Strains of Staphylococcus aureus (S. aureus) differentially impact healing outcomes in a variety of skin environments including in diabetic wounds. However, the role of S. aureus infection and S. aureus strain-level variation has not been explored during cutaneous leishmaniasis (CL). Leishmania is a neglected tropical parasite that infects an estimated 1 million people every year and causes a variable spectrum of disease ranging from single, healing lesions to chronic, non-healing lesions. Current standard-of-care treatment involves intravenous injections of pentavalent antimony which is ineffective at resolving disease in up to 60% of cases, despite a reduction in parasite burden. As a result, there is an urgent need to develop more effective treatment strategies against leishmaniasis. We hypothesize that the skin microbiome prolongs inflammation and delays healing in CL lesions, making it useful to study in the identification of novel anti-CL therapeutics. In Chapter 2, we show that S. aureus is the most common bacteria cultured from leishmaniasis lesions and that S. aureus exacerbates disease through the IL-1β pathway. In Chapter 3, we establish for the first time the importance of S. aureus strain-level variation in disease and show that more severe isolates of S. aureus delay healing through increased bacterial survival and elevated secretion of IL-1β by neutrophils compared to less severe isolates. In Chapters 3 and 4, we establish the importance of S. aureus strain-dependent evasion of bacterial killing by neutrophils in the context of diabetic wounds and in CL. Together, our data supports a model in which infection by more severe isolates of S. aureus leads to delayed healing through a positive feedback loop of elevated IL-1β secretion by host tissue, followed by chronic neutrophil recruitment, and enhanced bacterial survival to neutrophil killing, ultimately resulting in bacterial persistence and chronic inflammation. These findings provide insight into novel immune-based pathways that could be targeted in the treatment of leishmaniasis and identify bacterial-derived phenotypes that predict poor healing outcomes during S. aureus infection.