title: Differential timing of antibody-mediated phagocytosis and cell-free killing of invasive African Salmonella allows immune evasion.
abstract: Nontyphoidal Salmonellae commonly cause fatal bacteraemia in African children lacking anti-Salmonella antibodies. These are facultative intracellular bacteria capable of cell-free and intracellular survival within macrophages. To better understand the relationship between extracellular and intracellular infection in blood and general mechanisms of Ab-related protection against Salmonella, we used human blood and sera to measure kinetics of Ab and complement deposition, serum-mediated bactericidal killing and phagocytosis of invasive African Salmonella enterica serovar Typhimurium D23580. Binding of antibodies peaked by 30 s, but C3 deposition lagged behind, peaking after 2-4 min. C5b-9 deposition was undetectable until between 2 and 6 min and peaked after 10 min, after which time an increase in serum-mediated killing occurred. In contrast, intracellular, opsonized Salmonellae were readily detectable within 5 min. By 10 min, around half of monocytes and most neutrophils contained bacteria. The same kinetics of serum-mediated killing and phagocytosis were observed with S. enterica Typhimurium laboratory strain SL1344, and the S. enterica Enteritidis African invasive isolate D24954 and laboratory strain PT4. The differential kinetics between cell-free killing and phagocytosis of invasive nontyphoidal Salmonella allows these bacteria to escape the blood and establish intracellular infection before they are killed by the membrane attack complex.
authors.affiliation: Medical Research Council Centre for Immune Regulation and Clinical Immunology Service, Institute of Biomedical Research, School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, UK; Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Siggins
authors.forename: Colette M
authors.initials: CM
authors.lastname: O'Shaughnessy
authors.forename: John
authors.initials: J
authors.lastname: Pravin
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.forename: Ian R
authors.initials: IR
authors.lastname: Henderson
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Calman A
authors.initials: CA
authors.lastname: MacLennan
mesh_terms: D000328:Adult; D000907:Antibodies, Bacterial / Q000276:immunology*; D001770:Blood Bactericidal Activity; D003176:Complement C3 / Q000276:immunology; D050776:Complement C5b / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007700:Kinetics; D050296:Microbial Viability / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D009895:Opsonin Proteins / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology*; D012477:Salmonella enteritidis / Q000276:immunology* / Q000502:physiology; D012486:Salmonella typhimurium / Q000276:immunology* / Q000502:physiology; D044967:Serum / Q000276:immunology / Q000382:microbiology; D013997:Time Factors
chemical_list: D000907:Antibodies, Bacterial; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D009895:Opsonin Proteins; D050776:Complement C5b
keywords: Antibodies; Complement; Opsonization; Phagocytosis; Salmonella