Date Published: April 10, 2015
Publisher: Public Library of Science
Author(s): Hanna K. De Jong, Ahmed Achouiti, Gavin C. K. W. Koh, Christopher M. Parry, Stephen Baker, Mohammed Abul Faiz, Jaap T. van Dissel, Albert M. Vollaard, Ester M. M. van Leeuwen, Joris J. T. H. Roelofs, Alex F. de Vos, Johannes Roth, Tom van der Poll, Thomas Vogl, Willem Joost Wiersinga, Edward T. Ryan. http://doi.org/10.1371/journal.pntd.0003663
Abstract: BackgroundTyphoid 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.Methods and principal findingsS100A8/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.ConclusionS100A8/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.
Partial Text: Typhoid fever constitutes a global public health problem with more than 21 million cases worldwide each year resulting in over 217,000 deaths predominantly in Asia [1–3]. Infection with Salmonella (S.) enterica serovar Typhi, which is the Gram-negative intracellular bacterium, results in a bacteremic disease characterized by protracted and high-grade fever. Mortality usually results from intestinal perforation and peritonitis or from severe toxic encephalopathy associated with myocarditis and hemodynamic shock [3,4].
In this study we aimed to characterize the expression and function of S100A8/A9 in typhoid fever, linking observational studies in patients with functional studies in S100A9-/- mice. We here show that S100A8/A9 levels are markedly elevated in Bangladeshi patients with typhoid fever in plasma and feces and correlate with liver damage and duration of fever. The levels were persistently elevated in Indonesian patients 2–3 weeks into convalescence. In a murine Salmonella model induced by S. Typhimurium increased levels of endogenous S100A8/A9 complexes were seen both at the primary site of infection and at distant sites corresponding with stage and severity of disease. Furthermore S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. The functional role of S100A8/A9 in the host defense against murine Salmonella infection was limited however, given the fact that S100A9-/- mice were indistinguishable from WT mice with respect to survival, bacterial organ counts and inflammatory responses.