scholarly journals Ribosome Hibernation Facilitates Tolerance of Stationary-Phase Bacteria to Aminoglycosides

2015 ◽  
Vol 59 (11) ◽  
pp. 6992-6999 ◽  
Author(s):  
Susannah L. McKay ◽  
Daniel A. Portnoy
Keyword(s):  
Stationary Phase ◽  
Bacterial Pathogen ◽  
Clinical Implications ◽  
Beta Lactam ◽  
Content Type ◽  
Quinolone Antibiotics ◽  
Carbonyl Cyanide ◽  
Bacterial Uptake ◽  
Stationary Phase Analysis

ABSTRACTUpon entry into stationary phase, bacteria dimerize 70S ribosomes into translationally inactive 100S particles by a process called ribosome hibernation. Previously, we reported that the hibernation-promoting factor (HPF) ofListeria monocytogenesis required for 100S particle formation and facilitates adaptation to a number of stresses. Here, we demonstrate that HPF is required for the high tolerance of stationary-phase cultures to aminoglycosides but not to beta-lactam or quinolone antibiotics. The sensitivity of a Δhpfmutant to gentamicin was suppressed by the bacteriostatic antibiotics chloramphenicol and rifampin, which inhibit translation and transcription, respectively. Disruption of the proton motive force by the ionophore carbonyl cyanidem-chlorophenylhydrazone or mutation of genes involved in respiration also suppressed the sensitivity of the Δhpfmutant. Accordingly, Δhpfmutants had aberrantly high levels of ATP and reducing equivalents during prolonged stationary phase. Analysis of bacterial uptake of fluorescently labeled gentamicin demonstrated that the Δhpfmutant harbored increased intracellular levels of the drug. Finally, deletion of the main ribosome hibernation factor ofEscherichia coli, ribosome modulation factor (rmf), rendered these bacteria susceptible to gentamicin. Taken together, these data suggest that HPF-mediated ribosome hibernation results in repression of the metabolic activity that underlies aminoglycoside tolerance. HPF is conserved in nearly every bacterial pathogen, and the role of ribosome hibernation in antibiotic tolerance may have clinical implications.

scholarly journals Motility-Independent Formation of Antibiotic-TolerantPseudomonas aeruginosaAggregates

2019 ◽  
Vol 85 (14) ◽  
Author(s):  
Sally Demirdjian ◽  
Hector Sanchez ◽  
Daniel Hopkins ◽  
Brent Berwin
Keyword(s):  
Biofilm Formation ◽  
Bacterial Pathogen ◽  
Aggregate Formation ◽  
Flagellar Motility ◽  
Wild Type ◽  
Chronic Infections ◽  
Content Type ◽  
Temporal Adaptation ◽  
Bacterial Aggregates

ABSTRACTPseudomonas aeruginosais a bacterial pathogen that causes severe chronic infections in immunocompromised individuals. This bacterium is highly adaptable to its environments, which frequently select for traits that promote bacterial persistence. A clinically significant temporal adaptation is the formation of surface- or cell-adhered bacterial biofilms that are associated with increased resistance to immune and antibiotic clearance. Extensive research has shown that bacterial flagellar motility promotes formation of such biofilms, whereupon the bacteria subsequently become nonmotile. However, recent evidence shows that antibiotic-tolerant nonattached bacterial aggregates, distinct from surface-adhered biofilms, can form, and these have been reported in the context of lung infections, otitis media, nonhealing wounds, and soft tissue fillers. It is unclear whether the same bacterial traits are required for aggregate formation as for biofilm formation. In this report, using isogenic mutants, we demonstrate thatP. aeruginosaaggregates in liquid cultures are spontaneously formed independent of bacterial flagellar motility and independent of an exogenous scaffold. This contrasts with the role of the flagellum to initiate surface-adhered biofilms. Similarly to surface-attached biofilms, these aggregates exhibit increased antibiotic tolerance compared to planktonic cultures. These findings provide key insights into the requirements for aggregate formation that contrast with those for biofilm formation and that may have relevance for the persistence and dissemination of nonmotile bacteria found within chronic clinical infections.IMPORTANCEIn this work, we have investigated the role of bacterial motility with regard to antibiotic-tolerant bacterial aggregate formation. Previous work has convincingly demonstrated thatP. aeruginosaflagellar motility promotes the formation of surface-adhered biofilms in many systems. In contrast, aggregate formation byP. aeruginosawas observed for nonmotile but not for motile cells in the presence of an exogenous scaffold. Here, we demonstrate that both wild-typeP. aeruginosaand mutants that genetically lack motility spontaneously form antibiotic-tolerant aggregates in the absence of an exogenously added scaffold. Additionally, we also demonstrate that wild-type (WT) and nonmotileP. aeruginosabacteria can coaggregate, shedding light on potential physiological interactions and heterogeneity of aggregates.

scholarly journals Sigma S-Dependent Antioxidant Defense Protects Stationary-Phase Escherichia coli against the Bactericidal Antibiotic Gentamicin

2014 ◽  
Vol 58 (10) ◽  
pp. 5964-5975 ◽  
Author(s):  
Jing-Hung Wang ◽  
Rachna Singh ◽  
Michael Benoit ◽  
Mimi Keyhan ◽  
Matthew Sylvester ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Escherichia Coli ◽  
Stationary Phase ◽  
Antioxidant Defense ◽  
Physiological State ◽  
Pentose Phosphate ◽  
Phase Cell ◽  
Content Type

ABSTRACTStationary-phase bacteria are important in disease. The σs-regulated general stress response helps them become resistant to disinfectants, but the role of σsin bacterial antibiotic resistance has not been elucidated. Loss of σsrendered stationary-phaseEscherichia colimore sensitive to the bactericidal antibiotic gentamicin (Gm), and proteomic analysis suggested involvement of a weakened antioxidant defense. Use of the psfiAgenetic reporter, 3′-(p-hydroxyphenyl) fluorescein (HPF) dye, and Amplex Red showed that Gm generated more reactive oxygen species (ROS) in the mutant. HPF measurements can be distorted by cell elongation, but Gm did not affect stationary-phase cell dimensions. Coadministration of the antioxidantN-acetyl cysteine (NAC) decreased drug lethality particularly in the mutant, as did Gm treatment under anaerobic conditions that prevent ROS formation. Greater oxidative stress, due to insufficient quenching of endogenous ROS and/or respiration-linked electron leakage, therefore contributed to the greater sensitivity of the mutant; infection by a uropathogenic strain in mice showed this to be the case alsoin vivo. Disruption of antioxidant defense by eliminating the quencher proteins, SodA/SodB and KatE/SodA, or the pentose phosphate pathway proteins, Zwf/Gnd and TalA, which provide NADPH for ROS decomposition, also generated greater oxidative stress and killing by Gm. Thus, besides its established mode of action, Gm also kills stationary-phase bacteria by generating oxidative stress, and targeting the antioxidant defense ofE. colican enhance its efficacy. Relevant aspects of the current controversy on the role of ROS in killing by bactericidal drugs of exponential-phase bacteria, which represent a different physiological state, are discussed.

scholarly journals Phosphate Transporter PstSCAB of Campylobacter jejuni Is a Critical Determinant of Lactate-Dependent Growth and Colonization in Chickens

2020 ◽  
Vol 202 (7) ◽  
Author(s):  
Ritam Sinha ◽  
Rhiannon M. LeVeque ◽  
Marvin Q. Bowlin ◽  
Michael J. Gray ◽  
Victor J. DiRita
Keyword(s):  
Stationary Phase ◽  
Campylobacter Jejuni ◽  
Phosphate Transporter ◽  
Rna Seq ◽  
Wild Type ◽  
Content Type ◽  
High Affinity ◽  
Polyphosphate Metabolism

ABSTRACT Campylobacter jejuni causes acute gastroenteritis worldwide and is transmitted primarily through poultry, in which it is often a commensal member of the intestinal microbiota. Previous transcriptome sequencing (RNA-Seq) experiment showed that transcripts from an operon encoding a high-affinity phosphate transporter (PstSCAB) of C. jejuni were among the most abundant when the bacterium was grown in chickens. Elevated levels of the pstSCAB mRNA were also identified in an RNA-Seq experiment from human infection studies. In this study, we explore the role of PstSCAB in the biology and colonization potential of C. jejuni. Our results demonstrate that cells lacking PstSCAB survive poorly in stationary phase, in nutrient-limiting media, and under osmotic conditions reflective of those in the chicken. Polyphosphate levels in the mutant cells were elevated at stationary phase, consistent with alterations in expression of polyphosphate metabolism genes. The mutant strain was highly attenuated for colonization of newly hatched chicks, with levels of bacteria at several orders of magnitude below wild-type levels. Mutant and wild type grew similarly in complex media, but the pstS::kan mutant exhibited a significant growth defect in minimal medium supplemented with l-lactate, postulated as a carbon source in vivo. Poor growth in lactate correlated with diminished expression of acetogenesis pathway genes previously demonstrated as important for colonizing chickens. The phosphate transport system is thus essential for diverse aspects of C. jejuni physiology and in vivo fitness and survival. IMPORTANCE Campylobacter jejuni causes millions of human gastrointestinal infections annually, with poultry a major source of infection. Due to the emergence of multidrug resistance in C. jejuni, there is need to identify alternative ways to control this pathogen. Genes encoding the high-affinity phosphate transporter PstSCAB are highly expressed by C. jejuni in chickens and humans. In this study, we address the role of PstSCAB on chicken colonization and other C. jejuni phenotypes. PstSCAB is required for colonization in chicken, metabolism and survival under different stress responses, and during growth on lactate, a potential growth substrate in chickens. Our study highlights that PstSCAB may be an effective target to develop mechanisms for controlling bacterial burden in both chicken and human.

scholarly journals Mycobacterial SigA and SigB Cotranscribe Essential Housekeeping Genes during Exponential Growth

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Kelley Hurst-Hess ◽  
Rajesh Biswas ◽  
Yong Yang ◽  
Paulami Rudra ◽  
Erica Lasek-Nesselquist ◽  
...  
Keyword(s):  
Stationary Phase ◽  
Exponential Growth ◽  
Sigma Factor ◽  
Housekeeping Genes ◽  
Sigma Factors ◽  
Rrna Gene ◽  
Content Type ◽  
Group I ◽  
Group Ii

ABSTRACTMycobacterial σBbelongs to the group II family of sigma factors, which are widely considered to transcribe genes required for stationary-phase survival and the response to stress. Here we explored the mechanism underlying the observed hypersensitivity of ΔsigBdeletion mutants ofMycobacteriumsmegmatis,M. abscessus, andM. tuberculosisto rifampin (RIF) and uncovered an additional constitutive role of σBduring exponential growth of mycobacteria that complements the function of the primary sigma factor, σA. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we show that during exponential phase, σBbinds to over 200 promoter regions, including those driving expression of essential housekeeping genes, like the rRNA gene. ChIP-Seq of ectopically expressed σA-FLAG demonstrated that at least 61 promoter sites are recognized by both σAand σB. These results together suggest that RNA polymerase holoenzymes containing either σAor σBtranscribe housekeeping genes in exponentially growing mycobacteria. The RIF sensitivity of the ΔsigBmutant possibly reflects a decrease in the effective housekeeping holoenzyme pool, which results in susceptibility of the mutant to lower doses of RIF. Consistent with this model, overexpression of σArestores the RIF tolerance of the ΔsigBmutant to that of the wild type, concomitantly ruling out a specialized role of σBin RIF tolerance. Although the properties of mycobacterial σBparallel those ofEscherichiacoliσ38in its ability to transcribe a subset of housekeeping genes, σBpresents a clear departure from theE. coliparadigm, wherein the cellular levels of σ38are tightly controlled during exponential growth, such that the transcription of housekeeping genes is initiated exclusively by a holoenzyme containing σ70(E.σ70).IMPORTANCEAll mycobacteria encode a group II sigma factor, σB, closely related to the group I principal housekeeping sigma factor, σA. Group II sigma factors are widely believed to play specialized roles in the general stress response and stationary-phase transition in the bacteria that encode them. Contrary to this widely accepted view, we show an additional housekeeping function of σBthat complements the function of σAin logarithmically growing cells. These findings implicate a novel and dynamic partnership between σAand σBin maintaining the expression of housekeeping genes in mycobacteria and can perhaps be extended to other bacterial species that possess multiple group II sigma factors.

scholarly journals Interleukin-1 Receptor-Associated Kinase 4 Is Essential for Initial Host Control of Brucella abortus Infection

2011 ◽  
Vol 79 (11) ◽  
pp. 4688-4695 ◽  
Author(s):  
Fernanda S. Oliveira ◽  
Natália B. Carvalho ◽  
Ana Paula M. S. Brandão ◽  
Marco Túlio R. Gomes ◽  
Leonardo A. de Almeida ◽  
...  
Keyword(s):  
Immune Response ◽  
Brucella Abortus ◽  
Interleukin 1 ◽  
Bacterial Pathogen ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Ifn Γ

ABSTRACTBrucella abortusis a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Recent studies have revealed that Toll-like receptor (TLR)-initiated immune response toBrucellaspp. depends on myeloid differentiation factor 88 (MyD88) signaling. Therefore, we decided to study the role of the interleukin-1 receptor-associated kinase 4 (IRAK-4) in host innate immune response againstB. abortus. AfterBrucellainfection, it was shown that the number of CFU in IRAK-4−/−mice was high compared to that in IRAK-4+/−animals only at 1 week postinfection. At 3 and 6 weeks postinfection, IRAK-4−/−mice were able to control the infection similarly to heterozygous animals. Furthermore, the type 1 cytokine profile was evaluated. IRAK-4−/−mice showed lower production of systemic interleukin-12 (IL-12) and gamma interferon (IFN-γ). Additionally, a reduced percentage of CD4+and CD8+T cells expressing IFN-γ was observed compared to IRAK-4+/−. Further, the production of IL-12 and tumor necrosis factor alpha (TNF-α) by macrophages and dendritic cells from IRAK-4−/−mice was abolished at 24 h after stimulation withB. abortus. To investigate the role of IRAK-4 in mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, macrophages were stimulated withB. abortus, and the signaling components were analyzed by protein phosphorylation. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 and p38 as well as p65 NF-κB phosphorylation was profoundly impaired in IRAK-4−/−and MyD88−/−macrophages activated byBrucella. In summary, the results shown in this study demonstrated that IRAK-4 is critical to trigger the initial immune response againstB. abortusbut not at later phases of infection.

scholarly journals Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

2016 ◽  
Vol 84 (8) ◽  
pp. 2255-2263 ◽  
Author(s):  
Emir Tinaztepe ◽  
Jun-Rong Wei ◽  
Jenelle Raynowska ◽  
Cynthia Portal-Celhay ◽  
Victor Thompson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cell Envelope ◽  
Bacterial Pathogen ◽  
Transcriptional Response ◽  
Secretion Systems ◽  
Content Type ◽  
Type Vii Secretion ◽  
Significant Difference ◽  
Iron And Zinc

More people die every year fromMycobacterium tuberculosisinfection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogenMycobacterium smegmatis, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. InM. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. WithM. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of theesx-3locus to these metals. While iron regulated theesx-3expression in bothM. tuberculosisandM. smegmatis, there is a significant difference in the dynamics of this regulation. InM. smegmatis, theesx-3locus behaved like other iron-regulated genes such asmbtB. InM. tuberculosis, both iron and zinc modestly repressedesx-3expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction ofM. tuberculosiswith macrophages, leading to impaired intracellularM. tuberculosissurvival. Our findings detail the regulatory differences ofesx-3inM. tuberculosisandM. smegmatisand demonstrate the importance of metal-dependent regulation of ESX-3 for virulence inM. tuberculosis.

scholarly journals Oligoribonuclease Contributes to Tolerance to Aminoglycoside and β-Lactam Antibiotics by Regulating KatA inPseudomonas aeruginosa

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Bin Xia ◽  
Mei Li ◽  
Zhenyang Tian ◽  
Gukui Chen ◽  
Chang Liu ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Biofilm Formation ◽  
Bacterial Pathogen ◽  
Content Type ◽  
Oxidative Stresses ◽  
Fluoroquinolone Antibiotics

ABSTRACTPseudomonas aeruginosais an opportunistic bacterial pathogen and is intrinsically resistant to a variety of antibiotics. Oligoribonuclease (Orn) is a 3′-to-5′ exonuclease that degrades nanoRNAs. The Orn controls biofilm formation by influencing the homeostasis of cyclic-di-GMP. Previously, we demonstrated that Orn contributes to the tolerance ofP. aeruginosato fluoroquinolone antibiotics by affecting the production of pyocins. In this study, we found that mutation in theorngene reduces bacterial tolerance to aminoglycoside and β-lactam antibiotics, which is mainly due to a defective response to oxidative stresses. The major catalase KatA is downregulated in theornmutant, and overexpression of thekatAgene restores the bacterial tolerance to oxidative stresses and the antibiotics. We further demonstrated that Orn influenced the translation of thekatAmRNA and narrowed down the region in thekatAmRNA that is involved in the regulation of its translation. Therefore, our results revealed a novel role of the Orn in bacterial tolerance to oxidative stresses as well as aminoglycoside and β-lactam antibiotics.

scholarly journals Role of Mfd and GreA in Bacillus subtilis Base Excision Repair-Dependent Stationary-Phase Mutagenesis

2020 ◽  
Vol 202 (9) ◽  
Author(s):  
Hilda C. Leyva-Sánchez ◽  
Norberto Villegas-Negrete ◽  
Karen Abundiz-Yañez ◽  
Ronald E. Yasbin ◽  
Eduardo A. Robleto ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Stationary Phase ◽  
Excision Repair ◽  
Dna Lesions ◽  
Ap Endonuclease ◽  
Content Type ◽  
Error Prone Repair ◽  
Base Excision ◽  
Oxidized Guanine

ABSTRACT We report that the absence of an oxidized guanine (GO) system or the apurinic/apyrimidinic (AP) endonucleases Nfo, ExoA, and Nth promoted stress-associated mutagenesis (SAM) in Bacillus subtilis YB955 (hisC952 metB5 leuC427). Moreover, MutY-promoted SAM was Mfd dependent, suggesting that transcriptional transactions over nonbulky DNA lesions promoted error-prone repair. Here, we inquired whether Mfd and GreA, which control transcription-coupled repair and transcription fidelity, influence the mutagenic events occurring in nutritionally stressed B. subtilis YB955 cells deficient in the GO or AP endonuclease repair proteins. To this end, mfd and greA were disabled in genetic backgrounds defective in the GO and AP endonuclease repair proteins, and the strains were tested for growth-associated and stress-associated mutagenesis. The results revealed that disruption of mfd or greA abrogated the production of stress-associated amino acid revertants in the GO and nfo exoA nth strains, respectively. These results suggest that in nutritionally stressed B. subtilis cells, spontaneous nonbulky DNA lesions are processed in an error-prone manner with the participation of Mfd and GreA. In support of this notion, stationary-phase ΔytkD ΔmutM ΔmutY (referred to here as ΔGO) and Δnfo ΔexoA Δnth (referred to here as ΔAP) cells accumulated 8-oxoguanine (8-OxoG) lesions, which increased significantly following Mfd disruption. In contrast, during exponential growth, disruption of mfd or greA increased the production of His+, Met+, or Leu+ prototrophs in both DNA repair-deficient strains. Thus, in addition to unveiling a role for GreA in mutagenesis, our results suggest that Mfd and GreA promote or prevent mutagenic events driven by spontaneous genetic lesions during the life cycle of B. subtilis. IMPORTANCE In this paper, we report that spontaneous genetic lesions of an oxidative nature in growing and nutritionally stressed B. subtilis strain YB955 (hisC952 metB5 leuC427) cells drive Mfd- and GreA-dependent repair transactions. However, whereas Mfd and GreA elicit faithful repair events during growth to maintain genome fidelity, under starving conditions, both factors promote error-prone repair to produce genetic diversity, allowing B. subtilis to escape from growth-limiting conditions.

scholarly journals Distinct Subpopulations of Intravalvular Methicillin-Resistant Staphylococcus aureus with Variable Susceptibility to Daptomycin in Tricuspid Valve Endocarditis

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Christopher R. Miller ◽  
Somrita Dey ◽  
Paula D. Smolenski ◽  
Pushkar S. Kulkarni ◽  
Jonathan M. Monk ◽  
...  
Keyword(s):  
Methicillin Resistant Staphylococcus Aureus ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Content Type ◽  
Peripheral Blood Culture ◽  
Genomic Analyses ◽  
Pharmacokinetic Simulations ◽  
Selection Of

ABSTRACT We present a case of endocarditis wherein organisms cultured from different valve leaflets yielded different daptomycin susceptibilities from each other and from organisms obtained from peripheral blood culture. Genomic analyses showed mutations in mprF, purR, and agrA. Pharmacokinetic simulations showed consistent activity of daptomycin plus beta-lactam against all subpopulations. This represents an opportunity to understand S. aureus evolution and fitness in vivo on daptomycin therapy and the role of beta-lactams to prevent the selection of daptomycin-resistant subpopulations.

scholarly journals Role of Epidermal Growth Factor Receptor Signaling in the Interaction of Neisseria meningitidis with Endothelial Cells

2013 ◽  
Vol 82 (3) ◽  
pp. 1243-1255 ◽  
Author(s):  
Heiko Slanina ◽  
Sabrina Mündlein ◽  
Sabrina Hebling ◽  
Alexandra Schubert-Unkmeir
Keyword(s):  
Endothelial Cells ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Growth Factor Receptor ◽  
Content Type ◽  
Bacterial Uptake ◽  
Epidermal Growth

ABSTRACTNeisseria meningitidis, the causative agent of meningitis and septicemia, attaches to and invades various cell types. Both steps induce and/or require tyrosine phosphorylation of host cell proteins. Here, we used a phospho array platform to identify active receptor tyrosine kinases (RTKs) and key signaling nodes inN. meningitidis-infected brain endothelial cells to decipher RTK-dependent signaling pathways necessary for bacterial uptake. We detected several activated RTKs, including the ErbB family receptors epidermal growth factor receptor (EGFR), ErbB2, and ErbB4. We found that pharmacological inhibition and genetic ablation of ErbB receptor tyrosine phosphorylation and expression resulted in decreased bacterial uptake and heterologous expression of EGFR, ErbB2, or ErbB4 in Chinese ovary hamster (CHO-K1) cells, which do not express of EGFR and ErbB4; the decrease caused a significant increase in meningococcal invasion. Activation of EGFR and ErbB4 was mediated by transactivation via the common ligand HB-EGF (heparin-binding EGF-like ligand), which was significantly elevated in infected cell culture supernatants. We furthermore determined thatN. meningitidisinduced phosphorylation of EGFR at Tyr845 independent of ligand binding, which required c-Src activation and was involved in mediating uptake ofN. meningitidisinto eukaryotic cells. Increased uptake was repressed by expression of EGFR Y845F, which harbored a point mutation in the kinase domain. In addition, activation of ErbB4 at its autophosphorylation site, Tyr1284, and phosphorylation of ErbB2 Thr686 were observed. Altogether, our results provide evidence that EGFR, ErbB2, and ErbB4 are activated in response toN. meningitidisinfection and shed new light on the role of ErbB signaling in meningococcal infection biology.

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