Characterization of nontypeable Haemophilus influenzae innate interactions with human cells

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Non-typeable Haemophilus influenzae (NTHi) is a human pathogen causing diseases in the upper and lower respiratory tract. Otitis media-prone children and adults with cystic fibrosis or chronic obstructive pulmonary disease, are repeatedly infected by NTHi

Research in recent years brought to light the entry and survival of NTHi in epithelial cells and macrophages. Their internalization could be a means for the bacteria to escape the local immunity or the activity of antibiotics and to persist within the respiratory tract.

In the present thesis we have investigated the interactions of NTHi with human cells under nonopsonic conditions. We report that NTHi enters human epithelial and monocytic cells through a receptor-mediated endocytosis that requires microfilament and microtubuli polymerization. The adherence of NTHi to the cells and the subsequent internalization are events highly dependent on beta-glucan receptors on the eukaryotic cell surface. Moreover, the bacterial beta-glucans are pathogen-associated molecular patterns (PAMP) also involved in the NTHi-induced activation of eosinophils. Incubation of eosinophils with either bacteria or a beta-glucn derivative resulted in a time and dose-dependent production of hydrogen peroxide (respiratory burst). Furthermore, the inflammation triggered by NTHi is induced in the presence of lipopolysaccharide-binding protein (LBP), in conjunction with membrane CD14 and toll-like receptor 4 (TLR4).

In addition, we show that protein D, expressed on the surface of all H. influenzae strains, contributes to a more efficient binding and entry of NTHi into human monocytes. Finally, we present a new in vitro model system for studying the activity of antibacterial drugs against intracellular NTHi.

Details

Authors
  • Irini Lazou Ahrén
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Microbiology in the medical area

Keywords

  • mykologi, Microbiology, bacteriology, virology, mycology, Mikrobiologi, bakteriologi, virologi, inflammation, TLR4, LBP, protein D, nontypeable Haemophilus influenzae, beta-glucan
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2002 Oct 31
Publisher
  • Irini Lazou Ahrén, Dept. Medical Microbiology, University Hospital MAS, 205 02 Malmö,
Print ISBNs91-628-5379-1
Publication statusPublished - 2002
Publication categoryResearch

Bibliographic note

Defence details Date: 2002-10-31 Time: 13:15 Place: Patologens föreläsningssal, Ingång 78, MAS, Malmö External reviewer(s) Name: Stendahl, Olle Title: Prof. Affiliation: Linköping University, Sweden --- Article: 1. Irini Lazou Ahrén, David L. Williams, Peter J. Rice, Arne Forsgren and Kristian Riesbeck (2001). The importance of a beta-glucan receptor in the nonopsonic entry of nontypeable Haemophilus influenzae into human monocytic and epithelial cells. The Journal of Infectious Diseases 184: 150-158. Article: 2. Irini Lazou Ahrén, Håkan Janson, Arne Forsgren and Kristian Riesbeck (2001). Protein D expression promotes the adherence and internalization on nontypeable Haemophilus influenzae into human monocyti cells. Microbial Pathogenesis 31: 151-158. Article: 3. Irini Lazou Ahrén, Anders Bjartell, Arne Egesten and Kristian Riesbeck (2001). Lipopolysaccharide-binding protein increases Toll-like receptor 4-dependent activation by nontypeable Haemophilus influenzae. The Journal of Infectious Diseases 184: 926-930 (2001) Article: 4. Irini Lazou Ahrén, Eva Karlsson, Arne Forsgren and Kristian Riesbeck (2002). Comparison of the bactericidal activities of ampicillin, ciprofloxacin, clarithromycin, telithromycin and quinupristin/ dalfopristin against intracellular nontypeable Haemophilus influenzae. The Journal of Antimicrobial Chemotherapy, in press. Article: 5. Irini Lazou Ahrén, Arne Egesten and Kristian Riesbeck (2002). Non-typeable Haemophilus influenzae activates human eosinophils through an innate pattern recognition mechanism involving beta-glucan receptors. American Journal of Respiratory Cell and Molecular Biology, submitted for publication.