Staphylococcus aureus is the major cause of skin infection, ranging from cutaneous abcess to celluliltis and folliculitis. It has a well-recognized capacity to exhibit antibiotic resistance, limiting treatment options. Methicillin-resistant S. aurus (MRSA) was traditionally a nosocomial pathogen but community-associated MSRA clones have emerged as a cause of severe necrotizing cutaneous infection, particularly in young, previously healthy children. Better preventive and therapeutic options are important but a major deficiency is a lack of an effective vaccine. Our long-term goal is to reduce the burden of MRSA skin infection by developing broadly-effective immunotherapeutics and vaccines based on a deep understanding of host-microbial interactions and molecular mechanisms of bacterial pathogenesis. Leukotriene B4 (LTB4) is a potent lipid mediator produced during inflammation that is a well-known neutrophil chemoattractant. We have shown that LTB4 enhances macrophage phagocytosis and killing against different classes of pathogens (including Streptococcus pneumoniae and Leishmania amazonensis). In addition, we discovered that LTB4 is needed for optimal expression of the Toll-like receptor adaptor Myeloid Differentiation Factor -88 (MyD88) in macrophages. We newly hypothesize that LTB4 will improve host defense against MSRA. More specifically, we speculate that LTB4 will enhance innate immune responses, such as macrophage phagocytosis and killing, neutrophil leukocyte recruitment, and LTB4 will amplify cellular responsiveness to MRSA by enhancing MyD88 expression. We propose the following innovative Specific Aim: Investigate whether LTB4 enhances cutaneous MRSA clearance. Our objective is to investigate the extent to which LTB4 can be used as a novel immunotherapeutic agent against MRSA. Our in vivo experiments will test the immunoprotective actions of LTB4 and will reveal the signaling programs elicited by LTB4 that enhance host defense. Due to the known actions of LTB4 that enhance immune defenses in vivo, we predict that this lipid will exhibit potent immunotherapeutic properties in both lung and skin MRSA infection.
Methicillin-resistant S. aureus is a major public health threat worldwide, and both treatment protocols and vaccine development is an area of major interest. Virulent MSRA clones have emerged as a cause of severe skin and soft tissue infection. In this proposal, we are planning on employing a successful protocol on both treatment and prevention of MSRA infection by employing a potent bioactive lipid, LTB4, to enhance host defense in murine models.
