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PubMed2000

Collectins and pulmonary innate immunity.

The surfactant-associated proteins SP-A and SP-D are members of a family of host defense lectins, designated collectins. There is increasing evidence that these pulmonary, epithelial-derived proteins are important components of the innate immune response to microbial challenge and participate in other aspects of immune and inflammatory regulation within the lung. Both proteins bind to glycoconjugates and/or lipid moieties expressed by a wide variety of microorganisms, and to certain organic particles, such as pollens. SP-A and SP-D have the capacity to modulate leukocyte function and, in some circumstances; to opsonize and enhance the killing of microorganisms. The biologic activity of cell wall components, such as Gram-negative bacterial polysaccharides, or viral glycoproteins, such as the hemagglutinin of influenza viruses, may be altered by interactions with collectins. In addition, complementary or cooperative interactions between SP-A, SP-D and other host defense lectins could contribute to the efficiency of this defense system. Collectins could play particularly important roles in settings of inadequate or impaired specific immunity, and acquired alterations in the levels of active collectins within the airspaces and distal airways may increase susceptibility to infection.

Bacterial Infections↗
PubMed2006

New concepts in collectin-mediated host defense at the air-liquid interface of the lung.

OBJECTIVES: Surfactant proteins A (SP-A) and D are collectins that play key roles in innate immune defense of the lung. Recent studies suggest that these proteins have a direct effect on the growth and viability of Gram-negative bacteria, Mycoplasma pneumoniae and Histoplasma capsulatum. METHODOLOGY: The researchers examined membrane permeabilization by BAL fluid of mice that were sufficient or deficient in surfactant proteins, of rough and smooth LPS-containing membranes, and of genetically altered bacteria. The permeability assay is based on the ability of agents to promote access of impermeable dyes propidium iodide and ELF97 to intracellular targets. RESULTS: The permeabilizing activity of concentrated BAL material from SP-A+/+ mice was substantially greater than that from SP-A-/- animals, and was sensitive to hyperoxic exposure. Oxidation of the collectins in vitro also blocked their antimicrobial effects. Rough but not smooth LPS conferred susceptibility of model bacterial membranes to permeabilization by the collectins. The screening of genetically engineered SP-A mice with a Pseudomonas aeruginosa signature tagged mutagenesis library has revealed several pathways which are required for resistance to the permeabilizing effects of SP-A, including those required for salicylate biosynthesis and flagellar function. CONCLUSION: The researchers conclude that the pulmonary collectins directly permeabilize bacteria in an LPS-dependent and rough LPS-specific manner. Oxidative damage blocks the permeabilizing activity of alveolar lining fluid and purified proteins. The mechanism(s) of permeabilization is not known, but the crystal structure of SP-A reveals a hydrophobic cleft lined by charged residues which may play a role in membrane perturbation.

Animals↗
PubMed1999

Functional roles and structural analysis of lung collectins SP-A and SP-D.

Pulmonary surfactant proteins A and D (SP-A and SP-D) belong to the collectin subgroup of the C-type lectin superfamily along with mannose-binding protein (MBP) and conglutinin. Phospholipids are also ligands for collectins, in addition to carbohydrates and glycosphingolipids. SP-A binds dipalmitoylphosphatidylcholine, and SP-D and MBP bind phosphatidylinositol. SP-A also interacts with alveolar type II cells, implicating SP-A in surfactant phospholipid homeostasis. We analyzed an epitope for anti-SP-A monoclonal antibodies that block SP-A-specific functions using a phage display peptide library and SP-A/MBP chimeric proteins. We also investigated the regions of SP-A and SP-D that are required for ligand interactions using SP-A/SP-D chimeras. Lung collectins play key roles in the innate immune system of the lung which is critical for immediate antibody-independent host defense. We have found that SP-A exhibits different interactions with distinct serotypes of lipopolysaccharides and affects differently their elicited cellular responses by a direct interaction with the lipopolysaccharide receptor CD14. In addition to the basic aspects, lung collectins as clinical markers will be discussed.

Binding Sites↗
PubMed1998

Collectins and pulmonary host defense.

The surfactant-associated proteins SP-A and SP-D are members of a family of collagenous host defense lectins, designated collectins. There is increasing evidence that these pulmonary epithelial-derived proteins are important components of the innate immune response to microbial challenge, and that they participate in other aspects of immune and inflammatory regulation within the lung. The collectins bind to glycoconjugates and/or lipid moieties expressed by a wide variety of microorganisms and certain other organic particles in vitro. Although binding may facilitate microbial clearance through aggregation or other direct effects on the organism, SP-A and SP-D also have the capacity to modulate leukocyte function and, in some circumstances, to enhance their killing of microorganisms. The biologic activity of cell wall components, such as gram-negative bacterial polysaccharides, may be altered by interactions with collectins. Complementary or cooperative interactions between SP-A and SP-D could contribute to the efficiency of this defense system. Collectins may play particularly important roles in settings of inadequate or impaired specific immunity. Acquired or genetic alterations in the levels of active proteins within the airspaces and distal airways may increase susceptibility to infection.

Animals↗
PubMed1997

The C1q and collectin binding site within C1q receptor (cell surface calreticulin).

C1q receptor (C1qR/collectin receptor/cC1qR) has an almost complete amino acid sequence identity with calreticulin (CRT). C1qR/CRT is located on the surface of many cell types. Binding of C1q to C1q receptor elicits a range of immunological responses. C1qR also interacts with the collectins SP-A, MBL, CL43 and conglutinin via a cluster of charged residues on the collagen tails of the ligands. In order to localise C1q and collectin binding activity within C1qR/CRT, recombinant C1qR/CRT domains [N (residues 18-196), P (197-308) and C (309-417)] were produced. Both the N- and P-domains bound to C1q, demonstrating that the binding site spans the intersection of these domains. Amino acid alignment analysis identified a putative CUB module within this region. This S-domain (residues 160-283) was expressed and showed concentration-dependent binding to immobilised C1q, demonstrating that it contains the C1q binding site. Competitive inhibition studies of the S-domain-C1q interaction revealed that the S-domain binds to C1q collagen tails and to the collectin proteins, SP-A, MBL, CL43 and conglutinin. The C1q and collection binding site on C1qR/CRT has therefore been localised to the S-domain.

Amino Acid Sequence↗
PubMed1997

Mechanisms of anti-influenza activity of surfactant proteins A and D: comparison with serum collectins.

The present study provides the first direct comparison of anti-influenza A virus (IAV) activities of the collectins surfactant protein (SP) A and SP-D, mannose-binding lectin (MBL), and conglutinin. SP-D, MBL, and conglutinin inhibited IAV hemagglutination activity with a greater potency than and by a distinct mechanism from SP-A. Although isolated trimeric SP-D carbohydrate recognition domains inhibited hemagglutination activity, preparations of SP-D also containing the collagen domain and NH2 terminus caused greater inhibition. In contrast to SP-A (or nonmultimerized SP-D), absence of the N-linked attachment did not effect interactions of multimerized SP-D with IAV. SP-D, SP-A, and conglutinin caused viral precipitation through formation of massive viral aggregates, whereas MBL formed aggregates of smaller size that did not precipitate. All of the collectins enhanced IAV binding to neutrophils; however, in the case of MBL, this effect was modest compared with the binding enhancement induced by SP-D or conglutinin. These studies clarify the structural requirements for viral inhibition by SP-D and reveal significant differences in the mechanisms of anti-IAV activity among the collectins.

Animals↗
PubMed2006

Collectins: opsonins for apoptotic cells and regulators of inflammation.

The collagenous C-type lectin family (collectins) members are humoral molecules found in the serum and on certain mucosal surfaces. In humans the family of collectins include the mannose-binding lectin, surfactant protein A and surfactant protein D. They demonstrate broad ligand specificity for both pathogenic bacteria and viruses. Over the past 5 years data have emerged indicating that these molecules are able to bind self-derived ligands in the form of apoptotic cells and regulate inflammatory responses. Furthermore, exciting new data from murine models have begun to define the in vivo importance of these molecules as regulators of inflammation and immunity. Here will discuss our current understanding of the process of collectin recognition of dying and damaged cells and its implications for autoimmune and inflammatory diseases.

Animals↗
PubMed2003

Innate immune collectins bind nucleic acids and enhance DNA clearance in vitro.

Collectins are a class of innate immune proteins that opsonize microbes and other ligands via their carbohydrate-recognition domains and enhance their clearance by phagocytes. We hypothesized that collectins, such as pulmonary surfactant protein (SP-) A and D and mannose-binding lectin (MBL), could bind nucleic acid, which is a pentameric sugar-based anionic polymer. We have shown that SP-D and MBL bind to both DNA and RNA effectively and also that SP-D enhances the uptake of DNA by human monocytic cells. Therefore, our results suggest that nucleic acids may be a novel class of ligands for collectins. This class of innate immune proteins could enhance the clearance of DNA that is released by necrotic cells or microbial cells. Our findings may have important biological implications, such as the alleviation of DNA-mediated tissue inflammation.

Binding Sites↗
PubMed2002

Molecular cloning of mouse collectin liver 1.

Collectins are members of the superfamily of vertebrate C-type lectins that contain a collagen-like region, and are involved in first-line host defense. We earlier cloned and characterized a new kind of collectin, collectin liver 1 (CL-L1). In this study, we isolated the mouse homologue of CL-L1 encoding 277 amino acid residues; its deduced protein sequence was 88% identical with human CL-L1. Mouse CL-L1 mRNA was expressed mainly in the liver and stomach, but was found also in muscles, testes, intestines, and embryos. In mouse embryos, the level of CL-L1 mRNA gradually increased with embryonic age. In 16-day-old mouse embryos, CL-L1 mRNA was expressed in the liver, amnion, and visceral yolk sac. The mouse CL-L1 gene, Cll1 was found on chromosome 15 in a region syntenic with human chromosome 8q. CL-L1 was a highly conserved protein in mammals, birds, and fish.

Amino Acid Sequence↗
PubMed2005

Interactions of the extracellular matrix proteoglycans decorin and biglycan with C1q and collectins.

Decorin and biglycan are closely related abundant extracellular matrix proteoglycans that have been shown to bind to C1q. Given the overall structural similarities between C1q and mannose-binding lectin (MBL), the two key recognition molecules of the classical and the lectin complement pathways, respectively, we have examined functional consequences of the interaction of C1q and MBL with decorin and biglycan. Recombinant forms of human decorin and biglycan bound C1q via both collagen and globular domains and inhibited the classical pathway. Decorin also bound C1 without activating complement. Furthermore, decorin and biglycan bound efficiently to MBL, but only biglycan could inhibit activation of the lectin pathway. Other members of the collectin family, including human surfactant protein D, bovine collectin-43, and conglutinin also showed binding to decorin and biglycan. Decorin and biglycan strongly inhibited C1q binding to human endothelial cells and U937 cells, and biglycan suppressed C1q-induced MCP-1 and IL-8 production by human endothelial cells. In conclusion, decorin and biglycan act as inhibitors of activation of the complement cascade, cellular interactions, and proinflammatory cytokine production mediated by C1q. These two proteoglycans are likely to down-regulate proinflammatory effects mediated by C1q, and possibly also the collectins, at the tissue level.

Amino Acid Sequence↗
PubMed1996

Neutrophil deactivation by influenza A viruses: mechanisms of protection after viral opsonization with collectins and hemagglutination-inhibiting antibodies.

Bacterial superinfections are a major cause of morbidity and mortality during influenza A virus (IAV) epidemics. Depression of phagocyte functions resulting from attachment of the IAV hemagglutinin (HA) to cell surface sialo-glycoproteins is a likely contributory cause of these infections. We have proposed that the group of collagenous lectins (termed collectins) present in blood and pulmonary surfactant play a role in initial host defense against IAV. We used here several recombinant human surfactant protein D (RhSP-D) preparations to determine the mechanism through which opsonization of IAV with collectins protects neutrophils against the deactivating effects of IAV on cellular respiratory burst responses in vitro. RhSP-D was markedly more potent than antibodies that inhibited viral hemagglutination activity (anti-HA antibodies) at protecting neutrophils in this assay. Unlike the anti-HA antibodies, RhSP-D was protective at concentrations that minimally inhibited viral hemagglutination activity. Two related features of SP-D--the degree of multimerization and the ability to cause aggregation of IAV particles--were critical determinants of the ability of SP-D to protect neutrophils against deactivation. Similarly SP-D-induced viral aggregate formation resulted in enhanced IAV binding to neutrophils and potentiated the ability of the virus itself to trigger neutrophil respiratory burst responses. In contrast to the case of IAV-antibody complexes, SP-D-IAV complexes attached to and activated neutrophils through a neuraminidase-sensitive mechanism (ie, similar to unopsonized IAV). These results indicate that collectin-mediated viral aggregation per se may be an important host defense mechanism not only by virtue of reducing the number of infectious viral particles, but also by promoting phagocyte responsiveness.

Animals↗
PubMed1995

Characterization of murine mannose-binding protein genes Mbl1 and Mbl2 reveals features common to other collectin genes.

Mannose-binding protein (MBP) is a member of a family of collagenous lectins (collectins), which are believed to play an important role in first-line host defense. In this study, the two genes encoding MBP in mice--Mbl1 and Mbl2--have been isolated and their exon-intron structure studied to understand their evolutionary relationship to the single human (MBL) and the two rat MBP genes. Mouse Mbl1 and Mbl2 have five and six exons, respectively. The structure of the mouse Mbl genes is similar to that of the rat and human MBP genes and shows homology to the other collectin genes, with the entire carbohydrate recognition domain being encoded in a single exon and all introns being in phase 1. The MBP encoded by mouse Mbl1 with three cysteines in the first coding exon, like the rat Mbl1 and human MBL, is capable of a higher degree of multimerization and has apparent ability to fix complement in the absence of antibody or C1q. However, the structural features of other exons, that is, the larger size of collagen domain region in the first coding exon (64 bp in Mbl2 vs 46 bp in Mbl1) and the smaller size of the exon encoding the trimerization domain (69 bp in Mbl2 vs 75 bp in Mbl1) reveal that the single human MBL gene is closely related to rodent Mbl2 rather than rodent Mbl1. The findings in this study suggest that in contrast to the evolution of another collectin gene--bovine surfactant protein-D--which duplicated in bovidae after divergence from humans, MBP gene most likely duplicated prior to human-rodent divergence, and that the human homolog to Mbl1 was perhaps lost during evolution.

Amino Acid Sequence↗
PubMed2005

The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity.

Pulmonary surfactant, which covers the peripheral airway, is a mixture of lipids and proteins. The hydrophilic surfactant proteins A (SP-A) and D (SP-D) play important roles in host defense mechanisms of the lung. These proteins belong to a collectin subgroup in which lectin domains are associated with collagenous structures. Collectins involve mannose-binding lectin, and are considered to function in innate immune systems. SP-A and SP-D interact with various microorganisms and pathogen-derived components. They act as opsonins by binding and agglutinating pathogens. The lung collectins also possess direct inhibitory effects on bacterial growth. SP-A and SP-D associate with immune cells, and activate various cellular functions. The direct interactions of SP-A and SP-D with macrophages result in modulation of phagocytosis or the production of reactive oxygen species. Moreover, by associating with cell surface pattern-recognition receptors, SP-A and SP-D regulate inflammatory cellular responses such as the release of lipopolysaccharides-induced proinflammatory cytokines. Animal models of SP-A- or SP-D-deficiency reveal significant defect in host defense. Significant susceptibility to bacterial and viral infections, delayed microbial clearance, and overexpression of proinflammatory cytokines are observed in SP-A or SP-D knockout mice. A more complete understanding of the mechanisms is required, but the biological relevance of SP-A and SP-D against various respiratory infections has been increasingly recognized.

Animals↗
PubMed2003

Porcine pulmonary collectins show distinct interactions with influenza A viruses: role of the N-linked oligosaccharides in the carbohydrate recognition domain.

Influenza A virus (IAV) infections are a major cause of respiratory disease of humans and animals. Pigs can serve as important intermediate hosts for transmission of avian IAV strains to humans, and for the generation of reassortant strains; this may result in the appearance of new pandemic IAV strains in humans. We have studied the role of the porcine lung collectins surfactant proteins D and A (pSP-D and pSP-A), two important components of the innate immune response against IAV. Hemagglutination inhibition assays revealed that both pSP-D and pSP-A display substantially greater inhibitory activity against IAV strains isolated from human, swine, and horse, than lung collectins from other animal species. The more potent activity of pSP-D results from interactions mediated by the asparagine-linked oligosaccharide located in the carbohydrate recognition domain of pSP-D, which is absent in SP-Ds from other species characterized to date. Presence of this sialylated oligosaccharide moiety enhances the anti-influenza activity of pSP-D, as demonstrated by assays of viral aggregation, inhibition of infectivity, and neutrophil response to IAV. The greater hemagglutination inhibitory activity of pSP-A is due to porcine-specific structural features of the conserved asparagine-linked oligosaccharide in the carbohydrate recognition domain of SP-A. A more efficient lung collectin-mediated immune response against IAV in pigs may play a role in providing conditions by which pigs can act as "mixing vessel" hosts that can lead to the production of reassortant, pandemic strains of IAV.

Animals↗
PubMed2005

Innate immune collectin surfactant protein D enhances the clearance of DNA by macrophages and minimizes anti-DNA antibody generation.

Dying microbes and necrotic cells release highly viscous DNA that induces inflammation and septic shock, and apoptotic cells display DNA, a potential autoantigen, on their surfaces. However, innate immune proteins that mediate the clearance of free DNA and surface DNA-containing cells are not clearly established. Pulmonary surfactant proteins (SP-) A and D are innate immune pattern recognition collectins that contain fibrillar collagen-like regions and globular carbohydrate recognition domains (CRDs). We have recently shown that collectins SP-A, SP-D, and mannose binding lectin recognize DNA and RNA via their collagen-like regions and CRDs. Here we show that SP-D enhances the uptake of Cy3-labeled fragments of DNA and DNA-coated beads by U937 human monocytic cells, in vitro. Analysis of DNA uptake by freshly isolated mouse alveolar macrophages shows that SP-D, but not SP-A, deficiency results in reduced clearance of DNA, ex vivo. Analysis of bronchoalveolar lavage fluid shows that SP-D- but not SP-A-deficient mice are defective in clearing free DNA from the lung. Additionally, both SP-A- and SP-D-deficient mice accumulate anti-DNA Abs in sera in an age-dependent manner. Thus, we conclude that collectins such as SP-A and SP-D reduce the generation of anti-DNA autoantibody, which may be explained in part by the defective clearance of DNA from the lungs in the absence of these proteins. Our findings establish two new roles for these innate immune proteins and that SP-D enhances efficient pinocytosis and phagocytosis of DNA by macrophages and minimizes anti-DNA Ab generation.

Adjuvants, Immunologic↗
PubMed2001

Increased antiviral and opsonic activity of a highly multimerized collectin chimera.

Altering the carbohydrate binding properties of surfactant protein D (SP-D) [e.g., by replacing its carbohydrate recognition domain (CRD) with that of either mannose binding lectin (MBL) or conglutinin] can increase its activity against influenza A virus (IAV). The current study demonstrates that the degree of multimerization of SP-D is another independent determinant of antiviral activity. A chimeric collectin containing the N-terminus and collagen domain of human SP-D and the CRD of MBL formed high-molecular-weight multimers similar to those previously described for human SP-D. Using several complementary assays, and diverse viral strains, the chimeric multimers showed greater anti-IAV activity than similarly multimerized preparations of SP-D or incompletely oligomerized preparations of the chimera. More highly multimerized preparations of the chimera also caused greater increases in uptake of IAV by neutrophils. These studies may have implications for development of collectins as therapeutic agents and understanding of natural variations in susceptibility to IAV infection.

Animals↗
PubMed2004

A time-resolved immunofluorometric assay for quantification of collectin-43.

CL-43 is a serum collectin involved in the innate immunity of cattle and variability of serum CL-43 may relate to disease in cows. A high capacity time-resolved immunofluorometric assay (TRIFMA) for the bovine collectin-43 (CL-43) was developed. The TRIFMA was constructed as a noncompetitive sandwich based on polyclonal antibodies and a novel monoclonal antibody (mab) raised against CL-43 and was set up to run on an automatic analyser designed for the TRIFMA detection system. The polyclonal antibodies were immobilized on microtiter plate wells and incubated with diluted plasma samples, including quality controls (QC) and dilutions of a plasma with known CL-43 concentration. CL-43 was sandwiched between the capture antibodies and the monoclonal antibody and the detection was optimised with biotin-labelled secondary antibodies and streptavidin-Eu3+. Plates were washed four times between each step and finally incubated with enhancement solution before measuring the fluorescence. The assay detection limit was 0.24 ng/ml and the working range was 0.54-22 ng/ml. Recovery was 92.3% when samples were spiked with 2.0 ng/ml of CL-43. Intraplate and interplate coefficients of variation were in the range of 1.11-2.36% and 0.70-1.35%, respectively. No circadian rhythm (24-h variation) in CL-43 plasma levels was observed, indicating that plasma levels were not influenced by e.g. feeding. Samples could be stored at -20 degrees C and were not sensitive to repeated freezing and thawing. In conclusion, the developed TRIFMA for CL-43 is specific and reliable over a measurement range covering most situations.

Animals↗
PubMed1998

Interaction of C1q and the collectins with the potential receptors calreticulin (cC1qR/collectin receptor) and megalin.

Several proteins have been identified as candidate cell-surface receptors for the complement protein C1q. Some of these also interact with the structurally-related collectin proteins. Previous descriptions of C1q-binding properties of cells, and information on the cellular distribution of candidate receptors suggest that there is more than one physiologically relevant receptor for C1q. Two such candidate receptors, cell-surface calreticulin (also referred to as cC1qR or collectin receptor) and megalin are discussed in this review.

Amino Acid Sequence↗