Characterisation of the interaction between Neisseria meningitidis and human polymorphonuclear leukocytes

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Title: Characterisation of the interaction between Neisseria meningitidis and human polymorphonuclear leukocytes
Authors: Corbett, Anne
Item Type: Thesis or dissertation
Abstract: During infection with Neisseria meningitidis, an important causative agent of bacterial meningitis and septicaemia, the host innate immune system clears bacteria by complement-mediated lysis and phagocytosis. In order to evade phagocytosis, the bacterium expresses a number of surface components, including a polysaccharide capsule and sialylated lipopolysaccharide (LPS). The aim of this project was to investigate the influence of bacterial metabolism and DNA repair on the interaction with polymorphonuclear leukocytes (PMNs). Results demonstrated reduced expression of the polysaccharide capsule and lowered LPS sialylation in a strain (ΔlctP) unable to acquire exogenous lactate, but no effect in a strain unable to utilise glutamate (ΔperM). These changes were associated with increased phagocytosis of fixed bacteria by the human PMN cell line, HL60. Further investigations showed that capsule expression in the ΔlctP strain was restored to wild-type levels following exposure of live bacteria to PMNs. Next, assays were established using primary human PMNs to investigate post-phagocytic events. The wild-type meningococcus survives within PMNs and is able to delay host cell apoptosis. Furthermore, the ΔlctP and ΔperM strains were significantly killed by PMNs, indicating a role for acquisition of both lactate and glutamate for survival in PMNs. Killing was dependent on actin polymerisation and the PMN oxidative burst. The role of the meningococcal Base Excision Repair (BER) DNA repair pathway was also investigated through characterisation of two Apurinic / Apyrimidinic (AP) endonuclease paralogues, NExo and NApe. Both exhibit distinct biochemical functions and are required for resistance against oxidative stress. A strain lacking both these enzymes, which is attenuated in vivo, was significantly killed by human PMNs as a result of the oxidative burst.
Issue Date: Oct-2008
Date Awarded: Feb-2009
URI: http://hdl.handle.net/10044/1/4417
Supervisor: Tang, Christoph
Author: Corbett, Anne
Department: Microbiology
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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