Intestinally Secreted C-Type Lectin Reg3b Attenuates Salmonellosis but Not Listeriosis in Mice

The Reg3 protein family, including the human member designated pancreatitis-associated protein (PAP), consists of secreted proteins that contain a C-type lectin domain involved in carbohydrate binding. They are expressed by intestinal epithelial cells. Colonization of germ-free mice and intestinal infection with pathogens increase the expression of Reg3g and Reg3b in the murine ileum. Reg3g is directly bactericidal for Gram-positive bacteria, but the exact role of Reg3b in bacterial infections is unknown. To investigate the possible protective role of Reg3b in intestinal infection, Reg3b knockout (Reg3b−/−) mice and wild-type (WT) mice were orally infected with Gram-negativeSalmonella enteritidisor Gram-positiveListeria monocytogenes. At day 2 after oralListeriainfection and at day 4 after oralSalmonellainfection, mice were sacrificed to collect intestinal and other tissues for pathogen quantification. Protein expression of Reg3b and Reg3g was determined in intestinal mucosal scrapings of infected and noninfected mice. In addition,ex vivobinding of ileal mucosal Reg3b toListeriaandSalmonellawas investigated. Whereas recovery ofSalmonellaorListeriafrom feces of Reg3b−/−mice did not differ from that from feces of WT mice, significantly higher numbers of viableSalmonella, but notListeria, bacteria were recovered from the colon, mesenteric lymph nodes, spleen, and liver of the Reg3b−/−mice than from those of WT mice. Mucosal Reg3b binds to both bacterial pathogens and may interfere with their mode of action. Reg3b plays a protective role against intestinal translocation of the Gram-negative bacteriumS. enteritidisin mice but not against the Gram-positive bacteriumL. monocytogenes.

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The metabolism of the innate immunity cells in bacterial infections

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20156101105 ◽

2015 ◽

Vol 61 (1) ◽

pp. 105-114 ◽

Cited By ~ 2

Author(s):

N.G. Plekhova ◽

L.M. Somova ◽

E.I. Drobot

Keyword(s):

Innate Immunity ◽

Bacterial Infections ◽

Salmonella Enteritidis ◽

Yersinia Pseudotuberculosis ◽

Initial Period ◽

Bacterial Load ◽

Neutrophil Accumulation ◽

Gram Positive ◽

Gram Negative ◽

Innate Immunity Cells

Metabolic activity of innate immunity cells infected by various doses of Gram-negative (Yersinia pseudotuberculosis, Salmonella enteritidis) and Gram-positive (Staphylococcus aureus, Listeria monocytogenes) bacteria has been investigated. Using various animal models we found that during the initial period (up to 2 days) changes of infection in cellular responses depend on the type of the pathogen. In response to infection caused by Gram-negative bacteria predominant neutrophil accumulation in the foci of inflammation was observed, while Gram-positive bacteria induced preferential accumulation of macrophages. The study of metabolism of these cells showed that the response of terminally differentiated primed phagocytes to pathogen appearance was higher than in cells circulating in blood. In addition to the priming state the phagocyte reactivity is influenced by the bacterial load. At a low phagocyte/microbe ratio the cells reaction is almost undetectable, while an excess of microorganisms causes (despite of the increase of the phagocytic parameters) the hyperactivation of cell metabolism and production of maximal amounts of bactericide agents, which exhibit a damaging effect on the cell itself.

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CD137 Expressed on Neutrophils Plays Dual Roles in Antibacterial Responses against Gram-Positive and Gram-Negative Bacterial Infections

Infection and Immunity ◽

10.1128/iai.00115-13 ◽

2013 ◽

Vol 81 (6) ◽

pp. 2168-2177 ◽

Cited By ~ 8

Author(s):

Quang-Tam Nguyen ◽

Thu-Ha T. Nguyen ◽

Seong-A. Ju ◽

Yea-Sol Lee ◽

Seung Hyun Han ◽

...

Keyword(s):

Bacterial Infections ◽

Costimulatory Molecule ◽

Host Responses ◽

Gram Positive ◽

Necrosis Factor Alpha ◽

Gram Negative ◽

Content Type ◽

Stimulation Of

ABSTRACTSevere sepsis and septic shock caused mainly by bacterial infections are life-threatening conditions that urge the development of novel therapies. However, host responses to and pathophysiology of sepsis have not been clearly understood, which remains a major obstacle for the development of effective therapeutics. Recently, we have shown that stimulation of a costimulatory molecule, CD137, enhanced survival of mice infected with the Gram-positive (G+) intracellular bacteriumListeria monocytogenesbut decreased survival in a polymicrobial sepsis model. Herein, we report that CD137 deficiency or blocking of CD137 signaling decreased antibacterial responses of mice infected with G+bacteria (Staphylococcus aureus,Streptococcus pneumoniae, andEnterococcus faecalis) but increased these responses in mice infected with Gram-negative (G−) bacteria (Escherichia coli,Pseudomonas aeruginosa, andSalmonella entericaserovar Typhimurium). Consistent with these findings, stimulation of CD137 by administration of agonistic antibody enhanced responses against G+bacteria, whereas it decreased these responses against G−bacteria. Neutrophils were responsible for CD137-mediated opposite roles in control of G+and G−bacterial infections. Stimulation of CD137 enhanced activities of neutrophils againstS. aureusbut decreased these activities againstE. coli, while CD137 blocking produced opposite results with the stimulation of CD137in vivoandin vitro. Furthermore, we found that combined signaling of CD137 and Toll-like receptor 2 (TLR2) induced synergistic production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) by neutrophils, but combined signaling of CD137 and TLR4 did not. Our data strongly suggest that CD137 may play a dual role in sepsis in association with TLRs.

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Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00028-16 ◽

2016 ◽

Vol 80 (3) ◽

pp. 891-903 ◽

Cited By ~ 74

Author(s):

Minh Thu Nguyen ◽

Friedrich Götz

Keyword(s):

Immune Response ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative ◽

Content Type ◽

Gram Positive Bacteria ◽

Key Players ◽

Toll Like Receptor 2 ◽

Number Of Publications

SUMMARYSince the discovery in 1973 of the first of the bacterial lipoproteins (Lpp) inEscherichia coli, Braun's lipoprotein, the ever-increasing number of publications indicates the importance of these proteins. Bacterial Lpp belong to the class of lipid-anchored proteins that in Gram-negative bacteria are anchored in both the cytoplasmic and outer membranes and in Gram-positive bacteria are anchored only in the cytoplasmic membrane. In contrast to the case for Gram-negative bacteria, in Gram-positive bacteria lipoprotein maturation and processing are not vital. Physiologically, Lpp play an important role in nutrient and ion acquisition, allowing particularly pathogenic species to better survive in the host. Bacterial Lpp are recognized by Toll-like receptor 2 (TLR2) of the innate immune system. The important role of Lpp in Gram-positive bacteria, particularly in the phylumFirmicutes, as key players in the immune response and pathogenicity has emerged only in recent years. In this review, we address the role of Lpp in signaling and modulating the immune response, in inflammation, and in pathogenicity. We also address the potential of Lpp as promising vaccine candidates.

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Prc Contributes to Escherichia coli Evasion of Classical Complement-Mediated Serum Killing

Infection and Immunity ◽

10.1128/iai.00321-12 ◽

2012 ◽

Vol 80 (10) ◽

pp. 3399-3409 ◽

Cited By ~ 25

Author(s):

Chin-Ya Wang ◽

Shainn-Wei Wang ◽

Wen-Chun Huang ◽

Kwang Sik Kim ◽

Nan-Shan Chang ◽

...

Keyword(s):

Escherichia Coli ◽

Bacterial Infections ◽

Membrane Attack Complex ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Serum Killing ◽

High Level ◽

Classical Complement

ABSTRACTEscherichia coliis a common Gram-negative organism that causes bacteremia. Prc, a bacterial periplasmic protease, and its homologues are known to be involved in the pathogenesis of Gram-negative bacterial infections. The present study examined the role of Prc inE. colibacteremia and characterized the ability of theprcmutant of the pathogenicE. colistrain RS218 to cause bacteremia and survive in human serum. Theprcmutant of RS218 exhibited a decreased ability to cause a high level of bacteremia and was more sensitive to serum killing than strain RS218. This sensitivity was due to the mutant's decreased ability to avoid the activation of the antibody-dependent and -independent classical complement cascades as well as its decreased resistance to killing mediated by the membrane attack complex, the end product of complement system activation. The demonstration of Prc in the evasion of classical complement-mediated serum killing of pathogenicE. colimakes this factor a potential target for the development of therapeutic and preventive measures againstE. colibacteremia.

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Fusogenic porous silicon nanoparticles as a broad-spectrum immunotherapy against bacterial infections

Nanoscale Horizons ◽

10.1039/d0nh00624f ◽

2021 ◽

Author(s):

Byungji Kim ◽

Qinglin Yang ◽

Leslie W. Chan ◽

Sangeeta N. Bhatia ◽

Erkki Ruoslahti ◽

...

Keyword(s):

Porous Silicon ◽

Broad Spectrum ◽

Therapeutic Efficacy ◽

Bacterial Infections ◽

Silicon Nanoparticles ◽

First Line ◽

Gram Positive ◽

Gram Negative ◽

Porous Silicon Nanoparticles

RNAi-mediated immunotherapy provided by fusogenic porous silicon nanoparticles demonstrates superior therapeutic efficacy against both Gram-positive and Gram-negative bacterial infections compared with first-line antibiotics.

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Dynamics ofMycobacterium tuberculosisAg85B Revealed by a Sensitive Enzyme-Linked Immunosorbent Assay

mBio ◽

10.1128/mbio.00611-19 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 2

Author(s):

Joel D. Ernst ◽

Amber Cornelius ◽

Miriam Bolz

Keyword(s):

Protein Secretion ◽

Immunosorbent Assay ◽

Bacterial Population ◽

Enzyme Linked Immunosorbent Assay ◽

Bacterial Protein ◽

Gram Positive ◽

Gram Negative ◽

Content Type ◽

Bacterial Proteins

ABSTRACTSecretion of specific proteins contributes to pathogenesis and immune responses in tuberculosis and other bacterial infections, yet the kinetics of protein secretion and fate of secreted proteinsin vivoare poorly understood. We generated new monoclonal antibodies that recognize theMycobacteriumtuberculosissecreted protein Ag85B and used them to establish and characterize a sensitive enzyme-linked immunosorbent assay (ELISA) to quantitate Ag85B in samples generatedin vitroandin vivo. We found that nutritional or culture conditions had little impact on the secretion of Ag85B and that there is considerable variation in Ag85B secretion by distinct strains in theM. tuberculosiscomplex: compared with the commonly used H37Rv strain (lineage 4),Mycobacteriumafricanum(lineage 6) secretes less Ag85B, and two strains from lineage 2 secrete more Ag85B. We also used the ELISA to determine that the rate of secretion of Ag85B is 10- to 100-fold lower than that of proteins secreted by Gram-negative and Gram-positive bacteria, respectively. ELISA quantitation of Ag85B in lung homogenates ofM. tuberculosisH37Rv-infected mice revealed that although Ag85B accumulates in the lungs as the bacterial population expands, the amount of Ag85B per bacterium decreases nearly 10,000-fold at later stages of infection, coincident with the development of T cell responses and arrest of bacterial population growth. These results indicate that bacterial protein secretionin vivois dynamic and regulated, and quantitation of secreted bacterial proteins can contribute to the understanding of pathogenesis and immunity in tuberculosis and other infections.IMPORTANCEBacterial protein secretion contributes to host-pathogen interactions, yet the process and consequences of bacterial protein secretion during infection are poorly understood. We developed a sensitive ELISA to quantitate a protein (termed Ag85B) secreted byM. tuberculosisand used it to find that Ag85B secretion occurs with slower kinetics than for proteins secreted by Gram-positive and Gram-negative bacteria and that accumulation of Ag85B in the lungs is markedly regulated as a function of the bacterial population density. Our results demonstrate that quantitation of bacterial proteins during infection can reveal novel insights into host-pathogen interactions.

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Factors Influencing the Microbial Composition of Metalworking Fluids and Potential Implications for Machine Operator's Lung

Applied and Environmental Microbiology ◽

10.1128/aem.06230-11 ◽

2011 ◽

Vol 78 (1) ◽

pp. 34-41 ◽

Cited By ~ 26

Author(s):

Jean-Benjamin Murat ◽

Frédéric Grenouillet ◽

Gabriel Reboux ◽

Emmanuelle Penven ◽

Adam Batchili ◽

...

Keyword(s):

Metal Cutting ◽

Hypersensitivity Pneumonitis ◽

Environmental Parameters ◽

Metalworking Fluids ◽

Microbial Composition ◽

Gram Positive ◽

Gram Negative ◽

Content Type ◽

Kinetics Of

ABSTRACTHypersensitivity pneumonitis, also known as “machine operator's lung” (MOL), has been related to microorganisms growing in metalworking fluids (MWFs), especiallyMycobacterium immunogenum. We aimed to (i) describe the microbiological contamination of MWFs and (ii) look for chemical, physical, and environmental parameters associated with variations in microbiological profiles. We microbiologically analyzed 180 MWF samples from nonautomotive plants (e.g., screw-machining or metal-cutting plants) in the Franche-Comté region in eastern France and 165 samples from three French automotive plants in which cases of MOL had been proven. Our results revealed two types of microbial biomes: the first was from the nonautomotive industry, showed predominantly Gram-negative rods (GNR), and was associated with a low risk of MOL, and the second came from the automotive industry that was affected by cases of MOL and showed predominantly Gram-positive rods (GPR). Traces ofM. immunogenumwere sporadically detected in the first type, while it was highly prevalent in the automotive sector, with up to 38% of samples testing positive. The use of chromium, nickel, or iron was associated with growth of Gram-negative rods; conversely, growth of Gram-positive rods was associated with the absence of these metals. Synthetic MWFs were more frequently sterile than emulsions. Vegetable oil-based emulsions were associated with GNR, while mineral ones were associated with GPR. Our results suggest that metal types and the nature of MWF play a part in MWF contamination, and this work shall be followed by furtherin vitrosimulation experiments on the kinetics of microbial populations, focusing on the phenomena of inhibition and synergy.

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The role of PCSK9 in infectious diseases.

Current Medicinal Chemistry ◽

10.2174/0929867328666210714160343 ◽

2021 ◽

Vol 28 ◽

Author(s):

Laura Magnasco ◽

Chiara Sepulcri ◽

Roberta Maria Antonello ◽

Stefano Di Bella ◽

Laura Labate ◽

...

Keyword(s):

Infectious Diseases ◽

Malaria Infection ◽

Bacterial Infections ◽

Viral Infections ◽

Physiological Role ◽

Protective Role ◽

Loss Of Function ◽

Pcsk9 Inhibition ◽

Sepsis And Septic Shock

Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, particularly regarding its role in lipid metabolism, cardiovascular risk, and its role in innate immunity. Increasing evidence is available about the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, and the regulation of host response to bacterial infections, primarily sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. Objective: This paper aims to review the available published literature on the role of PCSK9 in a wide array of infectious diseases. Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients to treat HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Finally, a loss of function in the PCSK9-encoding gene has been reported to reduce malaria infection mortality.

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Effectiveness of Trisodium Phosphate, Acidified Sodium Chlorite, Citric Acid, and Peroxyacids against Pathogenic Bacteria on Poultry during Refrigerated Storage

Journal of Food Protection ◽

10.4315/0362-028x-70.9.2063 ◽

2007 ◽

Vol 70 (9) ◽

pp. 2063-2071 ◽

Cited By ~ 44

Author(s):

ELENA del RÍO ◽

REBECA MURIENTE ◽

MIGUEL PRIETO ◽

CARLOS ALONSO-CALLEJA ◽

ROSA CAPITA

Keyword(s):

Citric Acid ◽

Salmonella Enteritidis ◽

Pathogenic Bacteria ◽

Trisodium Phosphate ◽

Sodium Chlorite ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative ◽

Microbial Group ◽

And Control

The effects of dipping treatments (15 min) in potable water or in solutions (wt/vol) of 12% trisodium phosphate (TSP), 1,200 ppm acidified sodium chlorite (ASC), 2% citric acid (CA), and 220 ppm peroxyacids (PA) on inoculated pathogenic bacteria (Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, Salmonella Enteritidis, Escherichia coli, and Yersinia enterocolitica) and skin pH were investigated throughout storage of chicken legs (days 0, 1, 3, and 5) at 3 ± 1°C. All chemical solutions reduced microbial populations (P < 0.001) as compared with the control (untreated) samples. Similar bacterial loads (P > 0.05) were observed on water-dipped and control legs. Type of treatment, microbial group, and sampling day influenced microbial counts (P < 0.001). Average reductions with regard to control samples were 0.28 to 2.41 log CFU/g with TSP, 0.33 to 3.15 log CFU/g with ASC, 0.82 to 1.97 log CFU/g with CA, and 0.07 to 0.96 log CFU/g with PA. Average reductions were lower (P < 0.001) for gram-positive (0.96 log CFU/g) than for gram-negative (1.33 log CFU/g) bacteria. CA and ASC were the most effective antimicrobial compounds against gram-positive and gram-negative bacteria, respectively. TSP was the second most effective compound for both bacterial groups. Average microbial reductions per gram of skin were 0.87 log CFU/g with TSP, 0.86 log CFU/g with ASC, 1.39 log CFU/g with CA, and 0.74 log CFU/g with PA for gram-positive bacteria, and 1.28 log CFU/g with TSP, 2.03 log CFU/g with ASC, 1.23 log CFU/g with CA, and 0.78 log CFU/g with PA for gram-negative bacteria. With only a few exceptions, microbial reductions in TSP- and ASC-treated samples decreased and those in samples treated with CA increased throughout storage. Samples treated with TSP and samples dipped in CA and ASC had the highest and lowest pH values, respectively, after treatment. The pH of the treated legs tended to return to normal (6.3 to 6.6) during storage. However, at the end of storage, the pH of legs treated with TSP remained higher and that of legs treated with CA remained lower than normal.

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Cyclic Boronates Inhibit All Classes of β-Lactamases

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02260-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 59

Author(s):

Samuel T. Cahill ◽

Ricky Cain ◽

David Y. Wang ◽

Christopher T. Lohans ◽

David W. Wareham ◽

...

Keyword(s):

Crystal Structure ◽

Bacterial Infections ◽

Binding Mode ◽

Gram Negative ◽

Content Type ◽

Class A ◽

Class D ◽

Dual Action ◽

The Common ◽

Continued Use

ABSTRACT β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of “dual-action” inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.

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