Dihydrolipoamide dehydrogenase of Pseudomonas aeruginosa is a surface-exposed immune evasion protein that binds three members of the factor H family and plasminogen.
The opportunistic human pathogen Pseudomonas aeruginosa causes a wide range of diseases. To cross host innate immune barriers, P. aeruginosa has developed efficient strategies to escape host complement attack. In this study, we identify the 57-kDa dihydrolipoamide dehydrogenase (Lpd) as a surface-exposed protein of P. aeruginosa that binds the four human plasma proteins, Factor H, Factor H-like protein-1 (FHL-1), complement Factor H-related protein 1 (CFHR1), and plasminogen. Factor H contacts Lpd via short consensus repeats 7 and 18-20. Factor H, FHL-1, and plasminogen when bound to Lpd were functionally active. Factor H and FHL-1 displayed complement-regulatory activity, and bound plasminogen, when converted to the active protease plasmin, cleaved the chromogenic substrate S-2251 and the natural substrate fibrinogen. The lpd of P. aeruginosa is a rather conserved gene; a total of 22 synonymous and 3 nonsynonymous mutations was identified in the lpd gene of the 5 laboratory strains and 13 clinical isolates. Lpd is surface exposed and contributes to survival of P. aeruginosa in human serum. Bacterial survival was reduced when Lpd was blocked on the surface prior to challenge with human serum. Similarly, bacterial survival was reduced up to 84% when the bacteria was challenged with complement active serum depleted of Factor H, FHL-1, and CFHR1, demonstrating a protective role of the attached human regulators from complement attack. In summary, Lpd is a novel surface-exposed virulence factor of P. aeruginosa that binds Factor H, FHL-1, CFHR1, and plasminogen, and the Lpd-attached regulators are relevant for innate immune escape and most likely contribute to tissue invasion.
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany.
Teresia
T
Hallström
Matthias
M
Mörgelin
Diana
D
Barthel
Marina
M
Raguse
Anja
A
Kunert
Ralf
R
Hoffmann
Christine
C
Skerka
Peter F
PF
Zipfel
D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001770:Blood Bactericidal Activity / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D003180:Complement C3b Inactivator Proteins / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology*; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D009154:Mutation; D010958:Plasminogen / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
D001426:Bacterial Proteins; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D037521:Virulence Factors; D017242:Complement Factor H; D010958:Plasminogen; D008058:Dihydrolipoamide Dehydrogenase