title: Expression and function of S100A8/A9 (calprotectin) in human typhoid fever and the murine Salmonella model.
abstract: BACKGROUND
  Typhoid fever, caused by the Gram-negative bacterium Salmonella enterica serovar Typhi, is a major cause of community-acquired bacteremia and death worldwide. S100A8 (MRP8) and S100A9 (MRP14) form bioactive antimicrobial heterodimers (calprotectin) that can activate Toll-like receptor 4, promoting lethal, endotoxin-induced shock and multi-organ failure. We aimed to characterize the expression and function of S100A8/A9 in patients with typhoid fever and in a murine invasive Salmonella model.
  
  
  RESULTS
  S100A8/A9 protein levels were determined in acute phase plasma or feces from 28 Bangladeshi patients, and convalescent phase plasma from 60 Indonesian patients with blood culture or PCR-confirmed typhoid fever, and compared to 98 healthy control subjects. To functionally characterize the role of S100A8/A9, we challenged wildtype (WT) and S100A9-/- mice with S. Typhimurium and determined bacterial loads and inflammation 2- and 5- days post infection. We further assessed the antimicrobial function of recombinant S100A8/A9 on S. Typhimurium and S. Typhi replication in vitro. Typhoid fever patients demonstrated a marked increase of S100A8/A9 in acute phase plasma and feces and this increases correlated with duration of fever prior to admission. S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. WT mice inoculated with S. Typhimurium showed increased levels of S100A8/A9 in both the liver and the systemic compartment but S100A9-/- mice were indistinguishable from WT mice with respect to bacterial growth, survival, and inflammatory responses, as determined by cytokine release, histopathology and organ injury.
  
  
  CONCLUSIONS
  S100A8/A9 is markedly elevated in human typhoid, correlates with duration of fever prior to admission and directly inhibits the growth of S. Typhimurium and S. Typhi in vitro. Despite elevated levels in the murine invasive Salmonella model, S100A8/A9 does not contribute to an effective host response against S. Typhimurium in mice.
authors: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Hanna K
authors: HK
authors: De Jong
authors: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Ahmed
authors: A
authors: Achouiti
authors: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors: Gavin C K W
authors: GC
authors: Koh
authors: Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Center for Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, United Kingdom; Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors: Christopher M
authors: CM
authors: Parry
authors: Center for Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, United Kingdom; Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam.
authors: Stephen
authors: S
authors: Baker
authors: Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Chittagong Medical College Hospital, Chittagong, Bangladesh.
authors: Mohammed Abul
authors: MA
authors: Faiz
authors: Department of Infectious diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Jaap T
authors: JT
authors: van Dissel
authors: Department of Infectious diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Albert M
authors: AM
authors: Vollaard
authors: Department of Experimental Immunology, Academic Medical Center, Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
authors: Ester M M
authors: EM
authors: van Leeuwen
authors: Department of Pathology, Academic Medical Center, Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
authors: Joris J T H
authors: JJ
authors: Roelofs
authors: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Alex F
authors: AF
authors: de Vos
authors: Institute of Immunology, University of Muenster, Muenster, Germany.
authors: Johannes
authors: J
authors: Roth
authors: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Tom
authors: T
authors: van der Poll
authors: Institute of Immunology, University of Muenster, Muenster, Germany.
authors: Thomas
authors: T
authors: Vogl
authors: Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Willem Joost
authors: WJ
authors: Wiersinga
mesh_terms: D000818:Animals; D016470:Bacteremia; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D012485:Salmonella typhi; D051197:Toll-Like Receptor 4; D014435:Typhoid Fever / Q000378:metabolism*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D039841:Leukocyte L1 Antigen Complex; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4