Pathogene specificity of collectins and ficolins

As already mentioned previously, collectins and ficolins bind to carbohydrates with their lectin domain. The lectin domain of MBL is the CRB, respectively named FBG in ficolins.

With its CRD, MBL binds carbohydrates with 3- and 4-hydroxyl groups in the pyranose ring in the presence of calcium. Thus MBL ligands for MBL are mannose,

glucose, L-fucose, N-acetyl-mannosamine and N-acetylglucosamine (LU et al. 2002;

HOLMSKOV et al. 2003; FUJITA et al. 2004).With this wide range of ligands, MBL is able to recognize various types of bacteria.

Most carbohydrate structures in animals are terminated by sugars not recognized by the collectins, e.g., galactose or sialic acid. Mammalian cells do not present the pathogen-associated molecular patterns characteristically for microorganisms (HOLMSKOV et al. 2003).

In contrast to collectins, ficolins do not show such a wide variety of sugar binding capacity. Ficolins mainly bind to acetyl-D-glucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) (LE et al. 1997, 1998; LU et al. 2002; FUJITA et al.

2004). For humans it has been shown that L-ficolin recognizes cell wall components of Salmonella typhimurium.

Binding capacities of ficolins and collectins have been discussed controversial (POLOTSKY et al. 1996; LYNCH et al. 2004). The latter authors observed that L-ficolin, but not MBL or H-L-ficolin, specifically binds to lipoteichoic acid, common for Gram-positive bacterial cell walls. In contrast to this opinion, POLOTZKY et al. (1996) argues that also MBL shows binding capacity for lipoteichoic acid of Gram-positive bacteria.

In the literature, various descriptions of the recognition capacity of MBL for different microorganisms can be found. Generally spoken, common microbial structures recognized by the collectins are lipopolysaccharides (LPS) and mannan-like high mannose structures. Due to the fact LPS is a major glycolipid component on the outer membrane of Gram-negative bacteria, these are ideal ligands for collectins (LU et al. 2002; HOLMSKOV et al. 2003; VAN DE WETERING et al. 2004; GUPTA and SUROLIA 2007). Moreover, MBL has been shown to interact with a wide variety of Gram-positive bacteria, and various types of their cell wall component lipoteichoic acid (LTC) (POLOTSKY et al. 1996). LU et al (2002) sums up that the wide range of bacteria recognized by collectins highlights the importance of collectins in innate immunity.

Even though binding of collectins and ficolins to bacteria has been reviewed intensively for humans (HOLMSKOV et al. 2003; VAN DE WETERING et al. 2004;

GUPTA and SUROLIA 2007), information about their role in innate immunity of

animals is sparse. While most authors only casually mention binding of ficolins and collectins concerning animals, LILLIE et al. (2005) summarise the variety of binding sites of collectins and ficolins to microorganisms for animals in detail. For MBL-A, the authors observed binding to pathogenic bacteria species which infect pigs, such as different serotypes of Heamophilus parasuis, Actinobacillus suis and Actinobacillus pleuropneuminiae (APP).

Also, porcine ficolin-α binds to APP (BROOKS et al. 2003). Furthermore, porcine ficolin-α binds to LPS from E.coli, Salmonella typhimurium, Salmonella enteritidis, Pseudomonas aeruginosa and to LTA from Staphylococcus pyogenes, Bacillus subtilis and Staphylococcus aureus (RUNZA et al. 2008).

Concerning binding sites of MBL-C, LILLIE et al. (2005) mention pathogen MBL interaction with the following bacteria: Neisseria spp., Salmonella typhimurium, Yersinia enterocolica, Pseudomonas aeruginosa, Escherichia coli, Mycobacterium bovis and the yeast Candida albicans.

In order to offer a better overview, all microorganisms recognized by MBL and ficolins are listed in Tab. 2.2.

Tab 2.2: Comparison of animal collectins and ficolins and their antimicrobial activity (modified after LILLIE et al. (2005) and RUNZA et al. (2008))

Lectin Species distribution Pathogen interaction MBL-A (serum MBL) Pig, cattle, rat, mouse,

rhesus monkey Actinobacillus suis, A.pleuropneumoniae, Haemophilus parasuis MBL-C (liver MBL) Pig, cattle, rat, mouse,

rabbit, chimpanzee and

Ficolin-α Pig A. pleuropneumoniae,

Bacillus subtilis, E. coli, S.

typhimurium, S. enteritidis, Pseudomonas aeruginosa, Staphylococcus aureus

Staph. pyogenes

Ficolin-β Pig, cattle Not determined

Ficolin A Rat, mouse Not determined

Ficolin B Rat, mouse Not determined

Ficolin L Humans S. typhimurium, E. coli,

Staph. aureus, Streptococcus pyogenes,

Strep. agalactiae

For animals, there is still little known about the roles of the several collectins and ficolins in viral infections. Concerning MBL, no information was available up to now;

only for SP-A and SP-D increased expression has been observed in lambs infected with parainfluenza virus type 3 (GRUBOR et al. 2004).

In contrast to animals, detailed descriptions of target pathogens, beside bacteria, are available from several studies for humans.

Thus not only bacteria were recognized by MBL in humans, but also fungi. Especially the noncapsulated form of Cryptococcus neoformans (SCHELENZ et al. 1995) and Candida albicans (NETH et al. 2000) were mentioned in this connection.

Regarding infections with viruses, it was an outstanding finding that MBL binds to the human immunodeficiency virus (HIV) (HAURUM et al. 1993), and as well to influenza virus (READING et al. 1993). Other collectins, such as SP-A and SP-D, detect herpes simplex virus and the non-enveloped rotavirus (HOLMSKOV et al. 2003).

Concerning infections with parasites, binding of MBL to Leishmania species in humans was observed (GREEN et al. 1994). Leishmania is an intracellular parasite, mainly infecting macrophages, and in case of this infection it is considered that binding of MBL and covering with complement factors provides no protective effect, but in fact stimulates the uptake of the parasite via complement receptors on the surface of macrophages (SANTOS et al. 2001).

In contrast to MBL, for ficolin no other binding sites, except those for bacteria, have been described in the literature.

The general function of collectins, thus, is to protect the host by recognising PAMPs on microorganisms and eliciting appropriate responses by activation of multiple processes of innate immunity (HOLMSKOV et al. 2003; VAN DE WETERING et al.

2004).