Surgical revision of S. aureus infection increases virulence factor expression and activates a multi-tissue inflammatory response

Surgical revision of infection can involve multiple procedures. Each revision activates a tissue injury response and disrupts the established bacterial biofilm. However, it is not well understood how the bacteria, immune system, and overall tissue environment coordinate their response to revision. Our results show that immunological niches already compromised by infection – such as the bone marrow, lymph nodes, and circulating blood – further upregulate pro-inflammatory programs in response to revision surgery. This enhanced inflammation at the incision site has no effect on reducing bacteria numbers. Instead, it leads to increased expression of virulence factors, enhanced tissue remodeling, and damage including bone osteolysis and muscle fibrosis. Whereas muscle fibrosis appears to resolve 14 days post-revision, osteolysis continues to progress. These findings show that revision surgery negatively impacts all tissues within the surgical site. It is therefore essential to question the risks and benefits of each revision on a case-by-case basis. Further, understanding the timing and tissue changes associated with revision of infected orthopedic sites will help inform the design of additional interventions to minimize tissue damage and maximize bactericidal effects. Overall design: Gene expression was compared between uninfected and infected surgical incisions in Sprague-Dawley rats at a pre-revision surgery timepoint and between infected pre-revision rats and infected rats at three different timepoints (6 hours, 4 days, and 14 days post-revision). An index surgery created an initial incision, and revision surgery (and the pre-revision surgery timepoint) occurred 7 days after index. The rats were euthanized either pre-revision (7 days post index), 6 hours post-revision (7 days + 6 hours post-index), 4 days post-revision (11 days post-index), or 14 days post-revision (21 days post-index). The biceps femoris muscle was excised on the day of euthanasia for each rat and snap frozen. RNA was extracted from the snap-frozen muscle and sequenced at Novogene.