Complement evasion strategies of human pathogens - the evolutionary arms race

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Although the complement system, a pivotal component of innate immunty, is centrally involved in host defense against pathogens, its overactivation or deregulation may excessively amplify inflammation and contribute to immunopathology. Periodontitis, an oral infection-driven chronic inflammatory disease, has been linked with complement disruption by periodontal bacteria, resulting in inflammation and pathogenesis. The mechanisms of this disruption have partially been revealed, yet in this thesis we investigated novel periodontal pathogens and/or complement evasion pathways in periodontitis. Furthermore, complement inhibition by S. aureus is a key step in its infection, but the impact of its proteases on complement, highlighted in our studies, has not been well characterized before.
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.

Details

Authors
  • Monika Jusko
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Other Basic Medicine
  • Medical and Health Sciences

Keywords

  • complement system, pathogen, periodontitis, proteases, immune escape
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2014 Sep 5
Publisher
  • Protein Chemistry, Lund University
Print ISBNs978-91-7619-020-3
Publication statusPublished - 2014
Publication categoryResearch

Bibliographic note

Defence details Date: 2014-09-05 Time: 09:00 Place: Lilla Aulan, Jan Waldenströmsgata 5, Malmö External reviewer(s) Name: Hajishengallis, George Title: professor Affiliation: Department of Microbiology, University of Pennsylvania, School of Dental Medicine, Philadelphia, USA ---

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