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.

Vancomycin Resistance in Staphylococcus aureus
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The evolution of Staphylococcus aureus during the modern antibiotic era has been delineated by distinct strain emergence events, many of which include acquisition of antibiotic resistance. The relative high burden of methicillin-resistant S. aureus (MRSA) in healthcare and community settings is a major concern worldwide. Vancomycin, a glycopeptide antibiotic that inhibits cell wall biosynthesis, remains a drug of choice for treatment of severe MRSA infections. S. aureus strains exhibiting increased resistance to vancomycin, known as vancomycin intermediate-resistant S. aureus (VISA) (MIC = 4-8 µg/mL), were discovered in the 1990s. The molecular basis of resistance in VISA is polygenic and involves stepwise mutations in genes encoding molecules predominantly involved in cell envelope biosynthesis. S. aureus isolates with complete resistance to vancomycin (MIC ≥ 16 µg/mL) are termed vancomycin-resistant S. aureus (VRSA)-they were first reported in the U.S. in 2002. Resistance in VRSA is conferred by the vanA gene and operon, which is present on a plasmid. Although treatment of VRSA infections is challenging, the total number of human VRSA infections to date is limited (14 in the U.S.). By comparison, the burden of VISA is relatively high and the molecular mechanisms of resistance are less well-defined. VISA are associated with persistent infections, vancomycin treatment failure, and poor clinical outcomes. Here, we review in brief progress made toward understanding the acquisition of antibiotic resistance in S. aureus, with an emphasis on the molecular mechanisms underlying vancomycin resistance.

Evasion of Neutrophil Killing by Staphylococcus aureus.

Staphylococcus aureus causes many types of infections, ranging from self-resolving skin infections to severe or fatal pneumonia. Human innate immune cells, called polymorphonuclear leukocytes (PMNs or neutrophils), are essential for defense against S. aureus infections. Neutrophils are the most prominent cell type of the innate immune system and are capable of producing non-specific antimicrobial molecules that are effective at eliminating bacteria. Although significant progress has been made over the past few decades, our knowledge of S. aureus-host innate immune system interactions is incomplete. Most notably, S. aureus has the capacity to produce numerous molecules that are directed to protect the bacterium from neutrophils. Here we review in brief the role played by neutrophils in defense against S. aureus infection, and correspondingly, highlight selected S. aureus molecules that target key neutrophil functions.