Molecular studies of Neisseria : host cell interactions
Author: Rytkönen, Anne
Date: 2004-09-01
Location: MTC, Theorells väg 1
Time: 9.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
The Neisseria family includes many non-pathogenic species but also two strict human pathogens; Neisseria gonorrhoeae and Neisseria meningitidis. Both organisms colonise mucosal surfaces and may cause disseminated infections upon passage of the epithelial barrier. A correlation between neisserial pathogenesis and deficiencies in complement factors has been observed.
To investigate novel interactions between regulators of the complement system and Neisseria we focused on C4b-binding protein (C4BP), a cofactor for serine proteinase factor 1, preventing the assembly of C3-convertase. We found that the pilusassociated protein PilC of N. gonorrhoeae interacted with C4BP which may contribute to serum resistance by allowing the bacteria to escape complement attack. The human specificity of the pathogenic Neisseria strains has resulted in difficulties developing an animal model mimicking the course of disease seen in humans. Both organisms adhere to host cells by an interaction between pili and the cell surface complement regulator, CD46. By using mice expressing human CD46 we developed a model that resembles both the development of disease and the immune response seen in humans upon meningococcal infection. As in humans, meningococcal invasion of the intranasal epithelium was dependent on pilus expression and the production of proand anti-inflammatory cytokines in serum of CD46 transgenic mice were comparable to levels seen in humans with severe meningococcal disease. We also found that meningococcal passage of the blood-brain barrier required expression of human CD46.
To identify important virulence factors in human meningococcal disease we studied clinical isolates from patients with invasive meningococcal disease. Our data showed that meningococcal strains from the upper respiratory tract, blood and CSF possessed different binding capacities to epithelial cells and that PilC was an important factor for the initial binding. We also found that phase variation in the pilus-adhesin PilC and sequence variation in the pilus subunit PilE occurred among strains isolated from different locations within one individual.
To investigate novel interactions between regulators of the complement system and Neisseria we focused on C4b-binding protein (C4BP), a cofactor for serine proteinase factor 1, preventing the assembly of C3-convertase. We found that the pilusassociated protein PilC of N. gonorrhoeae interacted with C4BP which may contribute to serum resistance by allowing the bacteria to escape complement attack. The human specificity of the pathogenic Neisseria strains has resulted in difficulties developing an animal model mimicking the course of disease seen in humans. Both organisms adhere to host cells by an interaction between pili and the cell surface complement regulator, CD46. By using mice expressing human CD46 we developed a model that resembles both the development of disease and the immune response seen in humans upon meningococcal infection. As in humans, meningococcal invasion of the intranasal epithelium was dependent on pilus expression and the production of proand anti-inflammatory cytokines in serum of CD46 transgenic mice were comparable to levels seen in humans with severe meningococcal disease. We also found that meningococcal passage of the blood-brain barrier required expression of human CD46.
To identify important virulence factors in human meningococcal disease we studied clinical isolates from patients with invasive meningococcal disease. Our data showed that meningococcal strains from the upper respiratory tract, blood and CSF possessed different binding capacities to epithelial cells and that PilC was an important factor for the initial binding. We also found that phase variation in the pilus-adhesin PilC and sequence variation in the pilus subunit PilE occurred among strains isolated from different locations within one individual.
List of papers:
I. Blom AM, Rytkonen A, Vasquez P, Lindahl G, Dahlback B, Jonsson AB (2001). A novel interaction between type IV pili of Neisseria gonorrhoeae and the human complement regulator C4B-binding protein. J Immunol. 166(11): 6764-70.
Pubmed
II. Johansson L, Rytkonen A, Bergman P, Albiger B, Kallstrom H, Hokfelt T, Agerberth B, Cattaneo R, Jonsson AB (2003). CD46 in meningococcal disease. Science. 301(5631): 373-5.
Pubmed
III. Johansson L, Rytkonen A, Bergman P, Hokfelt T, Jonsson AB (2004). Meningococcal infection of CD46 transgenic mice induces human-like early immune responses. [Manuscript]
IV. Rytkonen A, Albiger B, Hansson-Palo P, Kallstrom H, Olcen P, Fredlund H, Jonsson AB (2004). Neisseria meningitidis undergoes PilC phase variation and PilE sequence variation during invasive disease. J Infect Dis. 189(3): 402-9. Epub 2004 Jan 20
Pubmed
I. Blom AM, Rytkonen A, Vasquez P, Lindahl G, Dahlback B, Jonsson AB (2001). A novel interaction between type IV pili of Neisseria gonorrhoeae and the human complement regulator C4B-binding protein. J Immunol. 166(11): 6764-70.
Pubmed
II. Johansson L, Rytkonen A, Bergman P, Albiger B, Kallstrom H, Hokfelt T, Agerberth B, Cattaneo R, Jonsson AB (2003). CD46 in meningococcal disease. Science. 301(5631): 373-5.
Pubmed
III. Johansson L, Rytkonen A, Bergman P, Hokfelt T, Jonsson AB (2004). Meningococcal infection of CD46 transgenic mice induces human-like early immune responses. [Manuscript]
IV. Rytkonen A, Albiger B, Hansson-Palo P, Kallstrom H, Olcen P, Fredlund H, Jonsson AB (2004). Neisseria meningitidis undergoes PilC phase variation and PilE sequence variation during invasive disease. J Infect Dis. 189(3): 402-9. Epub 2004 Jan 20
Pubmed
Issue date: 2004-08-11
Publication year: 2004
ISBN: 91-7140-018-4
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