title: C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients.
abstract: Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.
authors.affiliation: MRC/University Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. mozza@doctors.org.uk
authors.forename: Andrew Conway
authors.initials: AC
authors.lastname: Morris
authors.forename: Mairi
authors.initials: M
authors.lastname: Brittan
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wilkinson
authors.forename: Danny F
authors.initials: DF
authors.lastname: McAuley
authors.forename: Jean
authors.initials: J
authors.lastname: Antonelli
authors.forename: Corrienne
authors.initials: C
authors.lastname: McCulloch
authors.forename: Laura C
authors.initials: LC
authors.lastname: Barr
authors.forename: Neil A
authors.initials: NA
authors.lastname: McDonald
authors.forename: Kev
authors.initials: K
authors.lastname: Dhaliwal
authors.forename: Richard O
authors.initials: RO
authors.lastname: Jones
authors.forename: Annie
authors.initials: A
authors.lastname: Mackellar
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
authors.forename: Alasdair W
authors.initials: AW
authors.lastname: Hay
authors.forename: David G
authors.initials: DG
authors.lastname: Swann
authors.forename: Niall
authors.initials: N
authors.lastname: Anderson
authors.forename: Ian F
authors.initials: IF
authors.lastname: Laurenson
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Walsh
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson
mesh_terms: D000199:Actins / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D015936:Complement C5a / Q000276:immunology*; D016638:Critical Illness; D003428:Cross Infection / Q000453:epidemiology / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D058105:Polymerization; D020742:rhoA GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D000199:Actins; D015936:Complement C5a; D020742:rhoA GTP-Binding Protein