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Survival strategies of the human respiratory tract pathogen Haemophilus influenzae

Hallström, Teresia LU (2007)
Abstract
Haemophilus influenzae is an important respiratory tract pathogen responsible for a variety of infections in humans. Encapsulated H. influenzae belongs to one of six serotypes (a-f), of which type b is the most virulent one causing serious and sometimes life-threatening diseases (e.g., epiglottitis, septicaemia and meningitis). In contrast, non-typeable H. influenzae (NTHi) accounts for the majority of local and upper and lower respiratory tract infections.



The pathogenesis of many microorganisms relies on the capacity of pathogens to avoid, resist or neutralise the host defence including the complement system.



We demonstrate that H. influenzae interferes with both the classical/lectin and alternative... (More)
Haemophilus influenzae is an important respiratory tract pathogen responsible for a variety of infections in humans. Encapsulated H. influenzae belongs to one of six serotypes (a-f), of which type b is the most virulent one causing serious and sometimes life-threatening diseases (e.g., epiglottitis, septicaemia and meningitis). In contrast, non-typeable H. influenzae (NTHi) accounts for the majority of local and upper and lower respiratory tract infections.



The pathogenesis of many microorganisms relies on the capacity of pathogens to avoid, resist or neutralise the host defence including the complement system.



We demonstrate that H. influenzae interferes with both the classical/lectin and alternative pathways of the complement system. NTHi binds C4BP, the inhibitor of the classical pathway, and the majority of the H. influenzae tested bound factor H, the inhibitor of the alternative pathway. Importantly, the capacity to bind C4BP and factor H appears to render the bacteria more resistant to serum mediated killing. Furthermore, both C4BP and factor H bound to the surface of H. influenzae retains its cofactor activity as determined by analysis of C4b and/or C3b degradation.



In addition to interacting with the classical/lectin and alternative pathways, we demonstrate that Haemophilus surface fibrils (Hsf), which is expressed by encapsulated H. influenzae, binds vitronectin, a regulator of the terminal pathway of the complement system.



Mapping of the membrane bound Hsf with gold-labelled specific antibodies in transmission electron microscopy (TEM) revealed a double-folded 100 nm long fibrillar structure. Using a series of mutants, we showed that when the C-terminal translocator domain was inactivated, Hsf was not translocated to the bacterial surface. Interestingly, we also show that outer membrane vesicles (OMV) secreted by the bacteria carry Hsf, and that Hsf is secreted into the extracellular milieu.



IgD-binding is another important feature of encapsulated H. influenzae type b. By using a series of different IgD chimeric proteins, the site on the IgD molecule responsible for the interaction with H. influenzae was characterised. The binding site was localised to the CH1 region of IgD.



In summary, H. influenzae binds C4BP, factor H and vitronectin, which are regulators of the complement system. The interaction between H. influenzae and these regulators protects the bacteria and makes them more resistant to the bactericidal activity of human serum. Finally, H. influenzae type b binds human IgD. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Kilian, Mogens, Institute of medical microbiology and immunology, Aarhus University, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
mycology, Mikrobiologi, bakteriologi, bacteriology, virology, Haemophilus influenzae, IgD-binding, protein structure of Hsf, Microbiology, The complement system, virologi, mykologi
pages
68 pages
publisher
Medical Microbiology, Lund University
defense location
Patologens föreläsningssal UMAS, ingång 78 Malmö
defense date
2007-05-15 14:00
ISSN
1652-8220
ISBN
978-91-85559-60-2
language
English
LU publication?
yes
id
d794e3c6-81db-4ad5-b936-4e4fc49b7da5 (old id 548546)
date added to LUP
2007-09-12 07:46:47
date last changed
2016-09-19 08:44:54
@phdthesis{d794e3c6-81db-4ad5-b936-4e4fc49b7da5,
  abstract     = {Haemophilus influenzae is an important respiratory tract pathogen responsible for a variety of infections in humans. Encapsulated H. influenzae belongs to one of six serotypes (a-f), of which type b is the most virulent one causing serious and sometimes life-threatening diseases (e.g., epiglottitis, septicaemia and meningitis). In contrast, non-typeable H. influenzae (NTHi) accounts for the majority of local and upper and lower respiratory tract infections.<br/><br>
<br/><br>
The pathogenesis of many microorganisms relies on the capacity of pathogens to avoid, resist or neutralise the host defence including the complement system.<br/><br>
<br/><br>
We demonstrate that H. influenzae interferes with both the classical/lectin and alternative pathways of the complement system. NTHi binds C4BP, the inhibitor of the classical pathway, and the majority of the H. influenzae tested bound factor H, the inhibitor of the alternative pathway. Importantly, the capacity to bind C4BP and factor H appears to render the bacteria more resistant to serum mediated killing. Furthermore, both C4BP and factor H bound to the surface of H. influenzae retains its cofactor activity as determined by analysis of C4b and/or C3b degradation.<br/><br>
<br/><br>
In addition to interacting with the classical/lectin and alternative pathways, we demonstrate that Haemophilus surface fibrils (Hsf), which is expressed by encapsulated H. influenzae, binds vitronectin, a regulator of the terminal pathway of the complement system.<br/><br>
<br/><br>
Mapping of the membrane bound Hsf with gold-labelled specific antibodies in transmission electron microscopy (TEM) revealed a double-folded 100 nm long fibrillar structure. Using a series of mutants, we showed that when the C-terminal translocator domain was inactivated, Hsf was not translocated to the bacterial surface. Interestingly, we also show that outer membrane vesicles (OMV) secreted by the bacteria carry Hsf, and that Hsf is secreted into the extracellular milieu.<br/><br>
<br/><br>
IgD-binding is another important feature of encapsulated H. influenzae type b. By using a series of different IgD chimeric proteins, the site on the IgD molecule responsible for the interaction with H. influenzae was characterised. The binding site was localised to the CH1 region of IgD.<br/><br>
<br/><br>
In summary, H. influenzae binds C4BP, factor H and vitronectin, which are regulators of the complement system. The interaction between H. influenzae and these regulators protects the bacteria and makes them more resistant to the bactericidal activity of human serum. Finally, H. influenzae type b binds human IgD.},
  author       = {Hallström, Teresia},
  isbn         = {978-91-85559-60-2},
  issn         = {1652-8220},
  keyword      = {mycology,Mikrobiologi,bakteriologi,bacteriology,virology,Haemophilus influenzae,IgD-binding,protein structure of Hsf,Microbiology,The complement system,virologi,mykologi},
  language     = {eng},
  pages        = {68},
  publisher    = {Medical Microbiology, Lund University},
  school       = {Lund University},
  title        = {Survival strategies of the human respiratory tract pathogen Haemophilus influenzae},
  year         = {2007},
}