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Escherichia coli is a major cause of community‐acquired urinary tract infections (CA‐UTIs). In this study, we investigated the antimicrobial resistance patterns, the distribution of phylogenetic groups, and the prevalence and characteristics of integron-bearing E. coli isolates from outpatients with CA‐UTIs in El-Minia governorate, in Upper Egypt. Out of the 583 urine samples collected, 134 were positive for E. coli, from which the most resistant isolates (n = 80) were selected for further analysis. The majority of these isolates (62.5%, 50/80) showed multidrug resistance profiles. Group B2 was the most predominant phylogenetic group (52.5%), followed by group F (21.25%), Clades I or II (12.5%), and finally isolates of unknown phylogroup (13.75%). Of the 80 isolates, 7 (8.75%) carried class 1 integrons, which contained 3 different types of integrated gene cassettes, including those conferring resistance to streptomycin/spectinomycin, trimethoprim, and some open reading frames of unknown function (gcuF). In conclusion, the types and combinations of the gene cassettes in our study may reflect the specific selective pressures to which the isolates were subjected within the study region, therefore, providing valuable data for future intervention strategies that are precisely tailored to prevent the dissemination of the uropathogenic E. coli strains circulating within Upper Egypt.

The incidence of cancer is increasing worldwide; likewise, the emergence of antibiotic-resistant biofilm-forming pathogens has led to a tremendous increase in morbidity and mortality. This study aimed to evaluate the probiotic properties of bacteriocin-producing Enterococcus sp. with a focus on their anti-biofilm and anticancer activities. Three of 79 Enterococcus isolates (FM43, FM65, FM50) were identified as producers of broad-spectrum bioactive molecules and were molecularly characterized as Enterococcus faecium by 16S rRNA sequencing. Phenotypic and genotypic screening for potential virulence factors revealed no factors known to promote pathogenicity. Treatment with proteinase K resulted in diminished antimicrobial activity; PCR-based screening for bacteriocin genes suggested the presence of both entA and entB genes that encode enterocins A and B, respectively. Maximum antimicrobial activity was detected during the early stationary phase, while activity disappeared after 24 h in culture. Bacteriocins from these isolates were stable at high temperatures and over a wide range of pH. Interestingly, crude supernatants of Ent. faecium FM43 and Ent. faecium FM50 resulted in significant destruction (80% and 48%, respectively; P

Bacteriophage-encoded lysins are increasingly reported as alternatives to combat Acinetobacter baumannii infections, for which limited therapeutic options are available. Some lysins, such as LysMK34, have a C-terminal amphipathic helix allowing them to penetrate the otherwise-impermeable outer membrane barrier. Another approach to kill Gram-negative pathogens with lysins relies on fusion of a peptide with outer membrane- permeabilizing properties to the lysin. In this work, we aimed to leverage the intrinsic antibacterial activity of LysMK34 by fusing the peptide cecropin A to its N terminus via a linker of three Ala-Gly repeats, resulting in engineered LysMK34 (eLysMK34). The engineered lysin has an improved antibacterial activity compared to that of the parental lysin, LysMK34, in terms of MICs (0.45 to 1.2 μM), killing rate, and killing extent. eLysMK34 has a ≥2-foldincreased activity against stationary-phase cells, and the bactericidal effect becomes less dependent on the intracellular osmotic pressure. In particular, colistin-resistant strains become highly susceptible to eLysMK34, and enhanced antibacterial activity is observed in complement- deactivated human serum. These observations demonstrate that fusion of a lysin with intrinsic antibacterial activity with a selected outer membrane-permeabilizing peptide is a useful strategy to further improve the in vitro antibacterial properties of such lysins., K.A. was funded by the Missions Sector, Ministry of Higher Education, Egypt. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. D.G. is supported by the Research Foundation-Flanders (FWO) under grant G066919N. Y.B. is a coinventor of patents related to the Artilysin field. We thank S. Malhotra-Kumar (Laboratory of Medical Microbiology, Vaccine & Infectious Disease, University of Antwerp, Antwerp, Belgium) for providing the colistin-resistant A. baumannii strains (Greek46 and Greek47) and J. P. Pirnay (Laboratory for Molecular and Cellular Technology, Queen Astrid Hospital, Neder-over-Heembeek, Belgium) for providing A. baumannii RUH134 and P. aeruginosa PA14 and Br667.

Treatment of community urinary tract infections (UTIs) caused by extended-spectrum β lactamase (ESBL)- producing Escherichia coli (E. coli) is more expensive than treating ESBL-negative opposites. Evaluation of the prevalence of ESBL-production among urinary E. coli isolates is crucial due to its great impact on the choice of proper antimicrobials. Accordingly, the aim of this work was to detect and characterize ESBL-producing E. coli isolated from outpatients with signs of UTIs in Upper Egypt. Urinary E. coli isolates were identified by 16S rRNA and their ESBL-production was confirmed by Modified Double Disc Synergy Test (MDDST) and ESBL- CHROMagar media. Isolates were then subjected to Polymerase Chain Reaction (PCR) for new Clermont phylogrouping, ESBL genes detection and CTX-M typing. The study enrolled 583 patients with clinically diagnosed UTIs. Uropathogens were found in 400 urine samples (68.6%) out of which 134 E. coli isolates were identified. Among the examined uropathogenic E. coli (UPEC), 80 (59.7%) were recognized as ESBL-producers. Greater than half of the ESBL-producers were multi-drug resistant (MDR) (62%). All of them were susceptible to meropenem. Most of the E. coli isolates were distributed in 4 phylogenetic groups: B2 = 42 (52.5%), F = 17 (21.25%) and Clade I or II = 10 (12.5%). The predominant gene types were TEM 60 (75%) and CTX-M gene 45 (56.25%). The CTX-M-1 group was the most prevalent (62.2%), including the CTX-M-15 enzyme, followed by the CTX-M-2 group, CTX-M-8 group and CTX-M-9 group. In conclusion, the results present alarming evidence of a serious spread of ESBL genes in Egypt, especially the epidemiological CTX-M 15, with the potential for the dissemination of MDR UPEC strains in the community.

Quorum sensing (QS) regulates virulence factor expression in Pseudomonas aeruginosa. Inhibiting the QS-controlled virulence factors without inhibiting the growth of P. aeruginosa is a promising approach for overcoming the widespread resistance of P. aeruginosa. This study was proposed to investigate the effects of two novel synthetic peptides on the biofilm development and virulence factor production of P. aeruginosa. The tested strain was P. aeruginosa PAO1. The results indicated that both of the synthetic peptides (LIVRHK and LIVRRK) inhibited (P < 0.05) the formation of biofilms and the production of virulence factors, including pyocyanin, protease, and rhamnolipids, without inhibiting the growth of PAO1. Additionally, we detected transcriptional changes related to QS and found a significant reduction in the levels of gene expression of lasI, lasR, rhlI, and rhlR. This study demonstrates that LIVRRK and LIVRHK are novel synthetic peptides that can act as potent inhibitors of QS-regulated virulence factors in P. aeruginosa. Moreover, these synthetic peptides have potential applications in the treatment of biofilmrelated diseases. Both peptides may be able to control chronic infections and biofilm-associated problems of P. aeruginosa.

An important mechanism for microbial resistance to mercury is its reduction into elemental mercury (facilitated by the merA gene). Thirty-eight microbial isolates from a variety of wastewater sources in Egypt were collected. Approximately 14 of the 38 isolates exhibited not only a high degree of tolerance to mercury (up to 160 ppm) but also a high degree of resistance to other tested heavy metals (Cu, Co, Ni, and Zn). From these 14, the 10 most resistant isolates were selected for further study and were found to include 9 Gram-negative and 1 Gram-positive bacterial strains. Multi-antibiotic-resistance profiles were detected for 6 out of the 10 selected isolates. All the tested Gram-negative isolates (n = 9) harbored a plasmid-encoded merA gene. The mercury removal effectiveness for the 10 selected isolates ranged between 50% and 99.9%, among which Stenotrophomonas maltophilia ADW10 recorded the highest rate (99.9%; at an initial mercury concentration of 20 ppm). To the best of our knowledge, this is the first study to (i) demonstrate the presence of a multimetal-resistant S. maltophilia bacterium with a high mercury tolerance capacity that would make it a suitable candidate for future bioremediation efforts in heavy-metal-polluted areas in Egypt and (ii) report Pseudomonas otitidis as one of the mercury-resistant bacteria.

Expansion of COVID-19 worldwide increases interest in unraveling genomic variations of novel SARS-CoV-2 virus. Metadata of 408,493 SARS-CoV-2 genomes submitted to GISAID database were analyzed with respect to genomic clades and their geographic, age, and gender distributions. Of the currently known SARS-CoV-2 clades, clade GR was the most prevalent worldwide followed by GV then GH. Chronological analysis revealed expansion in SARS-CoV-2 clades carrying D614G mutations with the predominance of the newest clade, GV, in the last three months. D614G clades prevail in countries with more COVID-19 cases. Of them, the clades GH and GR were more frequently recovered from severe or deceased COVID-19 cases. In contrast, G and GV clades showed a significantly higher prevalence among asymptomatic patients or those with mild disease. Metadata analysis showed higher (p

The incidence of cancer is increasing worldwide; likewise, the emergence of antibiotic-resistant biofilm-forming pathogens has led to a tremendous increase in morbidity and mortality. This study aimed to evaluate the probiotic properties of bacteriocin-producing Enterococcus sp. with a focus on their anti-biofilm and anticancer activities. Three of 79 Enterococcus isolates (FM43, FM65, FM50) were identified as producers of broad-spectrum bioactive molecules and were molecularly characterized as Enterococcus faecium by 16S rRNA sequencing. Phenotypic and genotypic screening for potential virulence factors revealed no factors known to promote pathogenicity. Treatment with proteinase K resulted in diminished antimicrobial activity; PCR-based screening for bacteriocin genes suggested the presence of both entA and entB genes that encode enterocins A and B, respectively. Maximum antimicrobial activity was detected during the early stationary phase, while activity disappeared after 24 h in culture. Bacteriocins from these isolates were stable at high temperatures and over a wide range of pH. Interestingly, crude supernatants of Ent. faecium FM43 and Ent. faecium FM50 resulted in significant destruction (80% and 48%, respectively; P 0.05) of Streptococcus mutans ATCC 25175-associated preformed biofilms. Moreover, in vitro cytotoxicity assays revealed that extracts from Ent. faecium isolates FM43, FM65, and FM50 inhibited Caco-2 cell proliferation by 76.9%, 70%, and 85.3%, respectively. Taken together, the multifunctional capabilities of the microbial-derived proteins identified in our study suggest potentially important roles as alternative treatments for biofilm-associated infections and cancer.

The prevalence of extensively and pandrug-resistant strains of Acinetobacter baumannii leaves little or no therapeutic options for treatment for this bacterial pathogen. Bacteriophages and their lysins represent attractive alternative antibacterial strategies in this regard. We used the extensively drug-resistant A. baumannii strain MK34 to isolate the bacteriophage PMK34 (vB_AbaP_PMK34). This phage shows fast adsorption and lacks virulence genes; nonetheless, its narrow host spectrum based on capsule recognition limits broad application. PMK34 is a Fri1virus member of the Autographiviridae and has a 41.8-kb genome (50 open reading frames), encoding an endolysin (LysMK34) with potent muralytic activity (1,499.9 ± 131 U/μM), a typical mesophilic thermal stability up to 55°C, and a broad pH activity range (4 to 10). LysMK34 has an intrinsic antibacterial activity up to 4.8 and 2.4 log units for A. baumannii and Pseudomonas aeruginosa strains, respectively, but only when a high turgor pressure is present. The addition of 0.5 mM EDTA or application of an osmotic shock after treatment can compensate for the lack of a high turgor pressure. The combination of LysMK34 and colistin results in up to 32-fold reduction of the MIC of colistin, and colistin-resistant strains are resensitized in both Mueller-Hinton broth and 50% human serum. As such, LysMK34 may be used to safeguard the applicability of colistin as a last-resort antibiotic.

The prevalence of extensively and pandrug-resistant strains of Acinetobacter baumannii leaves little or no therapeutic options for treatment for this bacterial pathogen. Bacteriophages and their lysins represent attractive alternative antibacterial strategies in this regard. We used the extensively drug-resistant A. baumannii strain MK34 to isolate the bacteriophage PMK34 (vB_AbaP_PMK34). This phage shows fast adsorption and lacks virulence genes; nonetheless, its narrow host spectrum based on capsule recognition limits broad application. PMK34 is a Fri1virus member of the Autographiviridae and has a 41.8-kb genome (50 open reading frames), encoding an endolysin (LysMK34) with potent muralytic activity (1,499.9 ± 131 U/μM), a typical mesophilic thermal stability up to 55°C, and a broad pH activity range (4 to 10). LysMK34 has an intrinsic antibacterial activity up to 4.8 and 2.4 log units for A. baumannii and Pseudomonas aeruginosa strains, respectively, but only when a high turgor pressure is present. The addition of 0.5 mM EDTA or application of an osmotic shock after treatment can compensate for the lack of a high turgor pressure. The combination of LysMK34 and colistin results in up to 32-fold reduction of the MIC of colistin, and colistin-resistant strains are resensitized in both Mueller-Hinton broth and 50% human serum. As such, LysMK34 may be used to safeguard the applicability of colistin as a last-resort antibiotic. IMPORTANCE A. baumannii is one of the most challenging pathogens for which development of new and effective antimicrobials is urgently needed. Colistin is a last-resort antibiotic, and even colistin-resistant A. baumannii strains exist. Here, we present a lysin that sensitizes A. baumannii for colistin and can revert colistin resistance to colistin susceptibility. The lysin also shows a strong, turgor pressure-dependent intrinsic antibacterial activity, providing new insights in the mode of action of lysins with intrinsic activity against Gram-negative bacteria.

Background:Mercury is a toxic metal that is present in small amounts in the environment, but its level is rising steadily, due to different human activities, such as industrialization. It can reach humans through the food chain, amalgam fillings, and other sources, causing different neurological disorders, memory loss, vision impairment, and may even lead to death; making its detoxification an urgent task.Methods:Various physical and chemical mercury remediation techniques are available, which generally aim at: (i) reducing its mobility or solubility; (ii) causing its vaporization or condensation; (iii) its separation from contaminated soils. Biological remediation techniques, commonly known as bioremediation, are also another possible alternative, which is considered as cheaper than the conventional means and can be accomplished using either (i) organisms harboring themeroperon genes (merB,merA,merR,merP,merT,merD,merF,merC,merE,merHandmerG), or (ii) plants expressing metal-binding proteins. Recently, differentmerdeterminants have been genetically engineered into several organisms, including bacteria and plants, to aid in detoxification of both ionic and organic forms of mercury.Results:Bacteria that are resistant to mercury compounds have at least a mercuric reductase enzyme (MerA) that reduces Hg+2to volatile Hg0, a membrane-bound protein (MerT) for Hg+2uptake and an additional enzyme, MerB, that degrades organomercurials by protonolysis. Presence of bothmerA andmerB genes confer broad-spectrum mercury resistance. However,merA alone confers narrow spectrum inorganic mercury resistance.Conclusion:To conclude, this review discusses the importance of mercury-resistance genes in mercury bioremediation. Functional analysis ofmeroperon genes and the recent advances in genetic engineering techniques could provide the most environmental friendly, safe, effective and fantastic solution to overcome mercuric toxicity.

Introduction: Although miltefosine is the first line for treatment of leishmaniasis, it could have multiple un-recognized effects if any infection accidentally takes place during therapy. The aim is to precisely evaluate the molecular and biochemical remarks of miltefosine on Toxoplasma gondii accidental infection during miltefosine therapeutic course. Methodology: changes implied by miltefosine daily parenteral administration to Toxoplasma-infected mice, subcutaneously or intraperitoneal, have been investigated. Tumor necrosis factor-Alfa, immunoglobulin G and M, IL-12 and interferon-gamma release assay (IGRA) were measured in the animals’ sera post-miltefosine administration in addition to monitoring Tissue parasite load by measuring the daily changes of copy number of B1 gene using quantitative PCR technique (qPCR). Results: Miltefosine significantly increased inflammatory and immunological markers (TNF-α, IgG and IgM) measured on reference to control untreated group, with a significant increase in the parasite burden and distribution in all tested organs (F = 390.9, df = 9, P < 0.0001), (F = 4478.98, df = 4.75, P< 0.0001) and (F = 247.3, df = 4, P < 0.0001); heart, liver and lung, respectively, using MANOVA. Releasing capability of macrophages significantly increased during the first day of infection, however, it finally declined after seven consecutive doses of miltefosine (t = 7.96, P < 0.001). Conclusion: Miltefosine could not control the pathogenesis and multiplication of accidental Toxoplasma infection. Cumulative low parenteral daily doses of miltefosine (1.5 µM) could inversely affected the normal humoral immunity against toxoplasmosis. Therefore, a periodical screening for accidental Toxoplasma infection during the course of therapy is strongly recommended.

Neisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6-family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46-expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross-linking and enzyme-linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose-dependent increase in DC death via caspase-dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.

ABSTRACT: Aim: To quantitatively assess Staphylococcus aureus biofilms. Materials & methods: In addition to the qualitative Congo red agar (CRA) method, we used the bioluminescence (BLM), safranine (SAF), crystal violet (CRV) and resazurin (RES) high-throughput microtiter plate-based quantitative assays. Results: 60.47% (26/43) of S. aureus clinical isolates were weak biofilm producers. The CRA method detected positive-slime phenotypes (13.95%), but was unable to distinguish weak from negative producers. BLM assays demonstrated significant correlations with RES (highest), CRV and SAF (lowest). Lower coefficient of variation values indicate precision. BLM scored highest precision (coefficient of variation = 0.013) followed by RES, SAF and CRV. Conclusion: BLM and RES detect live biomass in S. aureus biofilms (for physiological studies). SAF and CRV detect live/dead bacteria plus biofilm matrix (for monitoring overall biofilm architecture, not only its cell viability). Reliable assays are essential for effective biofilm therapy.

Scientific Background: Non alcoholic fatty liver (NAFLD) is accumulation of fat in the liver cells of peoples who drink little or no alcohol causing mild steatosis with mostly no signs, symptoms or complication but this may progress to steatohepatitis (NASH) and may liver cirrhosis then failure. NAFLD is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD and its progress. A number of factors are linked with NAFLD such as obesity, type 2 diabetis mellitus (T2DM), hyperlipidemia, gastric Original Research Article International Journal of Biochemistry Research & Review, 4(6): 493-504, 2014 494 bypass, and its progress to NASH correlate with certain cytokines secreted like adiponectin, interlukin-6 (IL-6), and Creactive protein CRP. Adiponectin is a novel adipocyte-specific protein, which, it has been suggested, plays a role in the development of insulin resistance and atherosclerosis. The role of (IL-6) in liver pathology is very complex, and its participation in the development of NAFLD remains unclear. IL-6 is a key element in the acute phase response, mediating the synthesis of several acute phase proteins (such as CRP and serum amyloid A). Thus, we cannot exclude the possibility that IL-6 might also play an indirect deleterious role in NAFLD pathogenesis. In diet-induced obese mice, treatment with IL-6 antibodies improved sensitivity to insulin. Objective: This study aim is to evaluate the level of adiponectin, IL-6 and CRP in Egyptian patients with NAFLD. Methods: This study was conducted on 2 groups 104 NAFLD as diagnosed by ultrasound examination and 21 healthy participants as control group. All the subjects were subjected to an abdominal ultrasonography, liver enzymes ALT & AST, lipid profile (triglycerides, HDL, LDL, cholesterol, CRP, IL-6 & Adiponectin). Results: Plasma adiponectin levels were significantly lower in NAFLD patients than control gp (3.05±2.65μg/ml vs 10.52±3.35 (μg/ml). IL-6 level was higher in NAFLD than control gp but not significant (114.24±22.32pg/ml vs 104.9±19.98pg/ml). CRP was significantly higher in NAFLD than control gp (17.86±11.59mg/L vs 5.4±3.81mg/L). Adiponectin ROC curve showed an AUROC curve in NAFLD gp (0.918 p=0.0001). IL-6 ROC curve showed an AUROC curve in NAFLD gp (0.703 p=0.0003). CRP ROC curve showed an AUROC curve in NAFLD gp (0.853 p=0.0001). Conclusion: Patients with NAFLD have lower adiponectin levels and higher IL-6 and CRP levels compared with their control group.

Bacteriocins are proteinaceous antibacterial compounds, produced by diverse bacteria, which have been successfully used as: (i) food biopreservative; (ii) anti biofilm agents; and (iii) additives or alternatives to the currently existing antibiotics, to minimize the risk of emergence of resistant strains. However, there are several limitations that challenge the use of bacteriocins as biopreservatives / antibacterial agents. One of the most promising avenues to overcome these limitations is the use of nanoformulations. This review highlights the practical difficulties with using bacteriocins to control pathogenic microorganisms, and provides an overview on the role of nanotechnology in improving the antimicrobial activity and the physicochemical properties of these peptides.

The purpose of this study was to: (i) evaluate the antibacterial activities of three Egyptian honeys collected from different floral sources (namely, citrus, clover, and marjoram) against Escherichia coli; (ii) investigate the effects of these honeys on bacterial ultrastructure; and (iii) assess the anti-virulence potential of these honeys, by examining their impacts on the expression of eight selected genes (involved in biofilm formation, quorum sensing, and stress survival) in the test organism. The minimum inhibitory concentration (MIC) of the honey samples against E. coli ATCC 8739 were assessed by the broth microdilution assay in the presence and absence of catalase enzyme. Impacts of the honeys on the cellular ultrastructure and the expression profiles of the selected genes of E. coli were examined using transmission electron microscopy (TEM) and quantitative real-time polymerase chain reaction (qPCR) analysis, respectively. The susceptibility tests showed promising antibacterial activities of all the tested honeys against E. coli. This was supported by the TEM observations, which revealed “ghost” cells lacking DNA, in addition to cells with increased vacuoles, and/or with irregular shrunken cytoplasm. Among the tested honeys, marjoram exhibited the highest total antibacterial activity and the highest levels of peroxide-dependent activity. The qPCR analysis showed that all honey-treated cells share a similar overall pattern of gene expression, with a trend toward reduced expression of the virulence genes of interest. Our results indicate that some varieties of the Egyptian honey have the potential to be effective inhibitor and virulence modulator of E. coli via multiple molecular targets.

Summary N eisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6‐family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46‐expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross‐linking and enzyme‐linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose‐dependent increase in DC death via caspase‐dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.