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Host-Pathogen Interactions in Pseudomonas aeruginosa Invasive and Respiratory Tract Infection

Paulsson, Magnus LU (2017)
Abstract
Pseudomonas aeruginosa is an opportunistic bacterium that causes debilitating infections when the immune defence is compromised. It possesses an arsenal of virulence traits to colonize most compartments of the body and is often highly resistant against commonly used antimicrobial drugs.
Outer membrane vesicles (OMV) are spheres released from Gram-negative bacteria. They are packed with proteins, including beta-lactamase. By exploring OMV from a pathogen related to P. aeruginosa (Moraxella catarrhalis) we discovered that beta-lactamase inside OMV was protected from neutralization by IgG and could protect bacteria from amoxicillin.
Many pathogens avoid killing by the complement system by capturing complement... (More)
Pseudomonas aeruginosa is an opportunistic bacterium that causes debilitating infections when the immune defence is compromised. It possesses an arsenal of virulence traits to colonize most compartments of the body and is often highly resistant against commonly used antimicrobial drugs.
Outer membrane vesicles (OMV) are spheres released from Gram-negative bacteria. They are packed with proteins, including beta-lactamase. By exploring OMV from a pathogen related to P. aeruginosa (Moraxella catarrhalis) we discovered that beta-lactamase inside OMV was protected from neutralization by IgG and could protect bacteria from amoxicillin.
Many pathogens avoid killing by the complement system by capturing complement regulators at their bacterial surface. We found that P. aeruginosa from the airways bound more vitronectin than other clinical isolates. By using a proteomic approach, we identified vitronectin-binding adhesins and found that Pseudomonas uses Porin D to capture vitronectin on its surface.
To investigate the in vivo importance of vitronectin-binding, we analysed vitronectin concentrations in bronchoalveolar lavage fluid (BALF). Patients with pneumonia had significantly higher concentrations than control subjects. This vitronectin increase was confirmed by pulmonary exposure of endotoxins to healthy volunteers. We also found that bacteria could capture vitronectin from BALF and subsequently survive challenge with serum. Immunocytochemistry indicated that epithelial cells produced vitronectin. This production was confirmed in vitro and was triggered by OMV-dependent stimulation of epithelial cells.
Finally, after collecting data on bacteraemic P. aeruginosa episodes, we investigated the effect of comorbidities, treatment, and microbiological characteristics on the outcome of bacteraemia. The choice of treatment was critical, particularly choosing a combination-treatment including ciprofloxacin was beneficial. Moreover, respiratory origin of the infection correlated to high mortality, indicating that compartment-specific factors impacted the outcome.
In conclusion, interactions between the host and bacteria are multifaceted and P. aeruginosa utilizes outer membrane proteins and vesicles to protect against the attacks of the human immune system. (Less)
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author
supervisor
opponent
  • associate professor Bergman, Peter, Karolinska Institutet, Stockholm
organization
publishing date
type
Thesis
publication status
unpublished
subject
keywords
Pseudomonas aeruginosa, vitronectin, Respiratory tract infections, Innate Immunity, outer membrane vesicles, outer membrane proteins, beta-lactamase, ciprofloxacin, combination treatment, bacteraemia, Complement escape
pages
84 pages
publisher
Lund University, Faculty of Medicine
defense location
Föreläsningssalen, Patologihuset, Jan Waldenströmsgata 59, Skånes universitetssjukhus i Malmö.
defense date
2017-05-24 13:00
ISBN
978-91-7619-451-5
language
English
LU publication?
yes
id
076b2f13-acff-4bc5-9f27-f63e686345b4
date added to LUP
2017-04-28 11:16:59
date last changed
2017-05-02 14:26:00
@phdthesis{076b2f13-acff-4bc5-9f27-f63e686345b4,
  abstract     = {<i>Pseudomonas aeruginosa</i> is an opportunistic bacterium that causes debilitating infections when the immune defence is compromised. It possesses an arsenal of virulence traits to colonize most compartments of the body and is often highly resistant against commonly used antimicrobial drugs.<br/>Outer membrane vesicles (OMV) are spheres released from Gram-negative bacteria. They are packed with proteins, including beta-lactamase. By exploring OMV from a pathogen related to <i>P. aeruginosa</i> (<i>Moraxella catarrhalis</i>) we discovered that beta-lactamase inside OMV was protected from neutralization by IgG and could protect bacteria from amoxicillin.<br/>Many pathogens avoid killing by the complement system by capturing complement regulators at their bacterial surface. We found that <i>P. aeruginosa</i> from the airways bound more vitronectin than other clinical isolates. By using a proteomic approach, we identified vitronectin-binding adhesins and found that <i>Pseudomonas</i> uses Porin D to capture vitronectin on its surface.<br/>To investigate the <i>in vivo</i> importance of vitronectin-binding, we analysed vitronectin concentrations in bronchoalveolar lavage fluid (BALF). Patients with pneumonia had significantly higher concentrations than control subjects. This vitronectin increase was confirmed by pulmonary exposure of endotoxins to healthy volunteers. We also found that bacteria could capture vitronectin from BALF and subsequently survive challenge with serum. Immunocytochemistry indicated that epithelial cells produced vitronectin. This production was confirmed <i>in vitro</i> and was triggered by OMV-dependent stimulation of epithelial cells.<br/>Finally, after collecting data on bacteraemic <i>P. aeruginosa</i> episodes, we investigated the effect of comorbidities, treatment, and microbiological characteristics on the outcome of bacteraemia. The choice of treatment was critical, particularly choosing a combination-treatment including ciprofloxacin was beneficial. Moreover, respiratory origin of the infection correlated to high mortality, indicating that compartment-specific factors impacted the outcome.<br/>In conclusion, interactions between the host and bacteria are multifaceted and <i>P. aeruginosa</i> utilizes outer membrane proteins and vesicles to protect against the attacks of the human immune system.},
  author       = {Paulsson, Magnus},
  isbn         = {978-91-7619-451-5},
  keyword      = {Pseudomonas aeruginosa,vitronectin,Respiratory tract infections,Innate Immunity,outer membrane vesicles,outer membrane proteins,beta-lactamase,ciprofloxacin,combination treatment,bacteraemia,Complement escape},
  language     = {eng},
  pages        = {84},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Host-Pathogen Interactions in Pseudomonas aeruginosa Invasive and Respiratory Tract Infection},
  year         = {2017},
}