Toward Optimization of a Rabbit Model of Staphylococcus aureus (USA300) Skin and Soft Tissue Infection

Staphylococcus aureus remains a leading cause of skin and soft tissue infections (SSTIs) globally. In the United States, many of these infections are caused by isolates classified as USA300. Our understanding of the success of USA300 as a human pathogen is due in part to data obtained from animal infection models, including rabbit SSTI models. These animal models have been used to study S. aureus virulence and pathogenesis and to gain an enhanced understanding of the host response to infection. Although significant knowledge has been gained, the need to use a relatively high inoculum of USA300 (1 × 10⁸ to 5 × 10⁸ CFU) is a caveat of these infection models. As a step toward addressing this issue, we created mutations in USA300 that mimic those found in S. aureus strains with naturally occurring rabbit tropism-namely, single nucleotide polymorphisms in dltB and/or deletion of rot. We then developed a rabbit SSTI model that utilizes an inoculum of 10⁶ USA300 CFU to cause reproducible disease and tested whether primary SSTI protects rabbits against severe reinfection caused by the same strain. Although there was modest protection against severe reinfection, primary infection and reinfection with rabbit-tropic USA300 strains failed to increase the overall level of circulating anti-S. aureus antibodies significantly. These findings provide additional insight into the host response to S. aureus. More work is needed to further develop a low-inoculum infection model that can be used to better test the potential of new therapeutics or vaccine target antigens. IMPORTANCE Animal models of S. aureus infection are important for evaluating bacterial pathogenesis and host immune responses. These animal infection models are often used as an initial step in the testing of vaccine antigens and new therapeutics. The extent to which animal models of S. aureus infection approximate human infections remains a significant consideration for translation of results to human clinical trials. Although significant progress has been made with rabbit models of S. aureus infection, one concern is the high inoculum needed to cause reproducible disease. Here, we generated USA300 strains that have tropism for rabbits and developed a rabbit SSTI model that uses fewer CFU than previous models.