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.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
M R
MR
White
E
E
Crouch
D
D
Chang
K
K
Sastry
N
N
Guo
G
G
Engelich
K
K
Takahashi
R A
RA
Ezekowitz
K L
KL
Hartshorn
D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line / Q000276:immunology / Q000821:virology; D037222:Collectins; D004285:Dogs; D006023:Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D009980:Influenza A virus / Q000276:immunology / Q000378:metabolism; D037102:Lectins / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism*; D051379:Mice; D009005:Monosaccharides / Q000276:immunology / Q000494:pharmacology; D009895:Opsonin Proteins / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D013050:Spectrometry, Fluorescence
D000998:Antiviral Agents; D002352:Carrier Proteins; D037222:Collectins; D006023:Glycoproteins; D037102:Lectins; D009005:Monosaccharides; D009895:Opsonin Proteins; D010446:Peptide Fragments; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D008358:Mannose