Complement evasion strategies of human pathogens - the evolutionary arms race
Summary, in English
We focused on a major but relatively poorly studied periodontal bacterium T. forsythia. We showed that its two novel peptidases contribute to its complement resistance by cleaving several key complement components. Interestingly, both of the proteases were able to cleave C5 to release biologically active anaphylatoxins C5a, activity of which has been largely implicated in pathogenesis of periodontitis.
Further, we showed that another important periopathogen, Prevotella intermedia, acquires resistance towards complement by binding complement inhibitor found in human serum, factor I, and its two major cofactors C4b-binding protein (C4BP) and Factor H. This mechanism contributes to complement resistance of this bacterium.
We also found that major periopathogens have the ability to bind to the membrane-bound complement inhibitor CD46. Strikingly, even though this molecule improved initial attachment of bacteria to the epithelial cells, the final outcome was not beneficial for the bacteria – in cells without CD46 they persisted much longer without getting cleared, indicating activation of certain killing mechanisms upon CD46 stimulation. The phenomenon may be related to autophagy, which may be affected by CD46 as shown previously.
Recent studies implicated an involvement of a novel gram-positive Filifactor alocis in the pathogenesis of the periodontal disease. Taking into account the key role of complement deregulation by periodontal bacteria, we focused on F. alocis capacity to manipulate this system. We pinpointed different strategies, such as production of proteases or non-productive binding of C3, employed by this bacterium.
Finally, Staphylococcus aureus, is known for its impressive repertoire of complement inhibitors. We tested a panel of major proteases of S. aureus and identified their substrates within complement cascades. We also showed that two of the proteases are able to release C5a, similarly to proteases of periodontal bacteria.
Taken together, we explored the knowledge about complement manipulation by various common human pathogens. We identified both unique as wells as common strategies of bacterial complement evasion. Exploring virulence mechanisms shared by different pathogens can give rationales for developing effective therapies for infectious diseases.
Lund University Faculty of Medicine Doctoral Dissertation Series
Protein Chemistry, Lund University
- Other Basic Medicine
- Medical and Health Sciences
- complement system
- immune escape
- Protein Chemistry, Malmö
- ISSN: 1652-8220
- ISBN: 978-91-7619-020-3
5 september 2014
Lilla Aulan, Jan Waldenströmsgata 5, Malmö
- George Hajishengallis (professor)