Suppression of the Inflammatory Immune Response Prevents the Development of Chronic Biofilm Infection Due to Methicillin-Resistant Staphylococcus aureus

Abstract

ABSTRACTStaphylococcus aureusis a common cause of prosthetic implant infections, which can become chronic due to the ability ofS. aureusto grow as a biofilm. Little is known about adaptive immune responses to these infectionsin vivo. We hypothesized thatS. aureuselicits inflammatory Th1/Th17 responses, associated with biofilm formation, instead of protective Th2/Treg responses. We used an adapted mouse model of biofilm-mediated prosthetic implant infection to determine chronic infection rates, Treg cell frequencies, and local cytokine levels in Th1-biased C57BL/6 and Th2-biased BALB/c mice. All C57BL/6 mice developed chronicS. aureusimplant infection at all time points tested. However, over 75% of BALB/c mice spontaneously cleared the infection without adjunctive therapy and demonstrated higher levels of Th2 cytokines and anti-inflammatory Treg cells. When chronic infection rates in mice deficient in the Th2 cytokine interleukin-4 (IL-4) via STAT6 mutation in a BALB/c background were assessed, the mice were unable to clear theS. aureusimplant infection. Additionally, BALB/c mice depleted of Treg cells via an anti-CD25 monoclonal antibody (MAb) were also unable to clear the infection. In contrast, the C57BL/6 mice that were susceptible to infection were able to eliminateS. aureusbiofilm populations on infected intramedullary pins once the Th1 and Th17 responses were diminished by MAb treatment with anti-IL-12 p40. Together, these results indicate that Th2/Treg responses are mechanisms of protection against chronicS. aureusimplant infection, as opposed to Th1/Th17 responses, which may play a role in the development of chronic infection.