The Impact of Staphylococcal Immune-Evasive Genes on Orthopedic Device Infection.

Abstract

<i>Staphylococcus aureus</i> infection of orthopedic devices is a major source of device failure and patient morbidity. Immunotherapy is an intriguing strategy to prevent and treat <i>S. aureus</i> device infection. Understanding mechanisms of bacterial immune evasion in device infection is a fundamental gap that must be addressed to better engineer immune-based strategies. In this study, <i>S. aureus</i> genes involved in three different immune-evasive pathways (<i>spa</i>, <i>isdB</i>, and <i>hla</i>) were studied in a well-established murine model of chronic femoral device infection. Mice underwent implant placement without infection, with infection caused by wild-type methicillin-resistant <i>S. aureus</i> strain JE2, or infection with three transposon insertion mutants for each of the genes of interest. Implants were harvested 28 days after infection to enumerate bacterial burden. Serum cytokines were assayed at Days 7 and 28, and splenic immune populations and antibody titers were assessed at Day 28 to probe host immunity. Device infection resulted in early host upregulation of Th17-associated cytokines followed by upregulation of Th1-, Th2-, and T-regulatory-associated cytokines in the chronic period, regardless of <i>S. aureus</i> genotype. Infection was associated with the expansion of splenic myeloid populations and increased anti-<i>S. aureus</i> antibody titers, although antibody production was decreased with disruption to <i>spa</i>. While all infected devices maintained a persistent bacterial burden, <i>S. aureus</i> lacking functional <i>spa</i> resulted in significantly lower bacterial burden compared with wild type infection. These results give insight into the role of bacterial immune-evasive genes and underscore the tenacity of <i>S. aureus</i> device infection. While still able to establish infection, strains lacking functional <i>spa</i> were unable to have the same burden as wild-type and <i>hla</i> mutant strains. These findings suggest that targeting these pathways and redundancies along the same immune-evasive mechanisms may assist in new immune-based therapies for <i>S. aureus</i> device infection.