While histones are best known for DNA binding and transcription-regulating properties, they also ... more While histones are best known for DNA binding and transcription-regulating properties, they also have antimicrobial activity against a broad range of potentially pathogenic organisms. Histones are abundant in neutrophil extracellular traps, where they play an important role in NET-mediated antimicrobial killing. Here, we show anti-influenza activity of histones against both seasonal H3N2 and H1N1, but not pandemic H1N1. The arginine rich histones, H3 and H4, had greater neutralizing and viral aggregating activity than the lysine rich histones, H2A and H2B. Of all core histones, histone H4 is most potent in neutralizing IAV, and incubation with IAV with histone H4 results in a decrease in uptake and viral replication by epithelial cells when measured by qRT-PCR. The antiviral activity of histone H4 is mediated principally by direct effects on viral particles. Histone H4 binds to IAV as assessed by ELISA and co-sedimentation of H4 with IAV. H4 also induces aggregation, as assessed by ...
Influenza is a major burden to public health. Due to high mutation rates and selection pressure, ... more Influenza is a major burden to public health. Due to high mutation rates and selection pressure, mutant viruses emerge which are resistant to currently used antiviral drugs. Therefore, there is a need for the development of novel classes of antiviral drugs that suffer less from the emergence of resistant viruses. Antiviral drugs based on collectin-like surfactant protein D (SP-D) may fulfil these requirements. Especially porcine SP-D displays strong antiviral activity to influenza A viruses. In the present study the antiviral activity of recombinant porcine SP-D was investigated in ex vivo cultures of respiratory tract tissue infected with human influenza A virus of the H3N2 subtype. Porcine SP-D has antiviral activity in these test systems. It is suggested that porcine SP-D may be used as a venue to develop a novel class of antiviral drugs.
ABSTRACT The focus of attention in immunology has classically been the adaptive immune system. Th... more ABSTRACT The focus of attention in immunology has classically been the adaptive immune system. The adaptive immune system is most effective when the host has had prior exposure to the pathogen. Accruing evidence suggests that the innate immune system plays an important role in the regulation of the adaptive immune response and in filling the temporal gap in host immunity. Pattern recognition molecules such as collectins are important components of the innate immune system. Herein we describe the structural aspects and immunological functions of the two lung collectins surfactant protein A (SP-A) and SP-D. Important clinical applications of pulmonary collectin research include the use of SP-A and -D in diagnosis and therapy. This survey focuses on the interactions of SP-A and -D with a wide variety of respiratory pathogens and the regulation of the immune cell response by these collectins.
Infection with gram-positive bacteria is a major cause of pneumonia. Surfactant proteins A (SP-A)... more Infection with gram-positive bacteria is a major cause of pneumonia. Surfactant proteins A (SP-A) and D (SP-D) are thought to play an important role in the innate immunity of the lung. Both proteins can bind to gram-positive bacteria. Until now, it was not known with which surface component(s) of gram-positive bacteria SP-A and SP-D interact. Lipoteichoic acid (LTA) and peptidoglycan (PepG) are components of the cell wall of gram-positive bacteria. By use of a solid phase-based binding assay, LTA of Bacillus subtilis was shown to be bound by SP-D but not by SP-A. Unmodified PepG of Staphylococcus aureus was bound by SP-D. SP-D binding to both LTA and PepG was calcium dependent and carbohydrate inhibitable. These results indicate that SP-D interacts with gram-positive bacteria via binding to the cell wall components LTA and PepG and that the carbohydrate recognition domain is responsible for this binding.
Page 1. Chapter 2 Collectins - Interactions with Pathogens Astrid Hogenkamp, Martin van Eijk and ... more Page 1. Chapter 2 Collectins - Interactions with Pathogens Astrid Hogenkamp, Martin van Eijk and Henk P. Haagsman Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine Utrecht University, PO Box 80.175, 3508 TD Utrecht, The Netherlands ...
American Journal of Respiratory Cell and Molecular Biology, 2002
Surfactant protein D (SP-D) belongs to a subgroup of mammalian collagenous Ca(2+)-dependent lecti... more Surfactant protein D (SP-D) belongs to a subgroup of mammalian collagenous Ca(2+)-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 existence of many differently charged porcine SP-D isoforms. The removal of the carbohydrate moiety reduces the inhibitory effect of porcine SP-D on influenza A virus haemagglutination. Therefore, the carbohydrate moiety may influence interactions with pathogens.
While histones are best known for DNA binding and transcription-regulating properties, they also ... more While histones are best known for DNA binding and transcription-regulating properties, they also have antimicrobial activity against a broad range of potentially pathogenic organisms. Histones are abundant in neutrophil extracellular traps, where they play an important role in NET-mediated antimicrobial killing. Here, we show anti-influenza activity of histones against both seasonal H3N2 and H1N1, but not pandemic H1N1. The arginine rich histones, H3 and H4, had greater neutralizing and viral aggregating activity than the lysine rich histones, H2A and H2B. Of all core histones, histone H4 is most potent in neutralizing IAV, and incubation with IAV with histone H4 results in a decrease in uptake and viral replication by epithelial cells when measured by qRT-PCR. The antiviral activity of histone H4 is mediated principally by direct effects on viral particles. Histone H4 binds to IAV as assessed by ELISA and co-sedimentation of H4 with IAV. H4 also induces aggregation, as assessed by ...
Influenza is a major burden to public health. Due to high mutation rates and selection pressure, ... more Influenza is a major burden to public health. Due to high mutation rates and selection pressure, mutant viruses emerge which are resistant to currently used antiviral drugs. Therefore, there is a need for the development of novel classes of antiviral drugs that suffer less from the emergence of resistant viruses. Antiviral drugs based on collectin-like surfactant protein D (SP-D) may fulfil these requirements. Especially porcine SP-D displays strong antiviral activity to influenza A viruses. In the present study the antiviral activity of recombinant porcine SP-D was investigated in ex vivo cultures of respiratory tract tissue infected with human influenza A virus of the H3N2 subtype. Porcine SP-D has antiviral activity in these test systems. It is suggested that porcine SP-D may be used as a venue to develop a novel class of antiviral drugs.
ABSTRACT The focus of attention in immunology has classically been the adaptive immune system. Th... more ABSTRACT The focus of attention in immunology has classically been the adaptive immune system. The adaptive immune system is most effective when the host has had prior exposure to the pathogen. Accruing evidence suggests that the innate immune system plays an important role in the regulation of the adaptive immune response and in filling the temporal gap in host immunity. Pattern recognition molecules such as collectins are important components of the innate immune system. Herein we describe the structural aspects and immunological functions of the two lung collectins surfactant protein A (SP-A) and SP-D. Important clinical applications of pulmonary collectin research include the use of SP-A and -D in diagnosis and therapy. This survey focuses on the interactions of SP-A and -D with a wide variety of respiratory pathogens and the regulation of the immune cell response by these collectins.
Infection with gram-positive bacteria is a major cause of pneumonia. Surfactant proteins A (SP-A)... more Infection with gram-positive bacteria is a major cause of pneumonia. Surfactant proteins A (SP-A) and D (SP-D) are thought to play an important role in the innate immunity of the lung. Both proteins can bind to gram-positive bacteria. Until now, it was not known with which surface component(s) of gram-positive bacteria SP-A and SP-D interact. Lipoteichoic acid (LTA) and peptidoglycan (PepG) are components of the cell wall of gram-positive bacteria. By use of a solid phase-based binding assay, LTA of Bacillus subtilis was shown to be bound by SP-D but not by SP-A. Unmodified PepG of Staphylococcus aureus was bound by SP-D. SP-D binding to both LTA and PepG was calcium dependent and carbohydrate inhibitable. These results indicate that SP-D interacts with gram-positive bacteria via binding to the cell wall components LTA and PepG and that the carbohydrate recognition domain is responsible for this binding.
Page 1. Chapter 2 Collectins - Interactions with Pathogens Astrid Hogenkamp, Martin van Eijk and ... more Page 1. Chapter 2 Collectins - Interactions with Pathogens Astrid Hogenkamp, Martin van Eijk and Henk P. Haagsman Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine Utrecht University, PO Box 80.175, 3508 TD Utrecht, The Netherlands ...
American Journal of Respiratory Cell and Molecular Biology, 2002
Surfactant protein D (SP-D) belongs to a subgroup of mammalian collagenous Ca(2+)-dependent lecti... more Surfactant protein D (SP-D) belongs to a subgroup of mammalian collagenous Ca(2+)-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 existence of many differently charged porcine SP-D isoforms. The removal of the carbohydrate moiety reduces the inhibitory effect of porcine SP-D on influenza A virus haemagglutination. Therefore, the carbohydrate moiety may influence interactions with pathogens.
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