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Title: The key role of the Lectin Pathway enzyme MASP-3 in the innate immune protection against Neisseria meningitides
Author: Alshamrani, Saleh
ISNI:       0000 0004 5990 2412
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2016
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Neisseria meningitidis infections pose a worldwide threat to human health being a major cause of morbidity and mortality. The bacterium can often be found to live as a commensal organism in the upper respiratory-tract. However, under disease promoting circumstances it may cause invasive infections such as bacterial meningitis with a mortality rate of up to 10% in patients with sepsis. The complement system plays a vital role in immune protection from Neisseria meningitidis infections and ongoing research in our laboratories has recently observed that the serum of mice deficient in the lectin pathway of complement effector enzyme MASP-2 had a higher bactericidal activity towards Neisseria meningitidis as compared to MASP-2 sufficient serum. This work also revealed a key role of the lectin pathway components MBL and MASP-3 in driving serum bacteriolytic activity against Neisseria meningitidis and has identified a novel link between MASP-3 and the alternative pathway of complement activation. The work described in this thesis highlights the critical role that MASP-3 plays in the innate immune response to this pathogen using in vitro models of serum bactericidal activity and in vivo mouse models of Neisseria meningitidis infection. The failure of MASP-3 deficient non immune serum to lyse Neisseria meningitidis serotype A and serotype B was restored by adding a recombinant enzymatically active MASP-3 fragment to this serum while the therapeutic systemic injection of recombinant murine MASP-3 zymogen convincingly restored the defective alternative pathway functional activity and with that repaired the high susceptibility of MASP-1/3 deficient mice to Neisseria meningitidis infections. In line with the essential role that the alternative pathway plays in driving the innate immune response against Neisseria meningitidis, the early results of my study showed the therapeutic utility of enhancing the alternative pathway functional activity through the addition of recombinant murine properdin to WT mice sera and significantly increased the lytic activity against Neisseria meningitidis.
Supervisor: Schwaeble, Wilhelm ; Andrew, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available