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

Research output: ThesisDoctoral Thesis (compilation)

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Host-Pathogen Interactions in Pseudomonas aeruginosa Invasive and Respiratory Tract Infection. / Paulsson, Magnus.

Lund : Lund University, Faculty of Medicine, 2017. 84 p.

Research output: ThesisDoctoral Thesis (compilation)

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TY - THES

T1 - Host-Pathogen Interactions in Pseudomonas aeruginosa Invasive and Respiratory Tract Infection

AU - Paulsson, Magnus

N1 - Defence details Date: 2017-05-24 Time: 13:00 Place: Föreläsningssalen, Patologihuset, Jan Waldenströmsgata 59, Skånes universitetssjukhus i Malmö. External reviewer(s) Name: Bergman, Peter Title: associate professor Affiliation: Karolinska Institutet, Stockholm --- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:71

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Pseudomonas aeruginosa

KW - vitronectin

KW - Respiratory tract infections

KW - Innate Immunity

KW - outer membrane vesicles

KW - outer membrane proteins

KW - beta-lactamase

KW - ciprofloxacin

KW - combination treatment

KW - bacteraemia

KW - Complement escape

M3 - Doctoral Thesis (compilation)

SN - 978-91-7619-451-5

PB - Lund University, Faculty of Medicine

CY - Lund

ER -