causing elastase release from human neutrophils in the presence of exogenous soluble fibrinogen, whereas ADP and UDP were without effect. We investigated whether nucleotides depend on generated arachidonic acid metabolites to cause degranulation. However, phenidone and MK-886, inhibitors of the 5-lipoxygenase pathway, failed to block nucleotide-induced intracellular calcium mobilization and elastase release. ATP and UTP caused activation of p38 MAPK and ERK1/2 in human neutrophils. In addition, the inhibitors of the MAPK pathway, SB-203580 and U-0126, inhibited nucleotide-induced elastase release. We conclude that fibrinogen is required for nucleotide-induced primary granule release from human neutrophils through the P2Y2receptor without a role for arachidonic acid metabolites. Both ERK1/2 and p38 MAPK play an important role in nucleotide-induced primary granule release from human neutrophils.

scholarly journals In Vivo Transcriptional Profiling of Yersinia pestis Reveals a Novel Bacterial Mediator of Pulmonary Inflammation

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Roger D. Pechous ◽  
Christopher A. Broberg ◽  
Nikolas M. Stasulli ◽  
Virginia L. Miller ◽  
William E. Goldman
Keyword(s):  
Yersinia Pestis ◽  
Inflammatory Responses ◽  
Severe Pneumonia ◽  
Sudden Onset ◽  
Host Factors ◽  
Respiratory Pathogen ◽  
Bacterial Survival ◽  
Pneumonic Plague ◽  
Content Type

ABSTRACTInhalation ofYersinia pestisresults in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia. The disease begins with a period of extensive bacterial replication in the absence of disease symptoms, followed by the sudden onset of inflammatory responses that ultimately prove fatal. Very little is known about the bacterial and host factors that contribute to the rapid biphasic progression of pneumonic plague. In this work, we analyzed thein vivotranscription kinetics of 288 bacterial open reading frames previously shown by microarray analysis to be dynamically regulated in the lung. Using this approach combined with bacterial genetics, we were able to identify five Y. pestis genes that contribute to the development of pneumonic plague. Deletion of one of these genes,ybtX, did not alter bacterial survival but attenuated host inflammatory responses during late-stage disease. Deletion ofybtXin another lethal respiratory pathogen,Klebsiella pneumoniae, also resulted in diminished host inflammation during infection. Thus, ourin vivotranscriptional screen has identified an important inflammatory mediator that is common to two Gram-negative bacterial pathogens that cause severe pneumonia.IMPORTANCEYersinia pestis is responsible for at least three major pandemics, most notably the Black Death of the Middle Ages. Due to its pandemic potential, ease of dissemination by aerosolization, and a history of its weaponization, Y. pestis is categorized by the Centers for Disease Control and Prevention as a tier 1 select agent most likely to be used as a biological weapon. To date, there is no licensed vaccine against Y. pestis. Importantly, an early “silent” phase followed by the rapid onset of nondescript influenza-like symptoms makes timely treatment of pneumonic plague difficult. A more detailed understanding of the bacterial and host factors that contribute to pathogenesis is essential to understanding the progression of pneumonic plague and developing or enhancing treatment options.

scholarly journals A Bacteriophage T4 Nanoparticle-Based Dual Vaccine against Anthrax and Plague

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Pan Tao ◽  
Marthandan Mahalingam ◽  
Jingen Zhu ◽  
Mahtab Moayeri ◽  
Jian Sha ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacillus Anthracis ◽  
Yersinia Pestis ◽  
Pathogenic Bacteria ◽  
Bacteriophage T4 ◽  
The United States ◽  
Complete Protection ◽  
Pneumonic Plague ◽  
Content Type ◽  
Phage T4

ABSTRACT Bacillus anthracis and Yersinia pestis, the causative agents of anthrax and plague, respectively, are two of the deadliest pathogenic bacteria that have been used as biological warfare agents. Although Biothrax is a licensed vaccine against anthrax, no Food and Drug Administration-approved vaccine exists for plague. Here, we report the development of a dual anthrax-plague nanoparticle vaccine employing bacteriophage (phage) T4 as a platform. Using an in vitro assembly system, the 120- by 86-nm heads (capsids) of phage T4 were arrayed with anthrax and plague antigens fused to the small outer capsid protein Soc (9 kDa). The antigens included the anthrax protective antigen (PA) (83 kDa) and the mutated (mut) capsular antigen F1 and the low-calcium-response V antigen of the type 3 secretion system from Y. pestis (F1mutV) (56 kDa). These viral nanoparticles elicited robust anthrax- and plague-specific immune responses and provided complete protection against inhalational anthrax and/or pneumonic plague in three animal challenge models, namely, mice, rats, and rabbits. Protection was demonstrated even when the animals were simultaneously challenged with lethal doses of both anthrax lethal toxin and Y. pestis CO92 bacteria. Unlike the traditional subunit vaccines, the phage T4 vaccine uses a highly stable nanoparticle scaffold, provides multivalency, requires no adjuvant, and elicits broad T-helper 1 and 2 immune responses that are essential for complete clearance of bacteria during infection. Therefore, phage T4 is a unique nanoparticle platform to formulate multivalent vaccines against high-risk pathogens for national preparedness against potential bioterror attacks and emerging infections. IMPORTANCE Following the deadly anthrax attacks of 2001, the Centers for Disease Control and Prevention (CDC) determined that Bacillus anthracis and Yersinia pestis that cause anthrax and plague, respectively, are two Tier 1 select agents that pose the greatest threat to the national security of the United States. Both cause rapid death, in 3 to 6 days, of exposed individuals. We engineered a virus nanoparticle vaccine using bacteriophage T4 by incorporating key antigens of both B. anthracis and Y. pestis into one formulation. Two doses of this vaccine provided complete protection against both inhalational anthrax and pneumonic plague in animal models. This dual anthrax-plague vaccine is a strong candidate for stockpiling against a potential bioterror attack involving either one or both of these biothreat agents. Further, our results establish the T4 nanoparticle as a novel platform to develop multivalent vaccines against pathogens of high public health significance.

scholarly journals Activation of Heme Oxygenase Expression by Cobalt Protoporphyrin Treatment Prevents Pneumonic Plague Caused by Inhalation of Yersinia pestis

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Joshua L. Willix ◽  
Jacob L. Stockton ◽  
Rachel M. Olson ◽  
Paul E. Anderson ◽  
Deborah M. Anderson
Keyword(s):  
Inflammatory Response ◽  
Yersinia Pestis ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Bacterial Invasion ◽  
Heme Oxygenase 1 ◽  
Lethal Challenge ◽  
Pneumonic Plague ◽  
Content Type ◽  
Cobalt Protoporphyrin

ABSTRACT Pneumonic plague, caused by the Gram-negative bacteria Yersinia pestis, is an invasive, rapidly progressing disease with poor survival rates. Following inhalation of Y. pestis, bacterial invasion of the lungs and a tissue-damaging inflammatory response allows vascular spread of the infection. Consequently, primary pneumonic plague is a multiorgan disease involving sepsis and necrosis of immune tissues and the liver, as well as bronchopneumonia and rampant bacterial growth. Given the likely role of the hyperinflammatory response in accelerating the destruction of tissue, in this work we evaluated the therapeutic potential of the inducible cytoprotective enzyme heme oxygenase 1 (HO-1) against primary pneumonic plague. On its own, the HO-1 inducer cobalt protoporphyrin IX (CoPP) provided mice protection from lethal challenge with Y. pestis CO92 with improved pulmonary bacterial clearance and a dampened inflammatory response compared to vehicle-treated mice. Furthermore, CoPP treatment combined with doxycycline strongly enhanced protection in a rat aerosol challenge model. Compared to doxycycline alone, CoPP treatment increased survival, with a 3-log decrease in median bacterial titer recovered from the lungs and the general absence of a systemic hyperinflammatory response. In contrast, treatment with the HO-1 inhibitor SnPP had no detectable impact on doxycycline efficacy. The combined data indicate that countering inflammatory toxicity by therapeutically inducing HO-1 is effective in reducing the rampant growth of Y. pestis and preventing pneumonic plague.

scholarly journals Yersinia pseudotuberculosis Blocks Neutrophil Degranulation

2016 ◽  
Vol 84 (12) ◽  
pp. 3369-3378 ◽  
Author(s):  
Nayyer Taheri ◽  
Anna Fahlgren ◽  
Maria Fällman
Keyword(s):  
Yersinia Pseudotuberculosis ◽  
Antimicrobial Properties ◽  
Cell Contact ◽  
Content Type ◽  
Essential Components ◽  
Proinflammatory Responses ◽  
Neutrophil Degranulation ◽  
Secondary Granule ◽  
Virulence Effectors ◽  
Granule Release

Neutrophils are essential components of immunity and are rapidly recruited to infected or injured tissue. Upon their activation, neutrophils release granules to the cell's exterior, through a process called degranulation. These granules contain proteins with antimicrobial properties that help combat infection. The enteropathogenic bacteriumYersinia pseudotuberculosissuccessfully persists as an extracellular bacterium during infection by virtue of its translocation of virulence effectors (Yersiniaouter proteins [Yops]) that act in the cytosol of host immune cells to subvert phagocytosis and proinflammatory responses. Here, we investigated the effect ofY. pseudotuberculosison neutrophil degranulation upon cell contact. We found that virulentY. pseudotuberculosiswas able to prevent secondary granule release. The blocking effect was general, as the release of primary and tertiary granules was also reduced. Degranulation of secondary granules was also blocked in primed neutrophils, suggesting that this mechanism could be an important element of immune evasion. Further, wild-type bacteria conferred a transient block on neutrophils that prevented their degranulation upon contact with plasmid-cured, avirulentY. pseudotuberculosisandEscherichia coli. Detailed analyses showed that the block was strictly dependent on the cooperative actions of the two antiphagocytic effectors, YopE and YopH, suggesting that the neutrophil target structures constituting signaling molecules needed to initiate both phagocytosis and general degranulation. Thus, via these virulence effectors,Yersiniacan impair several mechanisms of the neutrophil's antimicrobial arsenal, which underscores the power of its virulence effector machinery.

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