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Uffe Holmskov - One of the best experts on this subject based on the ideXlab platform.
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Surfactant Protein D multimerization anD gene polymorphism in copD anD asthma
Respirology, 2018Co-Authors: Uffe Holmskov, Dalia Fakih, Zeina Akiki, Kirsten Junker, Myrna Medlejhashim, Mirna Waked, Pascale Salameh, Hasnaa BouharountayounAbstract:BackgrounD anD objective A structural single nucleotiDe polymorphism rs721917 in the Surfactant Protein D (SP-D) gene, known as Met11Thr, was reporteD to influence the circulating levels anD Degree of multimerization of SP-D anD was associateD with both COPD anD atopy in asthma. Moreover, Disease-relateD processes are known to DegraDe multimerizeD SP-D, however, the Degree of the Protein DegraDation in these Diseases is not clarifieD. We aimeD to Determine the Distribution of multimerizeD (high molecular weight (HMW)) anD non-multimerizeD (low molecular weight (LMW)) species of serum SP-D anD their correlation with genetic polymorphisms anD presence of Disease in Lebanese COPD anD asthmatic patients. MethoDs Serum SP-D levels were measureD by ELISA in 88 COPD, 121 asthmatic patients anD 223 controls. RanDomly selecteD subjects were chosen for genotyping of rs721917 anD multimerization stuDies. HMW anD LMW SP-D were separateD by gel permeation chromatography. Results Serum SP-D levels were significantly increaseD in patients with COPD, but not in asthmatic patients, when compareD to controls. Met11Thr variation strongly affecteD serum SP-D levels anD the Degree of multimerization, but was not associateD with COPD anD asthma in the stuDy. Remarkably, HMW/LMW serum SP-D ratio was significantly lower in Met11/Met11 COPD anD asthmatic patients compareD to controls. Conclusion Collectively, non-multimerizeD species of serum SP-D were Dominant in COPD anD asthmatic patients suggesting that DegraDation of SP-D takes place to a significant Degree in pulmonary Disease. Assays that can separate SP-D proteolytic breakDown proDucts or moDifieD forms from naturally occurring SP-D trimers may result in optimal Disease markers for pulmonary inflammatory Diseases.
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circulating Surfactant Protein D is associateD to mortality in elDerly women a twin stuDy
Immunobiology, 2013Co-Authors: Helle Wulfjohansson, Uffe Holmskov, Mikael Thinggaard, Qihua Tan, Sofie Lock Johansson, Anders Schlosser, Kaare Christensen, Grith Lykke SørensenAbstract:Abstract BackgrounD Surfactant Protein D (SP-D) is proDuceD in the lungs anD aDDitional mucosal surfaces. Systemic SP-D levels are previously associateD to aging-relateD- anD lifestyle-relateD DisorDers anD preDicts mortality in carDiovascular anD lung Diseases. However, the association between higher serum SP-D levels anD mortality in the general population is unknown. We hypothesizeD that increaseD systemic levels of SP-D may be useD as prognostic factor for assessing the mortality in the elDerly. MethoDs anD results SP-D serum levels were measureD in 689 elDerly subjects anD mortality ratios were investigateD after a 13-year follow-up perioD. Survival analysis showeD that increasing quartiles of serum SP-D levels were associateD to mortality in 70+ year olD women (hazarD ratio [HR], 1.29; 95% confiDence interval [CI], 0.93–1.78; p = 0.032) aDjusteD for age, smoking anD BMI. Women with SP-D levels above 2100 ng/ml haD significantly increaseD mortality when compareD to elDerly women with SP-D levels equal to or below 2100 ng/ml (HR, 1.45; 95% CI, 1.12–1.88; p = 0.005). The likelihooD that the female twin with the highest SP-D level DieD first increaseD with increasing SP-D levels ( p = 0.031) – that is, the bigger intra-pair Difference in SP-D level, the higher the probability that the twin with the highest measure DieD first (oDDs ratio [OR], 1.66; p = 0.047). Conclusion The stuDy Demonstrates that higher circulating SP-D levels are associateD with increaseD mortality rate in elDerly women in this population-baseD cohort stuDy. SP-D may serve as a biomarker to track the carDio-pulmonary health status in elDerly women.
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the sars coronavirus spike glycoProtein is selectively recognizeD by lung Surfactant Protein D anD activates macrophages
Immunobiology, 2007Co-Authors: Rikke Lethlarsen, Fei Zhong, Vincent T K Chow, Uffe HolmskovAbstract:The severe acute respiratory synDrome coronavirus (SARS-CoV) infects host cells with its surface glycosylateD spike-Protein (S-Protein). Here we expresseD the SARS-CoV S-Protein to investigate its interactions with innate immune mechanisms in the lung. The purifieD S-Protein was DetecteD as a 210 kDa glycosylateD Protein. It was not secreteD in the presence of tunicamycin anD was DetecteD as a 130 kDa Protein in the cell lysate. The purifieD S-Protein bounD to Vero but not 293T cells anD was itself recognizeD by lung Surfactant Protein D (SP-D), a collectin founD in the lung alveoli. The binDing requireD Ca(2+) anD was inhibiteD by maltose. The serum collectin, mannan-binDing lectin (MBL), exhibiteD no Detectable binDing to the purifieD S-Protein. S-Protein binDs anD activates macrophages but not DenDritic cells (DCs). It suggests that SARS-CoV interacts with innate immune mechanisms in the lung through its S-Protein anD regulates pulmonary inflammation.
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reDuceD influenza viral neutralizing activity of natural human trimers of Surfactant Protein D
Respiratory Research, 2007Co-Authors: Kevan L Hartshorn, Grith Lykke Sørensen, Mitchell R White, Tesfaldet Tecle, Erika C Crouch, Ida Tornoe, Uffe HolmskovAbstract:Surfactant Protein D (SP-D) plays important roles in innate host Defense against influenza A virus (IAV) infection. Common human polymorphisms of SP-D have been founD in many human populations anD associateD with increaseD risk of certain infections. We recently reporteD that the Thr/Thr 11 form of SP-D is associateD with low serum levels anD assembles preDominantly as trimers as opposeD to the more common multimeric forms of SP-D. Preliminary experiments were Done to establish the effects of Different monoclonal antiboDies against SP-D on ability of SP-D to binD to or neutralize the virus. We then purifieD natural human trimeric anD multimeric forms of SP-D from amniotic fluiD anD testeD ability of these preparations to binD to IAV, to inhibit infectivity anD hemagglutination activity of IAV in vitro. In initial experiments mAbs DirecteD against Different areas on the CRD of SP-D were founD to have Differing effects on antiviral activity. Using an mAb that DiD not interfere with antiviral activity of SP-D, we confirm that natural SP-D trimers haD reDuceD ability to binD to IAV. In aDDition, the trimers haD reDuceD ability to neutralize IAV as compareD to natural human SP-D multimers as well as reDuceD hemagglutination inhibiting activity against several strains of IAV. Natural SP-D trimers also haD Different interactions with human neutrophil peptiDe Defensins (HNPs) in viral neutralization assays as compareD to multimeric SP-D. These stuDies inDicate that a common human polymorphic form of SP-D may moDulate host Defense against IAV anD give impetus to clinical stuDies correlating this genotype with risk for IAV infection in susceptible groups. We also show that mAbs DirecteD against Different areas on the carbohyDrate recognition Domain of SP-D can be useful for Dissecting out Different functional properties of the Protein.
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Surfactant Protein D augments bacterial association but attenuates major histocompatibility complex class ii presentation of bacterial antigens
American Journal of Respiratory Cell and Molecular Biology, 2007Co-Authors: Soren Hansen, Uffe Holmskov, Kathy S Evans, Pavlos Neophytou, Jo Rae WrightAbstract:Surfactant Protein D (SP-D) is a secreteD pattern recognition molecule associateD with lung Surfactant anD meDiates the clearance of pathogens in multiple ways. SP-D is an establisheD part of the innate immune system, but it also moDulates the aDaptive immune response by interacting with both antigen-presenting cells anD T cells. In a previous stuDy, antigen presentation by bone marrow–DeriveD DenDritic cells was enhanceD by SP-D. As DenDritic cell function varies DepenDing on the tissue of origin, we extenDeD these stuDies to antigen-presenting cells isolateD from mouse lung. Flow cytometric stuDies showeD that SP-D binDs calcium DepenDently anD specifically to lung CD11c-positive cells. Opsonization of fluorescently labeleD Escherichia coli by SP-D enhanceD uptake by lung DenDritic cells. SP-D facilitateD the association of E. coli anD antigen-presenting cells by increasing the frequency of CD11+ cells associateD with E. coli by up to 10-folD. In contrast to the effect on bone marrow–DeriveD DenDritic c...
Kevan L Hartshorn - One of the best experts on this subject based on the ideXlab platform.
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lectin meDiateD binDing anD sialoglycans of porcine Surfactant Protein D synergistically neutralize influenza a virus
Journal of Biological Chemistry, 2018Co-Authors: Martin Van Eijk, Kevan L Hartshorn, Mitchell R White, Tanya R Cafarella, Michael J Rynkiewicz, Kshitij Khatri, Nancy Leymarie, Joseph Zaia, Irma Van Die, Martin HessingAbstract:Innate immunity is critical in the early containment of influenza A virus (IAV) infection, anD Surfactant Protein D (SP-D) plays a crucial role in the pulmonary Defense against IAV. In pigs, which are important intermeDiate hosts During the generation of panDemic IAVs, SP-D uses its unique carbohyDrate recognition Domain (CRD) to interact with IAV. An N-linkeD CRD glycosylation proviDes interactions with the sialic aciD-binDing site of IAV, anD a tripeptiDe loop at the lectin-binDing site facilitates enhanceD interactions with IAV glycans. Here, to investigate both mechanisms of IAV neutralization in greater Detail, we proDuceD an N-glycosylateD neck-CRD fragment of porcine SP-D (RpNCRD) in HEK293 cells. X-ray crystallography DiscloseD that the N-glycan DiD not alter the CRD backbone structure, incluDing the lectin site conformation, but revealeD a potential seconD nonlectin-binDing site for glycans. IAV hemagglutination inhibition, IAV aggregation, anD neutralization of IAV infection stuDies showeD that RpNCRD, unlike the human analogue RhNCRD, exhibits potent neutralizing activity against panDemic A/Aichi/68 (H3N2), enableD by both porcine-specific structural features of its CRD. MS analysis revealeD an N-glycan site-occupancy of >98% at Asn-303 of RpNCRD with complex-type, heterogeneously brancheD anD preDominantly α(2,3)-sialylateD oligosacchariDes. Glycan-binDing array Data characterizeD both RpNCRD anD RhNCRD as mannose-type lectins. RpNCRD also bounD LewisY structures, whereas RhNCRD bounD polylactosamine-containing glycans. The presence of the N-glycan in the CRD increases the glycan-binDing specificity of RpNCRD. These insights increase our unDerstanDing of porcine-specific innate Defense against panDemic IAV anD may inform the Design of recombinant SP-D-baseD antiviral Drugs.
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molecular mechanisms of inhibition of influenza by Surfactant Protein D revealeD by large scale molecular Dynamics simulation
Biochemistry, 2013Co-Authors: Boon Chong Goh, Kevan L Hartshorn, Mitchell R White, Erika C Crouch, Tanya R Cafarella, Michael J Rynkiewicz, Kimberly Allen, Oliviana Calin, Peter H Seeberger, Klaus SchultenAbstract:Surfactant Protein D (SP-D), a mammalian C-type lectin, is the primary innate inhibitor of influenza A virus (IAV) in the lung. Interactions of SP-D with highly brancheD viral N-linkeD glycans on hemagglutinin (HA), an abunDant IAV envelope Protein anD critical virulence factor, promote viral aggregation anD neutralization through as yet unknown molecular mechanisms. Two truncateD human SP-D forms, wilD-type (WT) anD Double mutant D325A+R343V, representing neck anD carbohyDrate recognition Domains are compareD in this stuDy. Whereas both WT anD D325A+R343V binD to isolateD glycosylateD HA, WT Does not inhibit IAV in neutralization assays; in contrast, D325A+R343V neutralization compares well with that of full-length native SP-D. To eluciDate the mechanism for these biochemical observations, we have DetermineD crystal structures of D325A+R343V in the presence anD absence of a viral nonamannosiDe (Man9). On the basis of the D325A+R343V–Man9 structure anD other crystallographic Data, moDels of complexes betw...
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a unique sugar binDing site meDiates the Distinct anti influenza activity of pig Surfactant Protein D
Journal of Biological Chemistry, 2012Co-Authors: Martin Van Eijk, Kevan L Hartshorn, Mitchell R White, Erika C Crouch, Tanya R Cafarella, Michael J Rynkiewicz, Klaus Schulten, Xueqing Zou, Dong Luo, James F HeadAbstract:Pigs can act as intermeDiate hosts by which reassorteD influenza A virus (IAV) strains can be transmitteD to humans anD cause panDemic influenza outbreaks. The innate host Defense component Surfactant Protein D (SP-D) interacts with glycans on the hemagglutinin of IAV anD contributes to protection against IAV infection in mammals. This stuDy shows that a recombinant trimeric neck lectin fragment DeriveD from porcine SP-D (pSP-D) exhibits profounD inhibitory activity against IAV, in contrast to comparable fragments DeriveD from human SP-D. Crystallographic analysis of the pSP-D fragment complexeD with a viral sugar component shows that a unique tripeptiDe loop alters the lectin site conformation of pSP-D. Molecular Dynamics simulations highlight the role of this flexible loop, which aDopts a more stable conformation upon sugar binDing anD may facilitate binDing to viral glycans through contact with Distal portions of the brancheD mannosiDe. The combineD Data Demonstrate that porcine-specific structural features of SP-D contribute significantly to its Distinct anti-IAV activity. These finDings coulD help explain why pigs serve as important reservoirs for newly emerging pathogenic IAV strains.
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the ability of panDemic influenza virus hemagglutinins to inDuce lower respiratory pathology is associateD with DecreaseD Surfactant Protein D binDing
Virology, 2011Co-Authors: John C Kash, Kevan L Hartshorn, Erika C Crouch, Vivien G Dugan, Brett W Jagger, Yukfai Lau, Zhongmei Sheng, Jeffery K TaubenbergerAbstract:PanDemic influenza viral infections have been associateD with viral pneumonia. Chimeric influenza viruses with the hemagglutinin segment of the 1918, 1957, 1968, or 2009 panDemic influenza viruses in the context of a seasonal H1N1 influenza genome were constructeD to analyze the role of hemagglutinin (HA) in pathogenesis anD cell tropism in a mouse moDel. We also exploreD whether there was an association between the ability of lung Surfactant Protein D (SP-D) to binD to the HA anD the ability of the corresponDing chimeric virus to infect bronchiolar anD alveolar epithelial cells of the lower respiratory tract. Viruses expressing the hemagglutinin of panDemic viruses were associateD with significant pathology in the lower respiratory tract, incluDing acute inflammation, anD showeD low binDing activity for SP-D. In contrast, the virus expressing the HA of a seasonal influenza strain inDuceD only milD Disease with little lung pathology in infecteD mice anD exhibiteD strong in vitro binDing to SP-D.
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role of viral hemagglutinin glycosylation in anti influenza activities of recombinant Surfactant Protein D
Respiratory Research, 2008Co-Authors: Kevan L Hartshorn, Richard J Webby, Mitchell R White, Tesfaldet Tecle, Clark Pan, Susan Boucher, Rodney J Moreland, Erika C Crouch, Ronald K ScheuleAbstract:BackgrounD Surfactant Protein D (SP-D) plays an important role in innate Defense against influenza A viruses (IAVs) anD other pathogens.
Erika C Crouch - One of the best experts on this subject based on the ideXlab platform.
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structure binDing relationship of human Surfactant Protein D anD various lipopolysacchariDe inner core structures
Journal of Structural Biology, 2016Co-Authors: Erika C Crouch, Anika Reinhardt, Marko Wehle, Andreas Geissner, Yu Kang, You Yang, Chakkumkal Anish, Mark SanterAbstract:As a major player of the innate immune system, Surfactant Protein D (SP-D) recognizes anD promotes elimination of various pathogens such as Gram-negative bacteria. SP-D binDs to l-glycero-D-manno-heptose (Hep), a constituent of the partially conserveD lipopolysacchariDe (LPS) inner core of many Gram-negative bacteria. BinDing anD affinity of trimeric human SP-D to Hep in Distinct LPS inner core glycans Differing in linkages anD aDjacent resiDues was eluciDateD using glycan array anD surface plasmon resonance measurements that were compareD to in silico interaction stuDies. The combination of in vitro assays using DefineD glycans anD molecular Docking anD Dynamic simulation approaches proviDes insights into the interaction of trimeric SP-D with those glycan liganDs. Trimeric SP-D wilDtype recognizeD larger LPS inner core oligosacchariDes with slightly enhanceD affinity than smaller compounDs suggesting the involvement of stabilizing seconDary interactions. A trimeric human SP-D mutant D324N+D325N+R343K resembling rat SP-D bounD to various LPS inner core structures in a similar pattern as observeD for the wilDtype but with higher affinity. The selective mutation of SP-D promotes targeting of LPS inner core oligosacchariDes on Gram-negative bacteria to Develop novel therapeutic agents.
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oscar is a receptor for Surfactant Protein D that activates tnf α release from human ccr2 inflammatory monocytes
Journal of Immunology, 2015Co-Authors: Alexander D Barrow, Erika C Crouch, Karsten Skjodt, Yaseelan Palarasah, Mattia Bugatti, Alex S Holehouse, Derek E Byers, Michael J Holtzman, William Vermi, Marco ColonnaAbstract:Surfactant Protein D (SP-D) is critical for maintenance of lung homeostasis anD proviDes a first line of Defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D–encoDing gene SFTPD have been associateD with chronic obstructive pulmonary Disease anD ulcerative colitis. IDentification of the immunoreceptors that binD SP-D is essential for unDerstanDing its contribution to lung homeostasis anD mucosal Defense. We locateD a putative binDing motif for the osteoclast-associateD receptor (OSCAR) within the SP-D collagenous Domain. An OSCAR-Fc fusion Protein specifically bounD to the collagenous region of recombinant SP-D anD captureD native SP-D from human bronchoalveolar lavage. OSCAR localizeD in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we founD OSCAR on the surface of interstitial lung anD blooD CCR2+ inflammatory monocytes, which secreteD TNF-α when exposeD to SP-D in an OSCAR-DepenDent fashion. OSCAR anD SP-D DiD not exclusively colocalize in lung, as they were also highly expresseD in atherosclerotic plaques of human aorta, supporting a role for this interaction in atherosclerosis. Our results iDentify the OSCAR:SP-D interaction as a potential therapeutic target in chronic inflammatory Diseases of the lung as well as other Diseases involving tissue accumulation of SP-D, infiltration of inflammatory monocytes, anD release of TNF-α.
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molecular mechanisms of inhibition of influenza by Surfactant Protein D revealeD by large scale molecular Dynamics simulation
Biochemistry, 2013Co-Authors: Boon Chong Goh, Kevan L Hartshorn, Mitchell R White, Erika C Crouch, Tanya R Cafarella, Michael J Rynkiewicz, Kimberly Allen, Oliviana Calin, Peter H Seeberger, Klaus SchultenAbstract:Surfactant Protein D (SP-D), a mammalian C-type lectin, is the primary innate inhibitor of influenza A virus (IAV) in the lung. Interactions of SP-D with highly brancheD viral N-linkeD glycans on hemagglutinin (HA), an abunDant IAV envelope Protein anD critical virulence factor, promote viral aggregation anD neutralization through as yet unknown molecular mechanisms. Two truncateD human SP-D forms, wilD-type (WT) anD Double mutant D325A+R343V, representing neck anD carbohyDrate recognition Domains are compareD in this stuDy. Whereas both WT anD D325A+R343V binD to isolateD glycosylateD HA, WT Does not inhibit IAV in neutralization assays; in contrast, D325A+R343V neutralization compares well with that of full-length native SP-D. To eluciDate the mechanism for these biochemical observations, we have DetermineD crystal structures of D325A+R343V in the presence anD absence of a viral nonamannosiDe (Man9). On the basis of the D325A+R343V–Man9 structure anD other crystallographic Data, moDels of complexes betw...
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increaseD Surfactant Protein D fails to improve bacterial clearance anD inflammation in serpinb1 mice
American Journal of Respiratory Cell and Molecular Biology, 2012Co-Authors: Michael J Stolley, Erika C Crouch, Dapeng Gong, Kalamo Farley, Picheng Zhao, Jessica Cooley, Charaf Benarafa, Eileen RemoldodonnellAbstract:Previously, we DescribeD the protective role of the neutrophil serine protease inhibitor serpinB1 in preventing early mortality of PseuDomonas aeruginosa lung infection by fostering bacterial clearance anD limiting inflammatory cytokines anD proteolytic Damage. Surfactant Protein D (SP-D), which maintains the antiinflammatory pulmonary environment anD meDiates bacterial removal, was DegraDeD in infecteD serpinB1-Deficient mice. BaseD on the hypothesis that increaseD SP-D woulD rescue or mitigate the pathological effects of serpinB1 Deletion, we generateD two serpinB1(-/-) lines overexpressing lung-specific rat SP-D anD inoculateD the mice with P. aeruginosa. Contrary to preDictions, bacterial counts in the lungs of SP-D(low)serpinB1(-/-) anD SP-D(high) serpinB1(-/-) mice were 4 logs higher than wilD-type anD not Different from serpinB1(-/-) mice. SP-D overexpression also faileD to mitigate inflammation (TNF-α), lung injury (free Protein, albumin), or excess neutrophil Death (free myeloperoxiDase, elastase). These pathological markers were higher for infecteD SP-D(high)serpinB1(-/-) mice than for serpinB1(-/-) mice, although the Differences were not significant after controlling for multiple comparisons. The failure of transgenic SP-D to rescue antibacterial Defense of serpinB1-Deficient mice occurreD Despite 5-folD or 20-folD increaseD expression levels, largely normal structure, anD Dose-DepenDent bacteria-aggregating activity. SP-D of infecteD wilD-type mice was intact in 43-kD monomers by reDucing SDS-PAGE. By contrast, proteolytic fragments of 35, 17, anD 8 kD were founD in infecteD SP-D(low)serpinB1(-/-), SP-D(high) serpinB1(-/-) mice, anD serpinB1(-/-) mice. Thus, although therapies to increase lung concentration of SP-D may have beneficial applications, the finDings suggest that therapy with SP-D may not be beneficial for lung inflammation or infection if the unDerlying clinical conDition incluDes excess proteolysis.
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a unique sugar binDing site meDiates the Distinct anti influenza activity of pig Surfactant Protein D
Journal of Biological Chemistry, 2012Co-Authors: Martin Van Eijk, Kevan L Hartshorn, Mitchell R White, Erika C Crouch, Tanya R Cafarella, Michael J Rynkiewicz, Klaus Schulten, Xueqing Zou, Dong Luo, James F HeadAbstract:Pigs can act as intermeDiate hosts by which reassorteD influenza A virus (IAV) strains can be transmitteD to humans anD cause panDemic influenza outbreaks. The innate host Defense component Surfactant Protein D (SP-D) interacts with glycans on the hemagglutinin of IAV anD contributes to protection against IAV infection in mammals. This stuDy shows that a recombinant trimeric neck lectin fragment DeriveD from porcine SP-D (pSP-D) exhibits profounD inhibitory activity against IAV, in contrast to comparable fragments DeriveD from human SP-D. Crystallographic analysis of the pSP-D fragment complexeD with a viral sugar component shows that a unique tripeptiDe loop alters the lectin site conformation of pSP-D. Molecular Dynamics simulations highlight the role of this flexible loop, which aDopts a more stable conformation upon sugar binDing anD may facilitate binDing to viral glycans through contact with Distal portions of the brancheD mannosiDe. The combineD Data Demonstrate that porcine-specific structural features of SP-D contribute significantly to its Distinct anti-IAV activity. These finDings coulD help explain why pigs serve as important reservoirs for newly emerging pathogenic IAV strains.
Kenneth B M Reid - One of the best experts on this subject based on the ideXlab platform.
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Surfactant Protein D reDuces alveolar macrophage apoptosis in vivo
Journal of Immunology, 2002Co-Authors: Howard Clark, Samuel Hawgood, Nades Palaniyar, Peter Strong, Jess Edmondson, Kenneth B M ReidAbstract:Surfactant Protein D (SP-D) is a molecule of the innate immune system that recognizes the patterns of surface carbohyDrate on pathogens anD targets them for phagocytosis anD killing. SP-D-Deficient mice show an increaseD number of macrophages in the alveolar space, excess Surfactant phospholipiD, overproDuction of reactive oxygen species, anD the Development of emphysema. We report here that SP-D-Deficient mice have a 5- to 10-folD increase in the number of apoptotic anD necrotic alveolar macrophages, as DefineD by annexin V anD propiDium ioDine staining, respectively. Intrapulmonary aDministration of a truncateD 60-kDa fragment of human recombinant SP-D reDuces the number of apoptotic anD necrotic alveolar macrophages anD partially corrects the lipiD accumulation in SP-D-Deficient mice. The same SP-D fragment binDs preferentially to apoptotic anD necrotic alveolar macrophages in vitro, suggesting that SP-D contributes to immune homeostasis in the lung by recognizing anD promoting removal of necrotic anD apoptotic cells.
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cloning of gp 340 a putative opsonin receptor for lung Surfactant Protein D
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Uffe Holmskov, Kenneth B M Reid, Jens Madsen, Ida Tornoe, Anette Kliem, Jan Mollenhauer, Lars Vitved, Jorn Gronlund, Annemarie Poustka, Karsten SkjodtAbstract:Surfactant Protein D (SP-D) is an oligomeric C type lectin that promotes phagocytosis by binDing to microbial surface carbohyDrates. A 340-kDa glycoProtein (gp-340) has been shown to binD SP-D in the presence of calcium but Does so inDepenDently of carbohyDrate recognition. This Protein exists both in a soluble form anD in association with the membranes of alveolar macrophages. The primary structure of gp-340 has been establisheD by molecular cloning, which yielDeD a 7,686-bp cDNA sequence encoDing a polypeptiDe chain of 2,413 amino aciDs. The Domain organization features 13 scavenger receptor cysteine-rich (SRCR) Domains, each separateD by an SRCR-intersperseD Domain, except for SRCRs 4 anD 5, which are contiguous. The 13 SRCR Domains are followeD by two C1r/C1s Uegf Bmp1 Domains separateD by a 14th SRCR Domain anD a zona pelluciDa Domain. gp-340 seems to be an alternative spliceD form of DMBT1. Reverse transcription–PCR analysis showeD that the main sites of synthesis of gp-340 are lung, trachea, salivary glanD, small intestine, anD stomach. Immunohistochemistry revealeD strong staining for gp-340 in alveolar anD other tissue macrophages. Immunostaining of the macrophage membrane was either uniform or focal in a way that suggesteD capping, whereas other macrophages showeD strong intracellular staining within the phagosome/phagolysosome compartments. In some macrophages, SP-D anD gp-340 were locateD in the same cellular compartment. Immunoreactive gp-340 was also founD in epithelial cells of the small intestine anD in the Ducts of salivary glanDs. The Distribution of gp-340 in macrophages is compatible with a role as an opsonin receptor for SP-D.
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expression of the carbohyDrate recognition Domain of lung Surfactant Protein D anD Demonstration of its binDing to lipopolysacchariDes of gram negative bacteria
Biochemical and Biophysical Research Communications, 1994Co-Authors: Boon Leong Lim, Hansjurgen Hoppe, Uffe Holmskov, Jiu Yao Wang, Kenneth B M ReidAbstract:Abstract Surfactant Protein D is a collagenous C-type lectin (collectin) that is founD almost exclusively in the lung. A recombinant Protein, composeD of the neck-region anD the carbohyDrate binDing Domain of bovine lung Surfactant Protein D, has been overexpresseD in E. coli. The recombinant Protein showeD the same sugar binDing specificity as the native Protein anD was able to binD to the lipopolysacchariDes of several strains of Gram-negative bacteria, such as Klebsiella pneumoniae , PseuDomonas aeruginosa anD Escherichia coli , which are known to cause lung infections. This binDing was calcium-DepenDent anD was inhibiteD by maltose. Native bovine Surfactant Protein D was also shown to be able to binD to these lipopolysacchariDes in the same manner.
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primary structure of bovine collectin 43 cl 43 comparison with conglutinin anD lung Surfactant Protein D
Journal of Biological Chemistry, 1994Co-Authors: Boon Leong Lim, S B Laursen, Kenneth B M Reid, J C Jensenius, Antony C Willis, Uffe HolmskovAbstract:Abstract Collectin-43 (CL-43) is a bovine serum Protein that is composeD of subunits of three iDentical chains, each of which contains a collagen region anD a C-type carbohyDrate recognition Domain; thus, CL-43 belongs to the collectins (group III of the C-type lectins). We have DeriveD the complete primary sequence of CL-43 using partial Protein sequencing, cDNA cloning, anD reverse transcription-polymerase chain reaction techniques. The primary sequence of CL-43 shows that it contains an N-terminal region of 28 resiDues, followeD by a collagenous Domain of 38 repeats of Gly-Xaa-Yaa anD then a C-terminal section of 159 resiDues, containing a short "neck" region anD the carbohyDrate recognition Domain with the conserveD resiDues founD in all C-type lectins. The amino aciD sequence of CL-43 showeD 74% iDentity to bovine conglutinin anD 70% iDentity to bovine lung Surfactant Protein D (SP-D), but the collagen region is consiDerably shorter than the 57 Gly-Xaa-Yaa triplets founD in conglutinin anD SP-D. Northern blot analysis showeD that CL-43 was only synthesizeD in bovine liver, with no Detectable signal in a variety of other bovine tissues, incluDing lung. No cross-hybriDizing signals were DetecteD in mRNA from sheep, human, rat, or mouse liver. Since CL-43 anD conglutinin have only been DetecteD in members of boviDae, it is probable that an ancestral gene of these two Proteins was first DeriveD from a SP-D-like gene, anD that this ancestral gene DuplicateD During evolution.
Henk P Haagsman - One of the best experts on this subject based on the ideXlab platform.
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assessment of the antiviral properties of recombinant Surfactant Protein D against influenza b virus in vitro
Virus Research, 2015Co-Authors: Marine L B Hillaire, Martin Van Eijk, Stella Vogelzangvan E Trierum, Nella J Nieuwkoop, Henk P Haagsman, Debby Van Riel, Thijs Kuiken, Ron A. M. Fouchier, Guus F. RimmelzwaanAbstract:The armamentarium of antiviral Drugs against influenza viruses is limiteD. Furthermore, influenza viruses emerge that are resistant to existing antiviral Drugs like the M2 anD NA inhibitors. Therefore, there is an urgent neeD for the Development of novel classes of antiviral Drugs. Here we investigateD the antiviral properties of recombinant porcine Surfactant Protein D (RpSP-D), an innate Defense molecule with lectin properties, against influenza B viruses. We have previously shown that porcine SP-D has more potent neutralizing activity against influenza A viruses than human SP-D. Here we show that RpSP-D neutralizes influenza B viruses efficiently anD inhibiteD the binDing of these viruses to epithelial cells of the human trachea.
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pulmonary Surfactant Protein D in first line innate Defence against influenza a virus infections
Journal of Innate Immunity, 2013Co-Authors: Marine L B Hillaire, Guus F. Rimmelzwaan, Henk P Haagsman, Albert D M E Osterhaus, Martin Van EijkAbstract:Influenza A viruses (IAV) cause respiratory tract infections annually associateD with excess mortality anD morbiDity. Nonspecific, innate immune mechanisms play a key role in protection against viral invasion at early stages of infection. A soluble Protein present in mucosal secretions of the lung, Surfactant Protein D (SP-D), is an important component of this initial barrier that helps to prevent anD limit IAV infections of the respiratory epithelium. This collagenous C-type lectin binDs IAVs anD thereby inhibits attachment anD entry of the virus but also contributes to enhanceD clearance of SP-D-opsonizeD virus via interactions with phagocytic cells. In aDDition, SP-D moDulates the inflammatory response anD helps to maintain a balance between effective neutralization/killing of IAV, anD protection against alveolar Damage resulting from IAV-inDuceD excessive inflammatory responses. The mechanisms of interaction between SP-D anD IAV not only DepenD on the structure anD binDing properties of SP-D but also on strain-specific features of IAV, anD both issues will be DiscusseD. SP-D from pigs exhibits Distinct anti-IAV properties anD is DiscusseD in more Detail. Finally, the potential of SP-D as a prophylactic anD/or therapeutic antiviral agent to protect humans against infections by IAV is DiscusseD.
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interactions of influenza a virus with sialic aciDs present on porcine Surfactant Protein D
American Journal of Respiratory Cell and Molecular Biology, 2004Co-Authors: Martin Van Eijk, Henk P Haagsman, Mitchell R White, Joseph J Batenburg, Arie B Vaandrager, Lambert M G Van Golde, Kevan L HartshornAbstract:Pigs can be infecteD with both human anD avian influenza A virus (IAV) strains anD are therefore consiDereD to be important intermeDiates in the emergence of new IAV strains Due to mixing of viral genes DeriveD from human, avian, or porcine influenza viruses. These reassortant strains may have potential to cause panDemic influenza outbreaks in humans. The innate immune response against IAV plays a significant role in containment of IAV in the airways. We stuDieD the interactions of IAV with porcine Surfactant Protein D (pSP-D), an important component of this first line Defense system. Hemagglutination inhibition analysis shows that the Distinct interactions of pSP-D with IAV meDiateD by the N-linkeD carbohyDrate moiety in the carbohyDrate recognition Domain of pSP-D DepenD on the terminal sialic aciDs (SAs) present on this carbohyDrate. Analysis by both lectin staining anD by cleavage with linkage-specific sialiDases shows that the carbohyDrate of pSP-D is exclusively sialylateD with alpha(2,6)-linkeD SAs, in contrast to Surfactant Protein A, which contains both alpha(2,3)- anD alpha(2,6)-linkeD SAs on its N-linkeD carbohyDrate. Enzymatic moDification of the SA-linkages present on pSP-D Demonstrates that the type of SA-linkage is important for its hemagglutination-inhibitory activity, anD correlates with receptor-binDing specificity of the IAV strains. The SAs present on pSP-D appear especially important for interactions with poorly glycosylateD IAV strains. It remains to be eluciDateD to what extent the unique sialylation profile of pSP-D is involveD in host range control of IAV in pigs, anD whether it facilitates aDaptation of avian or human IAV strains that can contribute to the proDuction of reassortant strains in pigs.
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porcine Surfactant Protein D is n glycosylateD in its carbohyDrate recognition Domain anD is assembleD into Differently chargeD oligomers
American Journal of Respiratory Cell and Molecular Biology, 2002Co-Authors: Martin Van Eijk, Kevan L Hartshorn, Joseph J Batenburg, Chris H A Van De Lest, Arie B Vaandrager, Joseph Meschi, Lambert M G Van Golde, Henk P HaagsmanAbstract:Surfactant Protein D (SP-D) belongs to a subgroup of mammalian collagenous Ca2 +-DepenDent lectins known as the collectins. It is thought to play a significant role in the innate immune response against microorganisms within the lungs anD at other mucosal surfaces. This report Documents the isolation anD characterization of SP-D purifieD from porcine lung lavage using mannan affinity chromatography anD gel filtration. Ultrastructural analysis shows both DoDecameric anD higher orDer oligomeric complexes of SP-D. The molecular mass of monomeric porcine SP-D (50 kD) is larger than that of SP-D from humans (43 kD). The Difference in mass is Due to the presence of an Asparagine-linkeD glycosylation in the carbohyDrate recognition Domain of porcine SP-D, which is absent in SP-D of other species investigateD so far. Analysis of this carbohyDrate moiety inDicates that it is a highly heterogeneous, complex type oligosacchariDe which is sialylateD. The heterogeneity of oligosacchariDe sialylation results in the exi...