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PubMed2002

Contributions of the N- and C-terminal domains of surfactant protein d to the binding, aggregation, and phagocytic uptake of bacteria.

Collectins play important roles in host defense against infectious microorganisms. We now demonstrate that the serum collectins mannose-binding lectin (MBL) and conglutinin have less ability to bind to, aggregate, and enhance neutrophil uptake of several strains of gram-negative and gram-positive bacteria than pulmonary surfactant protein D (SP-D). Collectins are composed of four major structural domains (i.e., N-terminal, collagen, and neck and carbohydrate recognition domains). To determine which domains of SP-D are responsible for its greater bacterial binding or aggregating activity, activities of chimeric collectins containing the N-terminal and collagen domains of SP-D coupled to the neck recognition domains and carbohydrate recognition domains (CRD) of MBL or conglutinin (SP-D/Cong(neck+CRD) and SP-D/MBL(neck+CRD)) were tested. The SP-D/Cong(neck+CRD) and SP-D/MBL(neck+CRD) chimeras bound to and aggregated the bacteria more strongly than did wild-type MBL or conglutinin. SP-D/MBL(neck+CRD) also enhanced neutrophil uptake of bacteria more so than MBL. Hence, the SP-D N-terminal and/or collagen domains contribute to the enhanced bacterial binding and aggregating activities of SP-D. In prior studies, SP-D/Cong(neck+CRD) and SP-D/MBL(neck+CRD) had increased ability to bind to influenza virus compared not only with that of conglutinin or MBL but with that of wild-type SP-D as well. In contrast, the chimeras had either reduced or unchanged ability to bind to or aggregate bacteria compared to that of wild-type SP-D. Hence, although replacement of the neck recognition domains and CRDs of SP-D with those of MBL and conglutinin conferred increased viral binding activity, it did not favorably affect bacterial binding activity, suggesting that requirements for optimal collectin binding to influenza virus and bacteria differ.

Animals↗
PubMed1994

Mammalian lectins in activation and clearance mechanisms involving the complement system.

CRP and the mammalian lectins containing collagen-like structure (collectins) can clearly participate in a variety of antibody-independent recognition and clearance mechanisms which result in the neutralisation and elimination of pathogenic organisms (Fig. 2). Only CRP and MBP appear to have the capacity to activate complement, and while all the collectins (MBP, SP-A, SP-D and conglutinin) can utilise the C1q receptor, only conglutinin shows specificity for iC3b. The C-type lectin domains in the globular heads of the collectins have the capacity to recognise a range of specific carbohydrate structures which are found on the surfaces of pathogens commonly associated with infections in blood, lung and amniotic fluids. The proposed presentation of the carbohydrate-collectin complex to C1q receptors, via the collagen-like regions in the collectins is an attractive hypothesis for the triggering of protective mechanisms and there are already a number of publications which support this view. However, the precise manner by which these collagen 'stalks' interact with the C1q receptor and the complete characterisation of the receptor on a variety of different cell types remains to be elucidated. Similarly, whether or not there is a role for any of these lectins in autoimmunity/immunopathology has not, as yet, been addressed.

Animals↗
PubMed2000

Mechanism of binding of surfactant protein D to influenza A viruses: importance of binding to haemagglutinin to antiviral activity.

Collectins are important in the initial containment of a variety of pathogens, including influenza A virus (IAV). We provide the first systematic evaluation of the oligosaccharide-binding sites for pulmonary surfactant protein D (SP-D) on specific IAV coat glycoproteins and define the relationship between this binding and antiviral activity. With the use of several techniques, SP-D was found to bind via its carbohydrate-recognition domain (CRD) to mannosylated, N-linked carbohydrates on the HA(1) domain of the haemagglutinin (HA) and on the neuraminidase of IAV. Using a set of IAV strains that differed in the level and site of glycosylation, and a panel of recombinant collectins, we found that binding of SP-D to the globular domain of the HA was critical in mediating the inhibition of viral haemagglutination activity and infectivity. We also demonstrated that the pattern of binding of a collectin to IAV glycoproteins can be modified by altering the monosaccharide-binding affinity of its CRD or by linking the CRD to a different N-terminal/collagen domain. These studies clarify the mechanisms of viral neutralization by collectins and might be useful in engineering collectins for enhanced antiviral activity.

Amidohydrolases↗
PubMed2002

Lung surfactant protein D (SP-D) and the molecular diverted descendants: conglutinin, CL-43 and CL-46.

Lung surfactant protein D (SP-D), conglutinin, CL-43 and CL-46 belong to a group of proteins designated collectins that, besides a common structure made of a collagen-like region and a C-type lectin domain, are important components of the innate immune defence. They all bind complex glycoconjugates on microorganisms thereby inhibiting infection, enhancing the clearance by phagocytes and modulating the immune response. In addition, SP-D inhibits the generation of radical oxygen species or the propagation of lipid peroxidation. Knock-out mice deficient in SP-D have a disturbed homeostasis of pulmonary surfactant and suffer from oxidative stress leading to pulmonary inflammation upon microbial challenge. Conglutinin, CL-43 and CL-46 have in contrast to the rest of the collectin family only been found in cattle. During the characterization of the genes encoding conglutinin, CL-43 and CL-46 we observed several features showing that the additional bovine collectins are diverted molecular descendants of an ancestral SP-D gene. Since structural similarity often associates with common functionality, some of SP-D's effector mechanisms may apply to conglutinin, CL-43 and CL-46--and vice versa. This review focus on the structural and functional relationship of this group of collectins.

Animals↗
PubMed1998

Interactions of surfactant protein A with pathogens.

The lung is an organ with a large inner surface that is continuously in contact with the environment. Infection of this organ is prevented by several mechanisms. A recently described defence system is collectin-mediated innate immunity of the lung. Collectins are multimeric proteins characterized by carbohydrate recognition domains bound to collagen stalks. Surfactant protein (SP)-A and SP-D are collectins that are present in the epithelial lining fluid of the lung. SP-A interacts with viruses, bacteria and fungi. Furthermore, SP-A binds to various other inhaled glycoconjugates. SP-A receptors on phagocytic cells have been described that are important to ensure rapid pathogen clearance. This innate defence system of the lung may be particularly important during infections in young children when the acquired immune system has not yet become fully established. Also in later life SP-A could be very important to prevent the lungs from infections by pathogens not previously encountered. In addition, SP-A may limit the inflammatory response in the lungs, thus preventing damage to the delicate lung epithelia. Recently, evidence was presented that SP-A may modulate the allergic response to various glycosylated inhaled antigens. The presence of SP-A (and SP-D) in other organs indicates that these collectins may have a general role in mucosal immunity. In this review the interactions of SP-A with a variety of pathogens and its implications are discussed.

Bacteria↗
PubMed2000

Surfactant proteins A and D bind CD14 by different mechanisms.

Surfactant proteins A (SP-A) and D (SP-D) are lung collectins that are constituents of the innate immune system of the lung. Recent evidence (Sano, H., Sohma, H., Muta, T., Nomura, S., Voelker, D. R., and Kuroki, Y. (1999) J. Immunol. 163, 387-395) demonstrates that SP-A modulates lipopolysaccharide (LPS)-induced cellular responses by direct interaction with CD14. In this report we examined the structural elements of the lung collectins involved in CD14 recognition and the consequences for CD14/LPS interaction. Rat SP-A and SP-D bound CD14 in a concentration-dependent manner. Mannose and EDTA inhibited SP-D binding to CD14 but did not decrease SP-A binding. The SP-A binding to CD14 was completely blocked by a monoclonal antibody that binds to the SP-A neck domain but only partially blocked by an antibody that binds to the SP-A lectin domain. SP-A but not SP-D bound to deglycosylated CD14. SP-D decreased CD14 binding to both smooth and rough LPS, whereas SP-A enhanced CD14 binding to rough LPS and inhibited binding to smooth LPS. SP-A also altered the migration profile of LPS on a sucrose density gradient in the presence of CD14. From these results, we conclude that 1) lung collectins bind CD14, 2) the SP-A neck domain and SP-D lectin domain participate in CD14 binding, 3) SP-A recognizes a peptide component and SP-D recognizes a carbohydrate moiety of CD14, and 4) lung collectins alter LPS/CD14 interactions.

Animals↗
PubMed1999

Surfactant proteins A and D specifically stimulate directed actin-based responses in alveolar macrophages.

Surfactant protein (SP) A and SP-D are the pulmonary members of the collectin family, structurally related proteins involved in innate immune responses. Here, we have examined the abilities of SP-A, SP-D, mannose-binding protein (MBP), and the complement component C1q to stimulate actin-based cellular functions in rat alveolar macrophages and peripheral blood monocytes. Our goal in this study was to examine the cell specificity of the effects of the collectins to understand further the mechanisms by which SP-A and SP-D stimulate alveolar macrophages. We found that SP-A and SP-D have lung cell-specific effects at physiologically relevant concentrations; they stimulate directional actin polymerization and chemotaxis in alveolar macrophages but not in monocytes. Although C1q and MBP weakly stimulate the rearrangement of actin in both cell types, C1q is chemotactic only for peripheral blood monocytes and MBP does not stimulate chemotaxis of either cell type. Neither C1q nor MBP stimulates actin polymerization in alveolar macrophages. These results support the hypothesis that alveolar macrophages express receptors specific for the pulmonary collectins SP-A and SP-D and provide insight into the potential roles of collectins in the recruitment and maturation of mononuclear phagocytes in the lung.

Actins↗
PubMed2001

Surfactant proteins D and A in sputum.

The surfactant proteins SP-D and SP-A are collectins and central components of the innate immune system of the peripheral lungs. They bind to carbohydrates on microorganisms and promote their removal. In the larger airways their role and concentrations are not yet known. Sputum may thus potentially be useful to characterize the collectins in this compartment. Induced sputum was obtained from healthy adults and spontaneous sputum from patients with cystic fibrosis. ELISA and carbohydrate binding assays were used to quantify the amount and functional capacity of the collectins in plugs or sol-fractions, prepared by centrifugation of the plugs. SP-D and SP-A were detectable in only about 50% of the sputum plugs. Varying the salt, detergent and calcium conditions of the assay did not improve the results. In samples with reproducibly detectable SP-D or SP-A, their carbohydrate binding capacity was zero. Sputum sol fraction and LPS inhibited the binding of the collectins to carbohydrate in the presence of calcium. Whereas SP-D and SP-A are abundant in the peripheral lung, their presence in sputum derived from the larger airways is variable and their carbohydrate binding capacity is lost.

Adolescent↗
PubMed2001

Collections and ficolins: humoral lectins of the innate immune defense.

Collectins and ficolins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune systems, which recognize pathogen-associated molecular patterns. The human collectins, mannan-binding lectin (MBL) and surfactant protein A and D (SP-A and SP-D), are oligomeric proteins composed of carbohydrate-recognition domains (CRDs) attached to collagenous regions and are thus structurally similar to the ficolins, L-ficolin, M-ficolin, and H-ficolin. However, they make use of different CRD structures: C-type lectin domains for the collectins and fibrinogen-like domains for the ficolins. Upon recognition of the infectious agent, MBL and the ficolins initiate the lectin pathway of complement activation through attached serine proteases (MASPs), whereas SP-A and SP-D rely on other effector mechanisms: direct opsonization, neutralization, and agglutination. This limits the infection and concurrently orchestrates the subsequent adaptive immune response. Deficiencies of the proteins may predispose to infections or other complications, e.g., reperfusion injuries or autoimmune diseases. Structure, function, clinical implications, and phylogeny are reviewed.

Animals↗
PubMed1997

Immunomodulatory functions of surfactant.

The possibility that the lipoprotein complex of lung surfactant functions in pulmonary host defense as well as lowering surface tension at the air-liquid interface has been the subject of renewed interest in light of the finding that surfactant proteins A and D (SP-A and SP-D) are members of a family of proteins known as collectins. The collectins, so named because they have in common an NH2-terminal collagen-like domain and a COOH-terminal lectin (carbohydrate binding) domain, are found in both lung and serum and participate in "innate" immunity, acting before induction of an antibody-mediated response. In vitro, many of the collectins stimulate phagocytosis, chemotaxis, and production of reactive oxygen and regulate cytokine release by immune cells. It has been known for several years that surfactant lipids suppress a variety of immune cell functions, most notably lymphocyte proliferation, which, conversely, is augmented by SP-A. Thus surfactant lipids and proteins may be counterregulatory, and changes in lipid-to-protein ratios may be important in regulating the immune status of the lung. That these ratios change in disease states is clear, but it is not known whether the alterations are a cause or an effect. Important future studies with mice in which the SP-A and SP-D genes have been ablated will help clarify the role of surfactant in immune function.

Animals↗
PubMed2003

Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability.

The pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D), have been reported to bind lipopolysaccharide (LPS), opsonize microorganisms, and enhance the clearance of lung pathogens. In this study, we examined the effect of SP-A and SP-D on the growth and viability of Gram-negative bacteria. The pulmonary clearance of Escherichia coli K12 was reduced in SP-A-null mice and was increased in SP-D-overexpressing mice, compared with strain-matched wild-type controls. Purified SP-A and SP-D inhibited bacterial synthetic functions of several, but not all, strains of E. coli, Klebsiella pneumoniae, and Enterobacter aerogenes. In general, rough E. coli strains were more susceptible than smooth strains, and collectin-mediated growth inhibition was partially blocked by coincubation with rough LPS vesicles. Although both SP-A and SP-D agglutinated E. coli K12 in a calcium-dependent manner, microbial growth inhibition was independent of bacterial aggregation. At least part of the antimicrobial activity of SP-A and SP-D was localized to their C-terminal domains using truncated recombinant proteins. Incubation of E. coli K12 with SP-A or SP-D increased bacterial permeability. Deletion of the E. coli OmpA gene from a collectin-resistant smooth E. coli strain enhanced SP-A and SP-D-mediated growth inhibition. These data indicate that SP-A and SP-D are antimicrobial proteins that directly inhibit the proliferation of Gram-negative bacteria in a macrophage- and aggregation-independent manner by increasing the permeability of the microbial cell membrane.

Animals↗
PubMed2000

Enhanced antiviral and opsonic activity of a human mannose-binding lectin and surfactant protein D chimera.

The carbohydrate recognition domains (CRDs) of human serum mannose-binding lectin (MBL) and pulmonary surfactant protein D (SP-D) have distinctive monosaccharide-binding properties, and their N-terminal and collagen domains have very different quaternary structures. We produced a chimeric protein containing the N terminus and collagen domain of human SP-D and the neck region and CRD of human MBL (SP-D/MBLneck+CRD) to create a novel human collectin. The chimera bound to influenza A virus (IAV), inhibited IAV hemagglutination activity and infectivity, and induced aggregation of viral particles to a much greater extent than MBL. Furthermore, SP-D/MBLneck+CRD caused much greater increases in neutrophil uptake of, and respiratory burst responses to, IAV than MBL. These results indicate that pathogen interactions mediated by the MBL CRD are strongly influenced by the N-terminal and collagen-domain backbone to which it is attached. The presence of the CRD of MBL in the chimera resulted in altered monosaccharide binding properties compared with SP-D. As a result, the chimera caused greater aggregation and neutralization of IAV than SP-D. Distinctive functional properties of collectin collagenous domains and CRDs can be exploited to generate novel human collectins with potential for therapy of influenza.

Animals↗
PubMed1999

Aerosolized endotoxin is immediately bound by pulmonary surfactant protein D in vivo.

Collectins are carbohydrate binding proteins that are implicated in innate host defense. The lung collectins, surfactant proteins A and D (SP-A and SP-D), bind a variety of pathogens in vitro and influence phagocytosis by alveolar macrophages. In this report we show that SP-D binds endotoxin (lipopolysaccharide, LPS) in vivo in a rat model of acute respiratory distress syndrome (ARDS). Intratracheal aerosolization of LPS in rats resulted in the typical features of human ARDS. Total amounts of SP-D, as well as the carbohydrate binding properties of SP-D were measured in lung lavage as a function of time. The amount of SP-D did not change during 24 h. Interestingly, SP-D in lung lavage isolated from rats during the first 2 h after LPS treatment, was not able to bind to carbohydrate. Further analysis revealed that the carbohydrate binding sites of SP-D were occupied by LPS, suggesting that SP-D is an LPS scavenging molecule in vivo. Electron microscopic analysis indicated that, 1 h after LPS aerosolization, aggregates of SP-D with LPS were found in lysosomal structures in alveolar macrophages. We conclude that the lung collectin SP-D binds inhaled endotoxin in vivo, which may help to protect the lung from endotoxin-induced disease.

Aerosols↗
PubMed1999

Introduction of mannose binding protein-type phosphatidylinositol recognition into pulmonary surfactant protein A.

Pulmonary surfactant protein A (SP-A) and mannose-binding protein A (MBP-A) are collectins in the C-type lectin superfamily. These collectins exhibit unique lipid binding properties. SP-A binds to dipalmitoyl phosphatidylcholine (DPPC) and galactosylceramide (GalCer) and MBP-A binds to phosphatidylinositol (PI). SP-A also interacts with alveolar type II cells. Monoclonal antibodies (mAbs PE10 and PC6) that recognize human SP-A inhibit the interactions of SP-A with lipids and alveolar type II cells. We mapped the epitopes for anti-human SP-A mAbs by a phage display peptide library. Phage selected by mAbs displayed the consensus peptide sequences that are nearly identical to 184TPVNYTNWYRG194 of human SP-A. The synthetic peptide GTPVNYTNWYRG completely blocked the binding of mAbs to human SP-A. Chimeric proteins were generated in which the rat SP-A region Thr174-Gly194 or the human SP-A region Ser174-Gly194 was replaced with the MBP-A region Thr164-Asp184 (rat ama4 or hu ama4, respectively). The mAbs failed to bind hu ama4. Rat ama4 bound to an affinity matrix on mannose-sepharose but lost all of the SP-A functions except carbohydrate binding and Ca2+-independent GalCer binding. Strikingly, the rat ama4 chimera acquired the PI binding property that MBP-A exhibits. This study demonstrates that the amino acid residues 174-194 of SP-A and the corresponding region of MBP-A are critical for SP-A-type II cell interaction and Ca2+-dependent lipid binding of collectins.

Animals↗
PubMed2003

Biochemistry and genetics of mannan-binding lectin (MBL).

Mannose- or mannan-binding lectin (MBL) is a member of the collectin protein family, which includes lung surfactant proteins SP-A and SP-D. Each member consists of similar or identical polypeptide chains with a region of collagen-like sequence followed by a C-type lectin domain. The polypeptides associate in threes to form a subunit containing a collagen-like helix, with three clustered lectin domains. These subunits associate into larger structures, usually with 12-18 polypeptides. The collectins bind to patterns of neutral sugars on surfaces (e.g. of micro-organisms) and mediate effector functions associated with killing/phagocytosis. MBL is the only collectin which activates complement. It resembles in quaternary structure the complement protein C1q, which recognizes targets via charge clusters. Binding of MBL to a surface activates MBL-associated serine proteases (MASPs) attached to MBL, and MASP-2 activates complement proteins C4 and C2. The MASPs are homologous to the C1q-associated proteases, C1r and C1s. MBL therefore activates complement by a mechanism very similar to C1q, and engages the opsonic activity of complement to clear micro-organisms. The serum concentration of MBL is very variable in humans. The variability is largely associated with mutations leading to amino acid substitutions in the collagen-like region which decrease MBL assembly and stability. Many studies demonstrate that MBL deficiency is associated with susceptibility to a range of infectious and inflammatory diseases.

Complement Pathway, Mannose-Binding Lectin↗
PubMed1996

A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin.

Collectins are C-type animal lectins with both collagenous and carbohydrate recognition domains and are involved in the first line host defense against pathogens. We report here a novel Ca(2+)-dependent and GlcNAc-binding lectin consisting of subunits of 35 kDa (P35) with a collagen-like sequence. When P35 is isolated from human serum, it forms a homopolymer by means of intermolecular disulfide bonding, as is the case with collectins. P35 cDNA was cloned from a human liver cDNA library, and the deduced amino acid sequence of 313 residues revealed that the mature form of P35 consists mainly of collagen- and fibrinogen-like domains. The latter contained two potential Ca(2+)-binding sites that may be involved in carbohydrate binding. The overall sequence of P35 was highly homologous to porcine ficolins alpha and beta. Northern blots of various human tissues showed that the major product of the 1.3-kilobase-long P35 transcript is expressed in liver. P35 enhanced phagocytosis of Salmonella typhimurium by neutrophils, suggesting an opsonic effect via the collagen region. P35 was found to bind to GlcNAc-conjugated bovine serum albumin, a neoglycoprotein, as well as to neoglycolipids containing complex-type oligosaccharides derived from glycoproteins, suggesting that P35 recognizes GlcNAc residues such as those found in microbial glycoconjugates and complex-type oligosaccharides. Therefore, P35 represents a new type of GlcNAc-binding lectin with structural and functional similarities to collectins involved in innate immunity.

Acetylglucosamine↗
PubMed2002

Respiratory syncytial virus and pulmonary surfactant.

Respiratory syncytial virus (RSV) infections peak in young infants and are associated with significant morbidity. The collectins surfactant protein-A (SP-A) and SP-D are pattern recognition molecules that belong to the innate immune system of the lungs, forming a first line of defense. On the one hand, SP-A and SP-D levels are reduced during RSV infection. This may critically influence the invasion of RSV and also the virus-induced cytokine patterns of the host. Both collectins enhance the in vivo elimination of RSV. Thus, interactions before the virus enters the epithelial cells may determine the course of the infection. On the other hand, during severe RSV infection in infants, the biophysical surfactant function is reduced and exogenous surfactant substitution may be a valid therapeutic option for selected infants. Thus, all components of the pulmonary surfactant system are involved during severe RSV infection. Especially the collectins SP-A and SP-D may play a pivotal role determining the short- and long-term course of RSV infections in early infancy.

Animals↗
PubMed2001

Rat mannose-binding protein a binds CD14.

Lipopolysaccharide (LPS) has been known to induce inflammation by interacting with CD14, which serves as a receptor for LPS. Mannose-binding protein (MBP) belongs to the collectin subgroup of the C-type lectin superfamily, along with surfactant proteins SP-A and SP-D. We have recently demonstrated that SP-A modulates LPS-induced cellular responses by interaction with CD14 (H. Sano, H. Sohma, T. Muta, S. Nomura, D. R. Voelker, and Y. Kuroki, J. Immunol. 163:387-395, 2000) and that SP-D also interacts with CD14 (H. Sano, H. Chiba, D. Iwaki, H. Sohma, D. R. Voelker, and Y. Kuroki, J. Biol. Chem. 275:22442-22451, 2000). In this study, we examined whether MBP, a collectin highly homologous to SP-A and SP-D, could bind CD14. Recombinant rat MBP-A bound recombinant human soluble CD14 in a concentration-dependent manner. Its binding was not inhibited in the presence of excess mannose or EDTA. MBP-A bound deglycosylated CD14 treated with N-glycosidase F, neuraminidase, and O-glycosidase, indicating that MBP-A interacts with the peptide portion of CD14. Since LPS was also a ligand for the collectins, we compared the characteristics of binding of MBP-A to LPS with those of binding to CD14. MBP-A bound to lipid A from Salmonella enterica serovar Minnesota and rough LPS (S. enterica serovar Minnesota Re595 and Escherichia coli J5, Rc), but not to smooth LPS (E. coli O26:B6 and O111:B4). Unlike CD14 binding, EDTA and excess mannose attenuated the binding of MBP-A to rough LPS. From these results, we conclude that CD14 is a novel ligand for MBP-A and that MBP-A utilizes a different mechanism for CD14 recognition from that for LPS.

Animals↗