Staphylococcus aureus Biofilm-Mediated Infections: Characterization of the Host Adaptive Immune Response and Its Role in Chronic Infection

Abstract

Staphylococcus aureus is one of the most common etiological agents of potentially life threatening prosthetic implant infections. Although it is well established that S. aureus infections can become chronic, due to the ability of S. aureus to grow as a biofilm, little is known about adaptive immune responses to these infections in vivo. We hypothesized that S. aureus elicits pro–inflammatory Th1 and Th17 responses, associated with biofilm formation and chronic implant infection, instead of protective Th2 and Treg responses. A previously developed murine model of prosthetic implant infection was modified to produce a long term, chronic biofilm infection. This model was utilized to determine chronic infection rates, local cytokine levels, Ab function, and T–cell populations at multiple time points throughout infection in both C57BL/6 and BALB/c mice. We also assessed chronic infection levels in STAT6 KO mice (BALB/c background), BALB/c mice receiving anti–CD25 treatment, and C57BL/6 mice receiving anti–IL–6 or anti–IL–12 p40 treatment. Similar to human hosts, S. aureus implant infection was chronic and remained localized in 100% of C57BL/6 mice, and was recalcitrant to the host immune response and antimicrobial therapy. In contrast, BALB/c mice were shown to more effectively clear the infection. Based on cytokine levels, we demonstrated that C57BL/6 mice mount ineffective Th1/Th17 responses, whereas BALB/c mice mount robust Th2/Treg responses compared to C57BL/6 mice. The ability of serum from these strains to enhance in vitro opsonization did not, however, differ. In addition, STAT6 KO mice lost the ability to effectively clear an S. aureus implant infection, as did BALB/c mice receiving anti–CD25. In contrast, C57BL/6 mice treated with anti–IL–12 p40 were able to more effectively clear the infection, although this protection was not observed after anti–IL–6 treatment. Together, these results indicate that Th2 and Treg responses are mechanisms of protection against chronic S. aureus implant infection, as opposed to Th1 and Th17 responses, which may play a role in development of chronic biofilm infection. Our results further suggest that anti–IL–12 p40 treatment may be used therapeutically to prevent chronic S. aureus implant infection in patients.