Molecular Host Defence
Thursday 29 November 2012
Professor H. (Henk) Haagsman, PhD
Every day humans and animals are exposed to an immense number of pathogens trying to invade the body. Therefore, the real question is not why we get sick but how do we manage to stay healthy?
For more information, please contact Edwin Veldhuizen
Our group focuses on this question and identified several key effector molecules of the innate immune system that can neutralize or kill pathogens. Two groups of effector molecules are studied: collectins and host defence peptides. Recent studies indicate that these molecules have important immunomodulatory functions.
Host Defence peptides
Host Defence Peptides (HDPs) are small peptides with broad-spectrum antimicrobial activity against a variety of Gram-negative and Gram-positive bacteria, fungi, protozoa and some enveloped virusesIn contrast to ‘classic’ antibiotics, HDPs use multiple mechanisms to kill bacteria such as cell wall permeabilisation, inhibition of DNA replication and protein synthesis. The effect of such peptides on bacterial ultrastructure peptide is shown in Fig. 1, showing both effects on the bacterial membrane as intracellular effects. In addition, these peptides exert multiple immunomodulatory functions, such as LPS neutralisation and orchestration of the cytokine production of immune cells. More importantly: these multiple actions of HDPs have prevented the development of antimicrobial resistance, despite the fact that these peptides are part of the natural host defence of animals for millions of years. Therefore, these peptides are an excellent paradigm for development of new antimicrobials. Our group is identifying the exact mode of antimicrobial action of these peptides in order to design potent peptide-based anti-infectives. In addition, we investigate the intricate interplay of host defence peptides with receptors (such as Toll-like receptors) and other components of the immune system in macrophages, neutrophils and epithelial cells.
FIG. 1. Transmission electron microscopy of C. perfringens cells incubated with synthetic Gal-6 peptide. Bacterial ells showed retracting cytoplasm (left panel), and lysis at the septa of dividing cells (right panel).
Collectins are large collagenous proteins that bind to sugar residues on the outer membrane of pathogenic microorganisms, which leads to aggregation and neutralization of these pathogens (Fig. 2). Our group is specifically interested in the interaction of the collectins Surfactant Protein A (SP-A) and SP-D with influenza virus (IAV). SP-A and SP-D neutralise IAV directly by binding to the glycosylated hemagglutinin molecules on the viral particle. This acute protection mechanism helps to prevent viral entry into lung epithelial cells (e.g. clearance via viral aggregation), but also modulates other immune defence mechanisms (e.g. phagocytic cells) to fight the virus infection. In addition, it was demonstrated that collectins may also modulate the adaptive immune response by interacting with dendritic cells and T-cells, showing that SP-D is actively involved at several stages of clearing/preventing viral infections.
Pigs can serve as important intermediate hosts for transmission of avian IAV strains to humans, and for the generation of reassortant strains; this may result in the appearance of new pandemic IAV strains in humans. Studies in our lab on porcine SP-D indicate that a naturally occurring glycan modification of SP-D dramatically increases IAV neutralisation activity in vitro. This extra glycoconjugate enables an extra binding possibility of SP-D to the sialic acid receptor on hemagglutinin of IAV. In addition, it was found for porcine SP-D that several porcine-specific structural elements in the lectin domain are likely to be involved in generating the distinct inhibitory activity of pSP-D against IAV. These make porcine SP-D the most active IAV neutralizing collectin known.
Our lab focuses on determining and characterizing the activity features specific for porcine collectins and to use these features to obtain a new protein-based antiviral drug. In addition, our lab studies the characteristics of chicken collectins in order to determine how differences in IAV susceptibility is related to differences in collectin features of birds and mammals.
Fig 2 interaction between Influenza A virus and porcine SP-D: left panel: multimeric porcine SP-D has approximately the same size as an viral particle. Right panel : the carbohydrate recognition domain of SP-D interacts with glycoconjugates present on IAVs hemagglutinin
Pezzulo AA, Tang XX, Hoegger MJ, Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenane CL, Haagsman HP, van Eijk M, Bánfi B, Horswill AR, Stoltz DA, McCray PB Jr, Welsh MJ, Zabner J. 2012. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 487(7405):109-13.
Veldhuizen EJA, van Eijk M, Haagsman HP. 2011. The carbohydrate recognition domain of collectins. FEBS J. 278, 3930-3941.
Hillaire ML, van Eijk M, van Trierum SE, van Riel D, Saelens X, Romijn RA, Hemrika W, Fouchier RA, Kuiken T, Osterhaus AD, Haagsman HP, Rimmelzwaan GF. 2011. Assessment of the Antiviral Properties of Recombinant Porcine SP-D against Various Influenza A Viruses In Vitro. PLoS One. V6,e25005.
van Eijk M, Bruinsma L, Hartshorn KL, White MR, Rynkiewicz MJ, Seaton BA, Hemrika W, Romijn RA, van Balkom BW, Haagsman HP. 2011. Introduction of N-linked glycans in the lectin domain of surfactant protein D: impact on interactions with influenza A viruses. J. Biol. Chem. 286,20137-20151.
van Dijk A, Molhoek EM, Bikker FJ, Yu PL, Veldhuizen EJ, Haagsman HP. 2011. Avian cathelicidins: Paradigms for the development of anti-infectives. Vet. Microbiol. 153, 27-36.
Molhoek EM, van Dijk A, Veldhuizen EJ, Haagsman HP, Bikker FJ. 2011. A cathelicidin-2-derived peptide effectively impairs Staphylococcus epidermidis biofilms. Int. J. Antimicrob. Agents 37,476-479.
van Dijk, A., Veldhuizen, E. J. A., Kalkhove, S. I., Tjeerdsma-van Bokhoven, J. L., Romijn, R. A., Haagsman, H. P., 2007. The beta-defensin gallinacin-6 is expressed in the chicken digestive tract and has antimicrobial activity against food-borne pathogens. Antimicrob. Agents Chemother. 51, 912-922.
Current group members:
Prof Dr. Henk P. Haagsman
Dr. Edwin Veldhuizen
Dr. Martin van Eijk
Dr. Albert van Dijk