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

2000 ◽  
Vol 351 (2) ◽  
pp. 449-458 ◽  
Author(s):  
Kevan L. HARTSHORN ◽  
Mitchell R. WHITE ◽  
Dennis R. VOELKER ◽  
John COBURN ◽  
Ken ZANER ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Surfactant Protein ◽  
Systematic Evaluation ◽  
Surfactant Protein D ◽  
Globular Domain ◽  
Influenza A Viruses ◽  
Viral Neutralization ◽  
The Relationship ◽  
Haemagglutination 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 HA1 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.

scholarly journals Salivary agglutinin and lung scavenger receptor cysteine-rich glycoprotein 340 have broad anti-influenza activities and interactions with surfactant protein D that vary according to donor source and sialylation

2005 ◽  
Vol 393 (2) ◽  
pp. 545-553 ◽  
Author(s):  
Kevan L. Hartshorn ◽  
Antoon Ligtenberg ◽  
Mitchell R. White ◽  
Martin van Eijk ◽  
Max Hartshorn ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Scavenger Receptor ◽  
Surfactant Protein ◽  
Sialic Acids ◽  
Surfactant Protein D ◽  
Influenza A Viruses ◽  
Viral Neutralization ◽  
Antiviral Activities ◽  
Innate Defence

We previously found that scavenger receptor cysteine-rich gp-340 (glycoprotein-340), isolated from lung or saliva, directly inhibits human IAVs (influenza A viruses). We now show that salivary gp-340 has broad antiviral activity against human, equine and porcine IAV strains. Although lung and salivary gp-340 are identical in protein sequence, salivary gp-340 from one donor had significantly greater antiviral activity against avian-like IAV strains which preferentially bind sialic acids in α(2,3) linkage. A greater density of α(2,3)-linked sialic acids was present on the salivary gp-340 from this donor as compared with salivary gp-340 from another donor or several preparations of lung gp-340. Hence, the specificity of sialic acid linkages on gp-340 is an important determinant of anti-IAV activity. Gp-340 binds to SP-D (surfactant protein D), and we previously showed that lung gp-340 has co-operative interactions with SP-D in viral neutralization and aggregation assays. We now report that salivary gp-340 can, in some cases, strongly antagonize certain antiviral activities of SP-D. This effect was associated with greater binding of salivary gp-340 to the carbohydrate recognition domain of SP-D as compared with the binding of lung gp-340. These findings may relate to inter-individual variations in innate defence against highly pathogenic IAV and to effects of aspiration of oral contents on SP-D-mediated lung functions.

scholarly journals The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins

2013 ◽  
Vol 94 (1) ◽  
pp. 40-49 ◽  
Author(s):  
Shweta Tripathi ◽  
Tesfaldet Tecle ◽  
Anamika Verma ◽  
Erika Crouch ◽  
Mitchell White ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Epithelial Cells ◽  
Antiviral Activity ◽  
Influenza A ◽  
Density Lipoprotein ◽  
Surfactant Protein ◽  
Host Defence ◽  
Surfactant Protein D ◽  
Influenza A Viruses ◽  
Cationic Antimicrobial Peptide

LL-37, the only human cathelicidin, is a cationic antimicrobial peptide with antibacterial and antifungal activity. LL-37 is released from neutrophil granules and produced by epithelial cells. It has been implicated in host defence against influenza A virus (IAV) in recent studies. We now demonstrate dose-related neutralizing activity of LL-37 against several seasonal and mouse-adapted IAV strains. The ability of LL-37 to inhibit these IAV strains resulted mainly from direct effects on the virus, since pre-incubation of virus with LL-37 was needed for optimal inhibition. LL-37 bound high-density lipoprotein (HDL), and pre-incubation of LL-37 with human serum or HDL reduced its antiviral activity. LL-37 did not inhibit viral association with epithelial cells as assessed by quantitative RT-PCR or confocal microscopy. This finding contrasted with results obtained with surfactant protein D (SP-D). Unlike collectins or human neutrophil defensins (HNPs), LL-37 did not induce viral aggregation under electron microscopy. In the electron microscopy studies, LL-37 appeared to cause disruption of viral membranes. LL-37 had additive antiviral activity when combined with other innate inhibitors like SP-D, surfactant protein A and HNPs. Unlike HNPs, LL-37 did not bind SP-D significantly. These findings indicate that LL-37 contributes to host defence against IAV through a mechanism distinct from that of SP-D and HNPs.

scholarly journals Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

2014 ◽  
Vol 306 (11) ◽  
pp. L1036-L1044 ◽  
Author(s):  
Nikolaos M. Nikolaidis ◽  
Mitchell R. White ◽  
Kimberly Allen ◽  
Shweta Tripathi ◽  
Li Qi ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Host Defense ◽  
Influenza A ◽  
Surfactant Protein ◽  
Viral Envelope ◽  
Surfactant Protein D ◽  
Carbohydrate Binding ◽  
Influenza A Viruses ◽  
Head Region ◽  
Pandemic Strains

We recently reported that a trimeric neck and carbohydrate recognition domain (NCRD) fragment of human surfactant protein D (SP-D), a host defense lectin, with combinatorial substitutions at the 325 and 343 positions (D325A+R343V) exhibits markedly increased antiviral activity for seasonal strains of influenza A virus (IAV). The NCRD binds to glycan-rich viral envelope proteins including hemagglutinin (HA). We now show that replacement of D325 with serine to create D325S+R343V provided equal or increased neutralizing activity compared with D325A+R343V. The activity of the double mutants was significantly greater than that of either single mutant (D325A/S or R343V). D325A+R343V and D325S+R343V also strongly inhibited HA activity, and markedly aggregated, the 1968 pandemic H3N2 strain, Aichi68. D325S+R343V significantly reduced viral loads and mortality of mice infected with Aichi68, whereas wild-type SP-D NCRD did not. The pandemic H1N1 strains of 1918 and 2009 have only one N-linked glycan side on the head region of the HA and are fully resistant to inhibition by native SP-D. Importantly, we now show that D325A+R343V and D325S+R343V inhibited Cal09 H1N1 and related strains, and reduced uptake of Cal09 by epithelial cells. Inhibition of Cal09 was mediated by the lectin activity of the NCRDs. All known human pandemic strains have at least one glycan attachment on the top or side of the HA head, and our results indicate that they may be susceptible to inhibition by modified host defense lectins.

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

2000 ◽  
Vol 351 (2) ◽  
pp. 449 ◽  
Author(s):  
Kevan L. HARTSHORN ◽  
Mitchell R. WHITE ◽  
Dennis R. VOELKER ◽  
John COBURN ◽  
Ken ZANER ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Influenza A Viruses

Critical role for cross-linking of trimeric lectin domains of surfactant protein D in antiviral activity against influenza A virus

2008 ◽  
Vol 412 (2) ◽  
pp. 323-329 ◽  
Author(s):  
Tesfaldet Tecle ◽  
Mitchell R. White ◽  
Grith Sorensen ◽  
Donald Gantz ◽  
Nilgun Kacak ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Critical Role ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Cross Linking ◽  
Viral Neutralization ◽  
Neutralizing Activity

Collectins are multimeric host defence lectins with trimeric CRDs (carbohydrate-recognition domains) and collagen and N-terminal domains that form higher-order structures composed of four or more trimers. Recombinant trimers composed of only the CRD and adjacent neck domain (termed NCRD) retain binding activity for some ligands and mediate some functional activities. The lung collectin SP-D (surfactant protein D) has strong neutralizing activity for IAVs (influenza A viruses) in vitro and in vivo, however, the NCRD derived from SP-D has weak viral-binding ability and lacks neutralizing activity. Using a panel of mAbs (monoclonal antibodies) directed against the NCRD in the present study we show that mAbs binding near the lectin site inhibit antiviral activity of full-length SP-D, but mAbs which bind other sites on the CRD do not. Two of the non-blocking mAbs significantly increased binding and antiviral activity of NCRDs as assessed by haemagglutination and neuraminidase inhibition and by viral neutralization. mAb-mediated cross-linking also enabled NCRDs to induce viral aggregation and to increase viral uptake by neutrophils and virus-induced respiratory burst responses by these cells. These results show that antiviral activities of SP-D can be reproduced without the N-terminal and collagen domains and that cross-linking of NCRDs is essential for antiviral activity of SP-D with respect to IAV.

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

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3450-3461 ◽  
Author(s):  
KL Hartshorn ◽  
KB Reid ◽  
MR White ◽  
JC Jensenius ◽  
SM Morris ◽  
...  
Keyword(s):  
Host Defense ◽  
Respiratory Burst ◽  
Influenza A ◽  
Defense Mechanism ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Hemagglutination Activity ◽  
Influenza A Viruses ◽  
Activated Neutrophils

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.

scholarly journals Monoclonal antibody-assisted structure-function analysis of the carbohydrate recognition domain of surfactant protein D

2010 ◽  
Vol 299 (3) ◽  
pp. L384-L392 ◽  
Author(s):  
Kevan L. Hartshorn ◽  
Mitchell R. White ◽  
Michael Rynkiewicz ◽  
Grith Sorensen ◽  
Uffe Holmskov ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Binding Site ◽  
Influenza A ◽  
Function Analysis ◽  
Specific Binding ◽  
Surfactant Protein ◽  
Receptor Protein ◽  
Surfactant Protein D ◽  
Carbohydrate Recognition Domain ◽  
Carbohydrate Recognition

Surfactant protein D (SP-D) plays important roles in host defense against a variety of pathogens including influenza A virus (IAV). Ligand binding by SP-D is mediated by the trimeric neck and carbohydrate recognition domain (NCRD). We used monoclonal antibodies (mAbs) against human SP-D and a panel of mutant collectin NCRD constructs to identify functionally and structurally important epitopes. The ability of SP-D to bind to IAV and mannan involved partially overlapping binding sites that are distinct from those involved in binding to the glycoprotein-340 (gp-340) scavenger receptor protein. A species-specific motif (D324,D325,R343), which has been implicated in the specific binding of several ligands, contributes to recognition by mAbs that block antiviral or mannan binding activity. D325, in particular, is involved in the epitopes of these blocking mAbs. Conversely, the interspecies substitution of arginine for Lys343 in the rat NCRD (rK343R) conferred binding to two of the mAbs. The single site substitution of alanine for R349 or E347 resulted in highly selective alterations in mAb binding and caused decreased antiviral activity. Mutations at Glu333 (E333A), Trp340 (W340F), and Phe335 (F335A), which abrogated antiviral activity, were associated with decreased binding to multiple blocking mAbs, consistent with critical structural roles. More conservative substitutions at 335, which showed a significant increase in neutralization activity, caused selective loss of binding to one mAb. The analysis reveals, for the first time, an extended binding site for IAV; calcium-dependent antiviral activity involves residues flanking the primary carbohydrate binding site as well as more remote residues displayed on the carbohydrate recognition domain surface.

scholarly journals Evidence for a protective role of pulmonary surfactant protein D (SP-D) against influenza A viruses.

1994 ◽  
Vol 94 (1) ◽  
pp. 311-319 ◽  
Author(s):  
K L Hartshorn ◽  
E C Crouch ◽  
M R White ◽  
P Eggleton ◽  
A I Tauber ◽  
...  
Keyword(s):  
Pulmonary Surfactant ◽  
Influenza A ◽  
Surfactant Protein ◽  
Protective Role ◽  
Surfactant Protein D ◽  
Influenza A Viruses ◽  
Pulmonary Surfactant Protein

scholarly journals Expression of Surfactant protein D (SP-D) distinguishes severe pandemic influenza A(H1N1) from COVID-19

2021 ◽  
Author(s):  
José Alberto Choreño-Parra ◽  
Luis Armando Jiménez-Álvarez ◽  
Gustavo Ramírez-Martínez ◽  
Alfredo Cruz-Lagunas ◽  
Mahima Thapa ◽  
...  
Keyword(s):  
Pandemic Influenza ◽  
Influenza A ◽  
Alveolar Epithelium ◽  
Surfactant Protein ◽  
High Serum ◽  
Surfactant Protein D ◽  
Diagnostic Challenge ◽  
Moderate Disease ◽  
Influenza A H1n1 ◽  
Novel Biomarkers

Abstract The differentiation of influenza and COVID-19 could constitute a diagnostic challenge during the ongoing winter due to their clinical similitude. Thus, novel biomarkers that enable distinguishing both diseases are required. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in severe pandemic influenza but not COVID-19 patients. This finding was validated in a separate cohort of mechanically ventilated COVID-19 patients who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with mortality and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.

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