C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Andrew Conway Morris, Mairi Brittan, Thomas S. Wilkinson, Danny F. McAuley, Jean Antonelli, Corrienne McCulloch, Laura C. Barr, Neil A. McDonald, Kev Dhaliwal, Richard Jones, Annie Mackellar, Christopher Haslett, Alasdair W. Hay, David G. Swann, Niall Anderson, Ian F. Laurenson, Donald J. Davidson, Adriano G. Rossi, Timothy S. Walsh, A. John Simpson

Research output: Contribution to journalArticlepeer-review

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 PI3K delta. The effects on RhoA, actin, and phagocytosis were fully reversed by GMCSF. 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. (Blood. 2011; 117(19): 5178-5188)

Original languageEnglish
Pages (from-to)5178-5188
Number of pages11
JournalBlood
Volume117
Issue number19
DOIs
Publication statusPublished - 12 May 2011

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