scholarly journals The Vi Capsular Polysaccharide Prevents Complement Receptor 3-Mediated Clearance ofSalmonella entericaSerotype Typhi

2010 ◽  
Vol 79 (2) ◽  
pp. 830-837 ◽  
Author(s):  
R. Paul Wilson ◽  
Sebastian E. Winter ◽  
Alanna M. Spees ◽  
Maria G. Winter ◽  
Jessalyn H. Nishimori ◽  
...  
Keyword(s):  
Capsular Polysaccharide ◽  
Immune Serum ◽  
Complement Receptor ◽  
Immune Recognition ◽  
Bacterial Binding ◽  
Intraperitoneal Infection ◽  
Complement Receptor 3 ◽  
Vi Capsular Polysaccharide

ABSTRACTCapsular polysaccharides are important virulence factors of invasive bacterial pathogens. Here we studied the role of the virulence (Vi) capsular polysaccharide ofSalmonella entericaserotype Typhi (S.Typhi) in preventing innate immune recognition by complement. Comparison of capsulatedS.Typhi with a noncapsulated mutant (ΔtviBCDE vexABCDEmutant) revealed that the Vi capsule interfered with complement component 3 (C3) deposition. Decreased complement fixation resulted in reduced bacterial binding to complement receptor 3 (CR3) on the surface of murine macrophagesin vitroand decreased CR3-dependent clearance of Vi capsulatedS.Typhi from the livers and spleens of mice. Opsonization of bacteria with immune serum prior to intraperitoneal infection increased clearance of capsulatedS.Typhi from the liver. Our data suggest that the Vi capsule prevents CR3-dependent clearance, which can be overcome in part by a specific antibody response.

scholarly journals β-Glucan enhances complement-mediated hematopoietic recovery after bone marrow injury

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 835-840 ◽  
Author(s):  
Daniel E. Cramer ◽  
Daniel J. Allendorf ◽  
Jarek T. Baran ◽  
Richard Hansen ◽  
Jose Marroquin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Serum ◽  
Complement Receptor ◽  
Dependent Manner ◽  
Complement Receptor 3 ◽  
Total Body ◽  
Stimulating Factor ◽  
Sublethal Irradiation ◽  
Classic Pathway

AbstractMyelotoxic injury in the bone marrow (BM) as a consequence of total body irradiation (TBI) or granulocyte colony-stimulating factor (G-CSF) mobilization results in the deposition of iC3b on BM stroma (stroma-iC3b). In the present study, we have examined how stroma-iC3b interacts with hematopoietic progenitor cells (HPCs) and the role of complement (C) and complement receptor 3 (CR3) in BM injury/repair. We demonstrate here that stroma-iC3b tethers HPCs via the inserted (I) domain of HPC complement receptor 3 (CR3, CD11b/CD18, Mac-1). Following irradiation, stroma-iC3b was observed in the presence of purified IgM and normal mouse serum (NMS), but not serum from Rag-2-/- mice, implicating a role for antibody (Ab) and the classic pathway of C activation. Furthermore, a novel role for soluble yeast β-glucan, a ligand for the CR3 lectin-like domain (LLD), in the priming of CR3+ HPC is suggested. Soluble yeast β-glucan could enhance the proliferation of tethered HPCs, promote leukocyte recovery following sublethal irradiation, and increase the survival of lethally irradiated animals following allogeneic HPC transplantation in a CR3-dependent manner. Taken together, these observations suggest a novel role for C, CR3, and β-glucan in the restoration of hematopoiesis following injury. (Blood. 2006;107:835-840)

Role of complement and Fcγ receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5170-5180 ◽  
Author(s):  
Federica Moalli ◽  
Andrea Doni ◽  
Livija Deban ◽  
Teresa Zelante ◽  
Silvia Zagarella ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Alternative Pathway ◽  
Complement Receptor ◽  
Protective Activity ◽  
Opsonic Activity ◽  
Reactive Protein ◽  
Complement Receptor 3 ◽  
Dependent Pathway

AbstractPentraxin 3 (PTX3) is a soluble pattern recognition molecule playing a nonredundant role in resistance against Aspergillus fumigatus. The present study was designed to investigate the molecular pathways involved in the opsonic activity of PTX3. The PTX3 N-terminal domain was responsible for conidia recognition, but the full-length molecule was necessary for opsonic activity. The PTX3-dependent pathway of enhanced neutrophil phagocytic activity involved complement activation via the alternative pathway; Fcγ receptor (FcγR) IIA/CD32 recognition of PTX3-sensitized conidia and complement receptor 3 (CR3) activation; and CR3 and CD32 localization to the phagocytic cup. Gene targeted mice (ptx3, FcR common γ chain, C3, C1q) validated the in vivo relevance of the pathway. In particular, the protective activity of exogenous PTX3 against A fumigatus was abolished in FcR common γ chain-deficient mice. Thus, the opsonic and antifungal activity of PTX3 is at the crossroad between complement, complement receptor 3-, and FcγR-mediated recognition. Because short pentraxins (eg, C-reactive protein) interact with complement and FcγR, the present results may have general significance for the mode of action of these components of the humoral arm of innate immunity.

scholarly journals CD44-mediated phagocytosis induces inside-out activation of complement receptor-3 in murine macrophages

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4492-4502 ◽  
Author(s):  
Eric Vachon ◽  
Raiza Martin ◽  
Vivian Kwok ◽  
Vera Cherepanov ◽  
Chung-Wai Chow ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Immunofluorescence Microscopy ◽  
Complement Receptor ◽  
Fcγ Receptors ◽  
Intracellular Signaling Pathways ◽  
Large Particles ◽  
Complement Receptor 3 ◽  
Inside Out ◽  
Β2 Integrins

Diverse receptors, including Fcγ receptors and β2 integrins (complement receptor-3 [CR3], CD11b/CD18), have been implicated in phagocytosis, but their distinct roles and interactions with other receptors in particle engulfment are not well defined. CD44, a transmembrane adhesion molecule involved in binding and metabolism of hyaluronan, may have additional functions in regulation of inflammation and phagocytosis. We have recently reported that CD44 is a fully competent phagocytic receptor that is able to trigger ingestion of large particles by macrophages. Here, we investigated the role of coreceptors and intracellular signaling pathways in modulation of CD44-mediated phagocytosis. Using biotinylated erythrocytes coated with specific antibodies (anti-CD44–coated erythrocytes [Ebabs]) as the phagocytic prey, we determined that CD44-mediated phagocytosis is reduced by 45% by a blocking CD11b antibody. Further, CD44-mediated phagocytosis was substantially (42%) reduced in CD18-null mice. Immunofluorescence microscopy revealed that CD11b is recruited to the phagocytic cup. The mechanism of integrin activation and mobilization involved activation of the GTPase Rap1. CD44-mediated phagocytosis was also sensitive to the extracellular concentration of the divalent cation Mg2+ but not Ca2+. In addition, buffering of intracellular Ca2+ did not affect CD44-mediated phagocytosis. Taken together, these data suggest that CD44 stimulation induces inside-out activation of CR3 through the GTPase Rap1.

scholarly journals Dectin-1 Is A Major β-Glucan Receptor On Macrophages

2002 ◽  
Vol 196 (3) ◽  
pp. 407-412 ◽  
Author(s):  
Gordon D. Brown ◽  
Philip R. Taylor ◽  
Delyth M. Reid ◽  
Janet A. Willment ◽  
David L. Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Drug Design ◽  
Mannose Receptor ◽  
Therapeutic Drug ◽  
Complement Receptor ◽  
Macrophage Mannose Receptor ◽  
Immunomodulatory Properties ◽  
Complement Receptor 3

Zymosan is a β-glucan– and mannan-rich particle that is widely used as a cellular activator for examining the numerous responses effected by phagocytes. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) have historically been considered the major macrophage lectins involved in the nonopsonic recognition of these yeast-derived particles. Using specific carbohydrate inhibitors, we show that a β-glucan receptor, but not the MR, is a predominant receptor involved in this process. Furthermore, nonopsonic zymosan binding was unaffected by genetic CD11b deficiency or a blocking monoclonal antibody (mAb) against CR3, demonstrating that CR3 was not the β-glucan receptor mediating this activity. To address the role of the recently described β-glucan receptor, Dectin-1, we generated a novel anti–Dectin-1 mAb, 2A11. Using this mAb, we show here that Dectin-1 was almost exclusively responsible for the β-glucan–dependent, nonopsonic recognition of zymosan by primary macro-phages. These findings define Dectin-1 as the leukocyte β-glucan receptor, first described over 50 years ago, and resolves the long-standing controversy regarding the identity of this important molecule. Furthermore, these results identify Dectin-1 as a new target for examining the immunomodulatory properties of β-glucans for therapeutic drug design.

scholarly journals Role of RpoS in Fine-Tuning the Synthesis of Vi Capsular Polysaccharide in Salmonella enterica Serotype Typhi

2006 ◽  
Vol 75 (3) ◽  
pp. 1382-1392 ◽  
Author(s):  
Javier Santander ◽  
Soo-Young Wanda ◽  
Cheryl A. Nickerson ◽  
Roy Curtiss
Keyword(s):  
Salmonella Enterica ◽  
Capsular Polysaccharide ◽  
Fine Tuning ◽  
O Antigen ◽  
Native Promoter ◽  
Regulatory Systems ◽  
Polysaccharide Synthesis ◽  
Clinical Detection ◽  
Vi Capsular Polysaccharide

ABSTRACT Regulation of the synthesis of Vi polysaccharide, a major virulence determinant in Salmonella enterica serotype Typhi, is under the control of two regulatory systems, ompR-envZ and rscB-rscC, which respond to changes in osmolarity. Some serotype Typhi strains exhibit overexpression of Vi polysaccharide, which masks clinical detection of lipopolysaccharide O antigen. This variation in Vi polysaccharide and O antigen display (VW variation) has been observed since the initial studies of serotype Typhi. In this study, we report that rpoS plays a role in this increased expression in Vi polysaccharide. We constructed a variety of isogenic serotype Typhi mutants that differed in their expression levels of RpoS and examined the role of the rpoS product in synthesis of Vi polysaccharide under different osmolarity conditions. Vi polysaccharide synthesis was also examined in serotype Typhi mutants in which the native promoter of the rpoS was replaced by an araCPBAD cassette, so that the expression of rpoS was arabinose dependent. The RpoS− strains showed increased syntheses of Vi polysaccharide, which at low and medium osmolarities masked O antigen detection. In contrast, RpoS+ strains showed lower syntheses of Vi polysaccharide, and an increased detection of O antigen was observed. During exponential growth, when rpoS is unstable or present at low levels, serotype Typhi RpoS+ strains overexpress the Vi polysaccharide at levels comparable to those for RpoS− strains. Our results show that RpoS is another regulator of Vi polysaccharide synthesis and contributes to VW variation in serotype Typhi, which has implications for the development of recombinant attenuated Salmonella vaccines in humans.

scholarly journals Role of Vibrio cholerae O139 Surface Polysaccharides in Intestinal Colonization

2002 ◽  
Vol 70 (11) ◽  
pp. 5990-5996 ◽  
Author(s):  
Jutta Nesper ◽  
Stefan Schild ◽  
Crystal M. Lauriano ◽  
Anita Kraiss ◽  
Karl E. Klose ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Capsular Polysaccharide ◽  
Genetically Engineered ◽  
Side Chain ◽  
Intestinal Colonization ◽  
Core Oligosaccharide ◽  
Infant Mouse ◽  
Surface Polysaccharides

ABSTRACT Since the first occurrence of O139 Vibrio cholerae as a cause of cholera epidemics, this serogroup has been investigated intensively, and it has been found that its pathogenicity is comparable to that of O1 El Tor strains. O139 isolates express a thin capsule, composed of a polymer of repeating units structurally identical to the lipopolysaccharide (LPS) O side chain. In this study, we investigated the role of LPS O side chain and capsular polysaccharide (CPS) in intestinal colonization by with genetically engineered mutants. We constructed CPS-negative, CPS/LPS O side chain-negative, and CPS-positive/LPS O side chain-negative mutants. Furthermore, we constructed two mutants with defects in LPS core oligosaccharide (OS) assembly. Loss of LPS O side chain or CPS resulted in a ≈30-fold reduction in colonization of the infant mouse small intestine, indicating that the presence of both LPS O side chain and CPS is important during the colonization process. The strain lacking both CPS and LPS O side chain and a CPS-positive, LPS O side chain-negative core OS mutant were both essentially unable to colonize. To characterize the role of surface polysaccharides in survival in the host intestine, resistance to several antimicrobial substances was investigated in vitro. These investigations revealed that the presence of CPS protects the cell against attack of the complement system and that an intact core OS is necessary for survival in the presence of bile.

scholarly journals Complement Receptor 1 Expression on Mouse Erythrocytes Mediates Clearance of Streptococcus pneumoniae by Immune Adherence

2010 ◽  
Vol 78 (7) ◽  
pp. 3129-3135 ◽  
Author(s):  
Jie Li ◽  
Jennifer P. Wang ◽  
Ionita Ghiran ◽  
Anna Cerny ◽  
Alexander J. Szalai ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Direct Evidence ◽  
Wild Type Mouse ◽  
Complement Receptor ◽  
Blood Clearance ◽  
Wild Type ◽  
Immune Adherence ◽  
Complement Receptor 1

ABSTRACT Complement-containing immune complexes can be presented to phagocytes by human erythrocytes bearing complement receptor 1 (CR1). Although this has long been assumed to be a mechanism by which humans are able to protect themselves from “extracellular” bacteria such as pneumococci, there is little direct evidence. In these studies we have investigated this question by comparing results for erythrocytes from transgenic mice expressing human CR1 on their erythrocytes to the results for wild-type mouse erythrocytes that do not express CR1. We demonstrate that human CR1 expression on murine erythrocytes allows immune adherence to beads opsonized with either mouse or human serum as a source of complement. The role of CR1 in immune adherence was supported by studies showing that it was blocked by the addition of antibody to human CR1. Furthermore, human CR1 expression enhances the immune adherence of opsonized pneumococci to erythrocytes in vitro, and the pneumococci attached to erythrocytes via CR1 can be transferred in vitro to live macrophages. Even more importantly, we observed that if complement-opsonized pneumococci are injected intravenously with CR1+ mouse erythrocytes into wild-type mice (after a short in vitro incubation), they are cleared faster than opsonized pneumococci similarly injected with wild-type mouse erythrocytes. Finally, we have shown that the intravenous (i.v.) injection of pneumococci into CR1+ mice also results in more rapid blood clearance than in wild-type mice. These data support that immune adherence via CR1 on erythrocytes likely plays an important role in the clearance of opsonized bacteria from human blood.

The role of serum in leucocyte adherence to the plerocercoid of Ligula intestinalis (Cestoda: Pseudophyllidea)

Parasitology ◽  
1986 ◽  
Vol 92 (2) ◽  
pp. 413-424 ◽  
Author(s):  
P. Hoole ◽  
C. Arme
Keyword(s):  
Rutilus Rutilus ◽  
Immune Serum ◽  
Adherent Cells ◽  
Percoll Gradient ◽  
Serum Dilution ◽  
Ligula Intestinalis ◽  
Discontinuous Percoll Gradient ◽  
Leucocyte Adherence

SUMMARYThe role of serum in the adherence of roach (Rutilus rutilus) leucocytes to the plerocercoid of Ligula intestinalis has been investigated in vitro. Roach plerocercoids, either untreated, cultured or killed (fixation in 0·5 % buffered glutaraldehyde or heat at 50°C for 45 mm), were exposed to serum and 4×106 leucocytes obtained from the pronephros of non-infected roach using a discontinuous Percoll gradient. At normal roach serum (NRoS) dilutions of 1:5000 to 1:100, leucocyte adherence was observed on all living parasites but was negligible in killed parasites or in complement-depleted NRoS assays. The number of adherent cells increased with increasing NRoS concentration. Leucocytes bound more avidly in the presence of heat-inactivated immune serum (hi IRoS); at a serum dilution of 1:5000 the percentage of the parasite surface covered by leucocytes was approximately 3 times greater in hi IRoS than in NRoS. Ultrastructural observations on parasites revealed that plerocercoids exposed to cells and hi IRoS had, in some areas, abnormal inclusions in their tegument and lacked a microthrix border and distal cytoplasm. In addition, the efflux of radioactivity from [14C] cycloleucine-labelled worms was greater in parasites incubated in the presence of hi IRos.

Endothelial Progenitor Cell Transplantation Attenuated Synaptic Loss by Enhancing CR3 Dependent Microglial Phagocytosis in Mice

2021 ◽  
Author(s):  
Yuanyuan Ma ◽  
Lu Jiang ◽  
Liping Wang ◽  
Yongfang Li ◽  
Yanqun Liu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Progenitor Cell ◽  
Focal Ischemia ◽  
Complement Receptor ◽  
Primary Microglia ◽  
Synaptic Loss ◽  
Ischemic Brain ◽  
Microglial Phagocytosis ◽  
Complement Receptor 3

Abstract Background: Endothelial progenitor cell (EPC) transplantation has been shown to have therapeutic effects in cerebral ischemia. However, whether the therapeutic effect of EPCs is a result of the modulation of microglia activity remain elusive. Methods: Adult male mice (n=184) underwent 90 minute-middle cerebral artery occlusion and EPCs were transplanted into the peri-infarct region immediately after the surgery. Microglia migration and phagocytosis were evaluated in the ischemic brain in vivo and underwent oxygen-glucose-deprivation culture condition in vitro. Complement receptor 3 was examined in ischemic brain and cultured primary microglia. Complement receptor 3 agonist leukadherin-1 was intraperitoneally injected to mice immediately after ischemia to imitate the EPC effect. Expression of synapse remodeling related synaptophysin and PSD-95 proteins was detected in the EPC and leukadherin-1 treated mice, separately. Results: EPC transplantation increased the number of microglia in the peri-infarct region of the brain at 3 days after focal ischemia (p<0.05). The ability of phagocytizing apoptotic cells of microglia was higher in EPCs transplanted group at 3 days after ischemia compared to the controls (p<0.05). In vitro study showed that cultured microglia displayed a higher migration (p<0.05) and phagocytosis ability (p<0.05) under the stimulation of EPC conditioned medium or cultured EPCs compared to the controls. Complement receptor 3 expression in the ischemic mouse brain with EPC transplantation (p<0.05), and primary microglia treated by EPC conditioned medium or cultured EPCs was up-regulated (p<0.05). Leukadherin-1 reduced brain atrophy volume at 14 days (p<0.05) and ameliorated neurological deficiency during 14 days after cerebral ischemia (p<0.05). Both EPC transplantation and leukadherin-1 injection increased synaptophysin (p<0.05) and PSD-95 expressions (p<0.05) at 14 days after focal ischemia. Conclusion: We concluded that EPC transplantation promoted regulating complement receptor 3 mediated microglial phagocytosis at acute phase, and subsequently benefited for attenuating synaptic loss at the recovery phase of ischemic stroke, which provided a novel therapeutic mechanism of EPC for cerebral ischemia.

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