Structural studies on the meningococcal Immunoglobulin A protease
Lead Research Organisation:
University of Sheffield
Department Name: Molecular Biology and Biotechnology
Abstract
Some strains of bacteria can escape our natural antibody response defences and cause serious diseases like meningitis and blood poisoning. We need to understand how the germs that cause these diseases can avoid our immune system and invade the bloodstream. We hope this work will ultimately lead to the creation of new therapies and vaccines for meningitis.
Some of the more aggressive meningitis-causing bacteria fight our antibodies by secreting a substance called IgA1 protease. This substance chops up the antibodies into smaller fragments that are unable to attack the invading bacteria. The IgA1 protease also helps bacteria enter the bloodstream, triggering septicaemia, where it can target other blood components.
The IgA1 protease is a large, complex molecule able to interact with a number of host targets. We aim to determine its structure to try to understand how it is secreted. We are also studying how various parts of the IgA1 protease interact with blood components. This should help us understand how it contributes to the disease. We hope this work will lead to the development of new strategies to interfere with bacterial invaders producing IgA1 protease such as those causing meningitis and chronic chest infections (meningococci and Haemophilus influenzae) and gonorrhoea.
Some of the more aggressive meningitis-causing bacteria fight our antibodies by secreting a substance called IgA1 protease. This substance chops up the antibodies into smaller fragments that are unable to attack the invading bacteria. The IgA1 protease also helps bacteria enter the bloodstream, triggering septicaemia, where it can target other blood components.
The IgA1 protease is a large, complex molecule able to interact with a number of host targets. We aim to determine its structure to try to understand how it is secreted. We are also studying how various parts of the IgA1 protease interact with blood components. This should help us understand how it contributes to the disease. We hope this work will lead to the development of new strategies to interfere with bacterial invaders producing IgA1 protease such as those causing meningitis and chronic chest infections (meningococci and Haemophilus influenzae) and gonorrhoea.
Technical Summary
A number of human pathogens produce proteases able to degrade human IgA1 antibodies, key players in mucosal defence. These include Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae and Streptococcus pneumoniae.
The Neisserial IgA proteases are virulence factors which are synthesised as a single polypeptide consisting of an N-terminal signal sequence and three functional domains: the protease itself, the alpha protein, and an autotransporter domain which allows transport across the bacterial outer membrane. We have recently solved the crystal structure of the alpha protein from N. meningitidis and will now pursue structural studies on the protease and autotransporter domains. Understanding of structure-function relationships in these molecules will facilitate the development of anti-bacterial agents and vaccines.
The Neisserial IgA proteases are virulence factors which are synthesised as a single polypeptide consisting of an N-terminal signal sequence and three functional domains: the protease itself, the alpha protein, and an autotransporter domain which allows transport across the bacterial outer membrane. We have recently solved the crystal structure of the alpha protein from N. meningitidis and will now pursue structural studies on the protease and autotransporter domains. Understanding of structure-function relationships in these molecules will facilitate the development of anti-bacterial agents and vaccines.
