Complement system includes a conglomeration of a set of soluble factors and membrane anchored receptors, which has been designed to recognise and clear non self (pathogens) and altered self (apoptotic cells, necrotic cells and transformed cells). In a general theme, the recognition subcomponents bind to target, which is followed by limited proteolytic cleavage of downstream complement components. Three pathways namely classical, alternative and lectin converge on the generation of C3 convertase. The alternative pathway is activated by spontaneous cleavage of C3, generating C3a, an anaphylatoxin, and C3b, which binds to the surface of pathogens. A C3 convertase is formed, which has a half-life of about 90 seconds, is stabilised by properdin, and in an amplification loop a C5 convertase is formed leading to lytic pathway and cell lysis. This puts properdin at the heart of up regulator of alternative pathway. Properdin is structurally organised into seven thrombospondin repeats (TSR), whose functions have been delineated via deletion mutagenesis studies. In the chapter 3, we have expressed TSR4 and TSR5 in tandem in E. coli and shown that the two-module recombinant protein binds to C3b, sulfatides, and glycosaminoglycans similarly to native properdin. The recombinant module also seems to be an efficient inhibitor of properdin’s ability to stabilise C3bBb complex, thus offering a therapeutic possibility to dampen alternative pathway. Although properdin’s definite role in perpetuating the alternative pathway is well established, its structural organisation also appears to suggest its potential as an independent innate immune soluble factor that would not require engagement with complement system. In chapter 4, we report the ability of properdin to interact with mycobacterium (BCG) via TSR4+5 module, down regulate the microbial uptake by macrophages, and up regulate pro-inflammatory cytokine response via enhancing anti-mycobacterial TNF-α production. In chapter 5, we demonstrate that properdin as well as TSR4+5 interacts directly with a range of influenza A virus strains leading to inhibition of infection and dampening of pro-inflammatory response. The ability of properdin to interact with non-self is further reaffirmed by its ability to interact with nanoparticles and modulate subsequent immune cell response as presented under discussion chapter. Thus, this thesis reports a set of novel observations highlighting non-complement properties of properdin, which may be crucial in host pathogen interaction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:699251 |
| Date | January 2015 |
| Creators | Kouser, Lobna |
| Contributors | Kishore, U. ; Pathan, A. |
| Publisher | Brunel University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://bura.brunel.ac.uk/handle/2438/13602 |
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