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Survival strategies of the human respiratory tract pathogen Haemophilus influenzae

by Hallström, Teresia, PhD

Abstract (Summary)
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.
Bibliographical Information:

Advisor:

School:Lunds universitet

School Location:Sweden

Source Type:Doctoral Dissertation

Keywords:NATURAL SCIENCES; Biology; Mikrobiologi; mycology; bakteriologi; bacteriology; virology; Haemophilus influenzae; IgD-binding; protein structure of Hsf; Microbiology; The complement system; virologi; mykologi

ISBN:978-91-85559-60-2

Date of Publication:01/01/2007

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