Host Immune Response in Staphylococcus aureus Bacteremia: Differential Gene Expression of Toll-like Receptor 2 and Secretion of Cytokines

Abstract

Introduction: Staphylococcus aureus is a commensal bacterium causing diverse infections from asymptomatic colonization to fatal infections. There have been many studies exploring host response to S. aureus infection. Toll like receptors (TLRs) play an important role in innate immune response against infection. Among the known TLRs, TLR2 is the main pattern recognition receptor recognizing pathogen-associated molecular patterns in S. aureus infection. The cytokines released by intracellular signaling pathways of TLR2 are involved in either beneficial or detrimental immune responses to the infection. We aimed to examine the relationship of TLR2 expression and the concentration of proinflammatory and anti-inflammatory cytokines with the prognosis in patients with S. aureus bacteremia (SAB). Methods: Whole blood samples were collected at several time points categorized as within 5 days (≤ D5), between 6 to 9 days (D6-9), between 10-13 days (D10-13), between 14-19 days (D14-19) and after 20 days (≥ D20) of bacteremia, from patients diagnosed as SAB in Seoul National University Hospital and Seoul National University Bundang Hospital. We extracted RNA which was converted to cDNA by RT-PCR and separated plasma by centrifugation. The relative mRNA expression of TLR2 was measured by real-time PCR and the level of TNF-α, IL-6 and IL-10 was measured by Luminex mutli-bead assay. The findings were analyzed to identify associations with 30-day mortality and severity. Results: The level of TLR2 expression during the clinical course after the onset of bacteremia was variable among the 62 patients with SAB. In 10 patients with 30-day mortality, TLR2 expression was down-regulated and showed less dynamic changes throughout the whole period than in 52 survivors. IL-6 and IL-10 were significantly elevated in the mortal group. More patients (90%, 9/10) in the mortal group showed measurable IL-10 (>2.49 pg/mL) compared with the survived group (40%, 20/50) within 7 days of bacteremia. IL-6/IL-10 ratio tended to be either low or high in the patients with 30-day mortality, which implies excessive immune response of either proinflammation or anti-inflammation. The level of TLR2 expression within day 5 of bacteremia was higher in patients with severe clinical manifestations such as complicated bacteremia or septic shock. Conclusions: In SAB patients, down-regulated TLR2 expression and elevated IL-6 and/or IL-10 at early stage of bacteremia were associated with 30-day mortality. TLR2 expression within 5 days of bacteremia was higher in patients with severe presentations implying hyper-immune response. Host immune response including TLR2 expression and secretion of cytokines may be a potential prognostic factor in SAB.