2012hayataphd.pdf (4.1 MB)
The Molecular Interactions between Two Activation Pathways of Complement are Essential for a Protective Innate Immune Response to Neisseria Meningitidis Infection
thesisposted on 2012-09-05, 13:12 authored by Azam Hayat
The complement system forms a vital part of the immune system providing host defence against various pathogens, including N. meningitidis. The roles of the lectin and the alternative pathway of complement activation in meningococcal disease have been studied. Serum bactericidal assay against N.meningitidis suggested that both MBL and MASP-3 are essential for driving SBA on meningococci through a close association with the alternative pathway. A highly significant difference in survival between MASP-2-/- and MASP-2+/+ wild-type mice was observed following N. meningitidis infection with a lethal intraperitoneal dose, showing that MASP-2-/- mice were significantly protected against meningococcal infection. MASP-2-/- mice also exhibited a significantly lower meningococcal burden in blood and different organs when compared to MASP-2+/+ wild-type mice. The mRNA expression levels of inflammatory cytokines such as MIP-2, IFN-γ, IL-6 and IL-10 were significantly lower in different organs of MASP-2-/- mice compared to the MASP-2+/+ control group. Therapeutic benefits of anti MASP-2 antibodies that inhibit the lectin pathway functional activity was also tested, and the findings showed that C57BL/6 wild-type mice treated with inhibitory MASP-2 antibody showed a significantly better survival when compared with wild mice treated with an irrelevant isotype control antibody following infection with a high dose of N.meningitidis. Furthermore, significantly reduced mortality rates were observed following application of recombinant properdin in a murine model of meningococcal infection. Finally, a combination therapy using inhibitory MASP-2 antibody and recombinant properdin was analysed in murine model of meningococcal infection using C57BL/6 wild-type mice. Following N.meningitidis infection, mouse groups which received both properdin and inhibitory MASP-2 antibody showed better survival with less disease severity scores when compared to infected untreated control mouse group, or mouse groups which received recombinant properdin or inhibitory MASP-2 antibody alone.
Supervisor(s)Schwaeble, Wilhelm; Andrew, Peter
Date of award2012-06-22
Awarding institutionUniversity of Leicester