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PubMed1959

Studies on the pathogenicity of group A Streptococci. I. Its relation to surface phagocytosis.

Four strains of Group A streptococci, possessing different degrees of virulence for both mice and rats, were tested for susceptibility to phagocytosis on glass slides, in glass roller tubes, and on the surfaces of freshly excised tissues and moistened filter paper. All of the tests were performed in the absence of serum to exclude the possible presence of opsonins. Only under conditions which allowed surface phagocytosis to take place was there a correlation between virulence and susceptibility to phagocytosis. A similar relationship between virulence and surface phagocytosis was also demonstrable in vivo during the early stages of experimental streptococcal peritonitis. Systematic study of the evolution of the peritonitis revealed that its outcome was determined by the phagocytic reaction which occurred in the first few hours of the infection.

Animals↗
PubMed1959

Studies on the pathogenicity of group A streptococci. II. The antiphagocytic effects of the M protein and the capsular gel.

A QUANTITATIVE STUDY OF THE COMBINED ANTIPHAGOCYTIC EFFECTS OF THE M PROTEIN AND THE HYALURONIC ACID CAPSULES OF FOUR STRAINS OF GROUP A STREPTOCOCCI REVEALED THE FOLLOWING FACTS RELATING TO THEIR INTRAPERITONEAL VIRULENCE IN MICE AND RATS: 1. The most virulent strain, S23M (matt), produced both a large hyaluronic acid capsule and a full complement of M protein, the combined effects of which rendered the organism highly resistant to surface phagocytosis. 2. The slightly less virulent strain, T14/46 (matt virulent) was somewhat more susceptible to surface phagocytosis owing to the fact that its smaller capsule was less antiphagocytic than that of the S23M organism. 3. The glossy variant of the S23 strain (S23G), which ranked third in virulence, was still more susceptible to surface phagocytosis because of its lack of detectable M substance. Its large hyaluronic acid capsule, however, was capable of protecting it against phagocytosis on glass. 4. The least virulent strain, T14 (matt avirulent), was the most susceptible of all to phagocytosis. Though it possessed both M substance and capsule, which together prevented its phagocytosis on glass, each of them was shown to be quantitatively and functionally deficient as compared to Strain S23M. The differences in phagocytability, which appear to be directly related to the pathogenicity of the organisms, could be adequately demonstrated in vitro only by phagocytic tests designed to measure surface phagocytosis in the absence of opsonins. This fact is in keeping with the observation, previously reported, that surface phagocytosis plays a critical role in the defense of the host, particularly during the earliest stages of experimental streptococcal infections. Its possible relation to suppuration during the later stages of infection is also discussed.

Animals↗
PubMed1960

Functional and metabolic properties of polymorphonuclear leucocytes. II. The influence of a lipopolysaccharide endotoxin.

The effects of a purified bacterial lipopolysaccharide endotoxin on homogenous populations of rabbit polymorphonuclear leucocytes have been studied in vitro under defined conditions. Employing a 500-fold range of concentration (0.1 to 50.0 microg./ml.), it was shown that endotoxin enhanced the rate at which staphylococci were killed by leucocytes. The mechanism underlying the increased killing was found to be a direct stimulation of the phagocytic activity of the leucocyte and not mediated by the release of bactericidins or opsonins from the treated cells. In the presence of 10 per cent serum all concentrations of endotoxin enhanced phagocytosis, whereas at lower serum concentrations, the higher doses of lipopolysaccharide inhibited the phagocytic activity of the cells. Similar concentrations of endotoxin were capable of increasing the utilization of glucose and the production of lactic acid. Endotoxin treated leucocytes exhibited no change in oxygen consumption, and only a slight depression in glycogen synthesis. It appeared that endotoxin could interact and alter the functional and metabolic properties of leucocytes in the absence of serum. The demonstration of enhanced phagocytic activity of endotoxin-treated cells was dependent upon the particular opsonic requirements for the organism under study.

Animals↗
PubMed1963

Mechanisms of endotoxin tolerance. I. Relationship between tolerance and reticuloendothelial system phagocytic activity in the rabbit.

Pyrogenic tolerance following 7 daily intravenous injections of 2.0 microg/kg E. coli endotoxin in albino rabbits was associated with significant increases in RES phagocytic activity as measured with colloidal carbon. Nevertheless, 4 hours after RES blockade with thorotrast (3 ml/kg), the tolerant rabbits exhibited significantly lower fever indices following intravenous endotoxin challenge than did non-tolerant control animals despite comparably depressed capacities to clear carbon from the blood. Moreover, plasma from rabbits tolerant to endotoxin induced significant tolerance in normal rabbits prepared by thorotrast blockade without enhancing the depressed carbon clearance. This passive protection extended to heterologous endotoxins. Analysis of the data indicates that RES blockade does not abolish tolerance; rather blockade resets the reactivity to endotoxin in the normal and tolerant animal, rendering both exquisitely reactive, but permitting retention of the major portion of tolerance. Apparently the tolerant animal possesses a dual endotoxin defense system. One system is abolished by thorotrast; the other is in part humoral, accounts for the greater portion of tolerance, and is thorotrast-resistant. The nature of the humoral component is not defined but is consistent with that of an opsonin with high endotoxin specificity.

Animals↗
PubMed1976

Protection against group B meningococcal disease. I. Comparison of group-specific and type-specific protection in the chick embryo model.

Protection against group B meningococcal infection was examined using the chick embryo. 12-day-old embryos were challenged intravenously with various meningococcal strains. The chick embryo has an active reticuloendothelial system but lacks functional complement. In this model we found that protection against group B infection was primarily group specific. The group B polysaccharide antibody is an effective opsonin, but is a very poor bactericidal antibody. In contrast, the serotype antibody was bactericidal but only slightly protective in the chick embryo where protection is primarily phagocytic in nature. The group-specific and type-specific antibodies are strongly synergistic. Minute amounts of group B polysaccharide antibody caused a very significant increase in the protective effects of the serotype antibody.

Animals↗
PubMed1980

Fibronectin is produced by human macrophages.

Monocyte-enriched cultures were prepared from human blood mononuclear leukocytes by adherence to growth substratum. Synthesis and secretion of fibronectin was detected in these cultures concomitantly with morphological differentiation, starting on day 3--5. Production of fibronectin by macrophages was documented by metabolic labeling followed by immunoprecipitation and gel electrophoresis, radioimmunoassay specific for human fibronectin, and by indirect immunofluorescence. Fibronectin was detected mainly intracellularly but was also detected pericellularly only in minute amounts. No production of collagenous proteins was seen in these cultures. Macrophage fibronectin might act in vivo as a nonspecific opsonin and promote cell adhesion during macrophage migration in tissues.

Cells, Cultured↗
PubMed1981

C-reactive protein is protective against Streptococcus pneumoniae infection in mice.

C-reactive protein (CRP) has several properties that suggest that it may function as a bacterial opsonin. CRP shows binding reactivity with pneumococcal C-polysaccharide, the cell wall carbohydrate of Streptococcus pneumoniae. In this study we have demonstrated protection of mice against serotypes 3 and 4 of S. pneumoniae infection by a single prior injection of CRP. This effect was seen both in mice that lacked antibody to phosphocholine and in normal mice. Thus the opsonic properties of CRP previously described may be related to protection against pneumococcal infection.

Animals↗
PubMed1987

Phagocytosis of Legionella pneumophila is mediated by human monocyte complement receptors.

We have examined receptors mediating phagocytosis of the intracellular bacterial pathogen, Legionella pneumophila. Three mAbs against the type 3 complement receptor (CR3), which recognizes C3bi, inhibit adherence of L. pneumophila to monocytes by 64 +/- 8% to 74 +/- 11%. An mAb against the type 1 complement receptor (CR1), which recognizes C3b, inhibits adherence by 68 +/- 1%. mAbs against other monocyte surface antigens do not significantly influence adherence. Monocytes plated on substrates of L. pneumophila membranes modulate their CR1 and CR3 receptors but not Fc receptors; such monocytes bind 70% fewer C3b-coated erythrocytes and 53% fewer C3bi-coated erythrocytes than control monocytes. Adherence of L. pneumophila to monocytes in nonimmune sera is dependent on heat-labile serum opsonins; adherence is markedly reduced in heat-inactivated serum (84% reduction) or buffer alone (97% reduction) compared with fresh serum. mAbs against CR1 and CR3 receptors also inhibit L. pneumophila intracellular multiplication and protect monocyte monolayers from destruction by this bacterium. This study demonstrates that human monocyte complement receptors, CR1 and CR3, mediate phagocytosis of L. pneumophila. These receptors may play a general role in mediating phagocytosis of intracellular pathogens.

Antibodies, Monoclonal↗
PubMed1992

Phagocytic chimeric receptors require both transmembrane and cytoplasmic domains from the mannose receptor.

Phagocytosis has traditionally been viewed as a specialized function of myeloid and monocytic cells. The mannose receptor (MR) is an opsonin-independent phagocytic receptor expressed on tissue macrophages. When human MR cDNA is transfected into Cos cells, these usually non-phagocytic cells express cell surface MR and bind and ingest MR ligands such as zymosan, yeast, and Pneumocystis carinii. Expression of cDNA for Fc gamma RI (CD64), the high-affinity Fc receptor, in Cos cells confers binding but barely detectable phagocytosis of antibody-opsonized erythrocytes (EA). We report here that chimeric receptors containing the ligand-binding ectodomain of the Fc receptor and the transmembrane and cytoplasmic domains of the MR ingest bound EA very efficiently, whereas chimeras with the Fc receptor ecto- and transmembrane domains and the MR tail, or the Fc receptor ecto- and cytoplasmic domains and the MR transmembrane region, are significantly less phagocytic. All of the chimeric receptors bind ligand with equal avidity, but gain of functional phagocytosis is only conferred by the MR transmembrane and cytoplasmic domains. Endocytosis of monomeric immunoglobulin G by chimeric receptors demonstrates a similar pattern, with optimal uptake by the chimera containing both tail and transmembrane regions from the MR. The chimeric receptors with only the transmembrane or the cytoplasmic domain contributed by the MR were less efficient. Site-directed mutagenesis of the single tyrosine residue in the cytoplasmic tail (which is present in a motif homologous to an endocytosis consensus motif in the LDL receptor cytoplasmic tail [Chen, W.-J., J. L. Goldstein, and M. S. Brown. 1990. J. Biol. Chem. 265:3116]) reduces the efficiency of phagocytosis and endocytosis to a similar extent.

Animals↗
PubMed1997

Rho is required for the initiation of calcium signaling and phagocytosis by Fcgamma receptors in macrophages.

Phagocytosis of bacteria by macrophages and neutrophils is an essential component of host defense against infection. The mechanism whereby the interaction of opsonized particles with Fcgamma receptors triggers the engulfment of opsonized particles remains incompletely understood, although activation of tyrosine kinases has been recognized as an early step. Recent studies in other systems have demonstrated that tyrosine kinases can in turn signal the activation of small GTPases of the ras superfamily. We therefore investigated the possible role of Rho in Fc receptor-mediated phagocytosis. To this end we microinjected J774 macrophages with C3 exotoxin from Clostridium botulinum, which ADP-ribosylates and inactivates Rho. C3 exotoxin induced the retraction of filopodia, the disappearance of focal complexes, and a global decrease in the F-actin content of J774 cells. In addition, these cells exhibited increased spreading and the formation of vacuolar structures. Importantly, inactivation of Rho resulted in the complete abrogation of phagocytosis. Inhibition of Fcgamma receptor-mediated phagocytosis by C3 exotoxin was confirmed in COS cells, which become phagocytic upon transfection of the FcgammaRIIA receptor. Rho was found to be essential for the accumulation of phosphotyrosine and of F-actin around phagocytic cups and for Fcgamma receptor-mediated Ca2+ signaling. The clustering of receptors in response to opsonin, an essential step in Fcgamma-induced signaling, was the earliest event shown to be inhibited by C3 exotoxin. The effect of the toxin was specific, since clustering and internalization of transferrin receptors were unaffected by microinjection of C3. These data identify a role for small GTPases in Fcgamma receptor-mediated phagocytosis by leukocytes.

Actins↗
PubMed2000

Negative regulation of phagocytosis in murine macrophages by the Src kinase family member, Fgr.

Ingestion of opsonized pathogens by professional phagocytes results in the generation and release of microbicidal products that are essential for normal host defense. Because these products can result in significant tissue injury, phagocytosis must be regulated to limit damage to the host while allowing for optimal clearance and destruction of opsonized pathogens. To pursue negative regulation of phagocytosis, we assessed the effect of the Src kinase family member, Fgr, on opsonin-dependent phagocytosis by mouse macrophages. We chose Fgr because it is present in high concentrations in circulating phagocytes but is not essential for Fcgamma receptor-mediated ingestion by mouse macrophages. Although expression of Fgr both in a macrophage cell line and in primary macrophages significantly attenuates ingestion mediated by Fcgamma receptors and CR3, it does not affect macropinocytosis or receptor-mediated endocytosis. This selective effect of Fgr is independent of its tyrosine kinase function. After Fcgamma receptor cross-linking, Fgr becomes associated with the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, SIRPalpha (a member of the signal-regulatory protein family, also known as Src homology 2 domain-containing protein tyrosine phosphatase [SHP] substrate 1 [SHPS-1], brain immunoglobulin-like molecule with tyrosine-based activation motifs [BIT], and P84) and potentiates the association of the phosphatase SHP-1 with SIRPalpha. This association is responsible, at least in part, for decreasing positive signaling essential for optimal phagocytosis. These data demonstrate an important negative regulatory role for this Src kinase family member and suggest that this homeostatic function must be overcome for optimal uptake and clearance of opsonized pathogens.

Animals↗
PubMed2004

Granulocyte CEACAM3 is a phagocytic receptor of the innate immune system that mediates recognition and elimination of human-specific pathogens.

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are used by several human pathogens to anchor themselves to or invade host cells. Interestingly, human granulocytes express a specific isoform, CEACAM3, that participates together with CEACAM1 and CEACAM6 in the recognition of CEACAM-binding microorganisms. Here we show that CEACAM3 can direct efficient, opsonin-independent phagocytosis of CEACAM-binding Neisseria, Moraxella, and Haemophilus species. CEACAM3- but not CEACAM6-mediated uptake is blocked by dominant-negative versions of the small GTPase Rac. Moreover, CEACAM3 engagement triggers membrane recruitment and increased GTP loading of Rac that are not observed upon bacterial binding to CEACAM6. Internalization and Rac stimulation are also inhibited by compromising the integrity of an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence in the cytoplasmic tail of CEACAM3 or by interference with Src family protein tyrosine kinases that phosphorylate CEACAM3. In contrast to interfering with CEACAM6, blockage of CEACAM3-mediated events reduces the ability of primary human granulocytes to internalize and eliminate CEACAM-binding bacteria, indicating an important role of CEACAM3 in the control of human-specific pathogens by the innate immune system.

Base Sequence↗
PubMed1951

Studies on the cellular immunology of acute bacteremia. I. Intravascular leucocytic reaction and surface phagocytosis.

Evidence has been presented that the introduction of large numbers of bacteria into the blood stream causes a widespread intravascular reaction, characterized by the sticking of leucocytes to the endothelium of capillaries, arterioles, and venules. The adherent granulocytes promptly become motile and thus potentially phagocytic. This intravascular leucocytic response affords a rapid and efficient mobilization of a vast number of active phagocytes within the blood stream. In some of the smaller vessels of both the systemic and pulmonary circulation the reaction is accompanied by the deposition of what appears to be intravascular fibrin. Direct observation by the rabbit ear chamber technique has revealed that leucocytes thus mobilized in small peripheral vessels are capable of phagocyting fully encapsulated Friedländer's bacilli in the absence of antibody. Ingestion of the encapsulated blood-borne bacteria results from surface phagocytosis and occurs primarily in those vessels in which the flow of blood is either slowed or has temporarily stopped altogether. Leucocytes can be seen to phagocyte the organisms by first trapping them against the walls of the vessels or against adjacent leucocytes. Bacteria caught in the interstices of the intravascular "fibrin" may likewise be immobilized and readily phagocyted. Thus granulocytes, without the aid of opsonins, are able to ingest and destroy encapsulated blood-borne bacteria by the same mechanisms that operate in extravascular tissues. It is concluded from these studies that intravascular surface phagocytosis by polymorphonuclear leucocytes supplements the well known phagocytic activities of the reticulo-endothelial cells and therefore serves as an important defense of the host in acute infections caused by encapsulated bacteria and complicated by bacteriemia.

Antibodies↗
PubMed1999

Impaired phagocyte oxidative capacity in human immunodeficiency virus-infected children.

Children infected with the human immunodeficiency virus (HIV) have T helper cell deficiency, but frequent bacterial infections suggest phagocyte dysfunction. Whole blood chemiluminescence (CL) assays were used to measure the respiratory burst capacity of phagocytes from HIV-infected children, perinatally HIV-exposed but uninfected children, and normal healthy children. Phagocytes were stimulated by zymosan opsonized with human complement with and without priming by platelet-activating factor (PAF) or FMLP. Activities of enzymes involved in the respiratory burst, oxidase and myeloperoxidase, were examined after opsonin receptor-independent stimulation with PMA. Unprimed CL responses to opsonized zymosan were decreased for HIV-infected children with severe CD4 lymphocyte suppression compared with healthy children (P=.03), and PAF-primed CL responses to opsonized zymosan were decreased in HIV-infected children with both moderate and severe CD4 lymphocyte suppression (P=.02 and P=.01, respectively), despite normal or increased activities of the respiratory burst enzymes. These impairments may contribute to secondary bacterial infections.

Adolescent↗
PubMed2001

Immunosuppressed surfactant protein A-deficient mice have increased susceptibility to Pneumocystis carinii infection.

Immunosuppressed Swiss Black mice deficient in surfactant protein A (SP-A(-/-)) and wild-type control mice (SP-A(+/+)) were exposed to Pneumocystis carinii by environmental exposure, intratracheal inoculation, and direct exposure to other infected animals. The frequency and intensity of P. carinii infection were significantly greater in the SP-A(-/-) mice by all 3 methods of exposure. P. carinii free of SP-A and alveolar macrophages were isolated from SP-A(-/-) mice and were tested in an in vitro attachment assay. Pretreatment of P. carinii with human SP-A resulted in a significant dose-dependent increase of the adherence of P. carinii to the macrophages. Thus, SP-A plays a role in host defense against P. carinii in vivo, perhaps by functioning as a nonimmune opsonin.

Animals↗
PubMed2001

Two distinct receptors mediate nonopsonic phagocytosis of different strains of Pseudomonas aeruginosa.

Complement receptor 3 (CR3) mediates both opsonic and nonopsonic phagocytosis of bacteria. Leukocyte adhesion deficiency (LAD) allows for the study of CR3-dependent phagocyte-bacterial ingestion, since LAD phagocytes do not express this receptor. Phagocytes from an infant with LAD were unable to ingest 50% of the Pseudomonas aeruginosa strains studied, which indicates a requirement for CR3. However, the remaining strains were phagocytosed in the absence of CR3, and ingestion was blocked by monoclonal antibodies directed at CD14. This CR3/CD14 receptor bias was further confirmed by using thioglycollate-elicited murine peritoneal macrophages, which have nonfunctional CR3 before activation. Results indicate that either CR3 or CD14 is involved independently in nonopsonic phagocytosis of different P. aeruginosa strains. Clearance of P. aeruginosa from the endobronchial space may be facilitated by nonopsonic phagocytosis, since low levels of opsonins are present. The impact of lung infection with P. aeruginosa may be determined, in part, by the phagocytic receptor that mediates ingestion.

Adult↗
PubMed2003

Phagocytosis of Bordetella pertussis incubated with convalescent serum.

Convalescent serum samples were examined for the ability to promote phagocytosis of Bordetella pertussis by human neutrophils. One sample promoted phagocytosis, and 11 of the 51 samples caused a statistically significant reduction in phagocytosis, compared with that of bacteria not incubated with serum. Phagocytosis was influenced by interactions between antibodies that promoted phagocytosis and antibodies that inhibited phagocytosis. Adenylate cyclase toxin (ACT) has been shown to block phagocytosis by neutrophils. Antibodies to ACT were removed from the sample that promoted phagocytosis, by incubation with ACT-coated paramagnetic beads, and the depleted serum no longer enhanced phagocytosis. The adhesin filamentous hemagglutinin (FHA) has been shown to mediate attachment of B. pertussis to neutrophils in a way that promotes phagocytosis. Depletion of antibodies to FHA from samples that blocked phagocytosis improved phagocytosis, compared with the no-antibody control. These results suggest that antibodies to ACT can promote phagocytosis, whereas antibodies to FHA can counteract beneficial opsonins.

Adenylate Cyclase Toxin↗
PubMed1992

Lectin-carbohydrate interactions and infectivity of human immunodeficiency virus type 1 (HIV-1).

The aim of this study was to determine whether mannosyl-specific lectins, especially Concanavalin A (ConA), may bridge HIV-1 env glycoproteins to cell membranes to increase virus binding to its targets, and to what extent this lectin-carbohydrate interaction can modify HIV-1 infectivity for monocytic compared with lymphoid cells. Monocytic U937 and lymphoid CEM cells, which both express surface mannose, were utilized. Whether first incubated with env glycoprotein or with the cells, lectins bound both to the cells and to radiolabeled recombinant gp160 (rgp160). Thus, they enhanced rgp160 adsorption to the cells in a methyl-alpha-mannose inhibitable manner. ConA did not appear to bind to the V1 domain of CD4 at the U937 cell surface since Leu3a binding was not blocked in the presence of ConA, nor was recombinant CD4 retained on a ConA-agarose affinity matrix. Moreover, enhanced rgp160 binding to the cells was CD4 independent, since it was not modified by preincubating the cells with Leu3a. Finally, ConA did not inhibit the binding of CD4-IgG3 chimeric molecules to virions immobilized on nitrocellulose membrane, which argues against the possibility that it interferes with the interaction of gp120 and CD4. However, both when incubated with the virus or with the cells and despite mediating enhanced binding of env glycoprotein, ConA neutralized HIV-1 infectivity for monocytic U937 as well as for lymphoid CEM cells. In this respect, ConA behaves like neutralizing antibodies which do not interfere with CD4 binding of gp120 but rather with some later event that leads to virus entry. These findings obtained with plant lectins may be of relevance in vivo, inasmuch as endogenous mannosyl-binding proteins, which are known to function as opsonins, have been reported to inhibit in vitro infection by HIV-1.

Acquired Immunodeficiency Syndrome↗