Community-associated MRSA has emerged in the past decade as a major threat to public health. CA-MRSA, in particular the epidemic strain USA300, appears to be more virulent than traditional MRSA strains and has acquired greater fitness, allowing it to spread across continents. Our lab is interested in understanding the pathogenic mechanisms of USA300. We are particularly interested in probing the role of the Panton-Valentine leucocidin toxin in induction of host inflammation (Tseng PLoS ONE 2009, Lehman Clin Infect Dis 2009, Diep PNAS 2010).
|Panton-Valentine leukocidin toxin binds to murine muscle tissues.|
Bacterial immune evasion mechanisms
As a major pathogen, S. aureus has evolved many clever strategies to evade host immune clearance. Our lab is interested in identifying novel mechanisms utilized by S. aureus to thwart major host defenses. In recent years, we have identified the golden pigment of S. aureus as a virulence factor used to evade host oxidative killing (Liu PNAS 2004, Liu J Exp Med 2005). We showed that the golden pigment effectively quenches reactive oxygen species elaborated by neutrophils and promotes the survival of the pathogen. Interestingly, an initial step in the biosynthesis of the golden pigment resembles that of human cholesterol synthesis. We showed that biosynthesis of the golden pigment could be blocked using a cholesterol lowering drug and that leads to improved clearance of the pathogen (Liu Science 2008).
|Crystal structure of the S. aureus and human enzymes involved in the biosynthesis of the bacterial golden pigment and human cholesterol, respectively.|
Host antimicrobial mechanisms
In collaboration with Dr. Phil Koeffler (Cedars-Sinai), we studied S. aureus infection in mice with specific granule deficiency (SGD), a condition caused by mutations in the CEBP epsilon gene. We demonstrated that SGD mice are exquisitely susceptible to S. aureus and neutrophil defect contributes significantly to the infection. Conversely, we showed that CEBP epsilon can be upregulated in mature neutrophils by treatment with vitamin B3 or nicotinamide, and this enhances clearances of S. aureus in murine infection models (Kyme J Clin Invest 2012).
In a different project, we studied the impact of aging on susceptibility to S. aureus infection. We showed that aging is associated with impaired neutrophil function and neutrophil NETs. This in turn facilitates systemic spread of S. aureus (Tseng PLoS ONE 2012).
|Systemic dissemination of S. aureus in young and aged mice.|
Novel antibacterial therapeutics
Multidrug resistant gram-positive and gram-negative pathogens are becoming increasingly prevalent, but the drug pipeline appears unable to keep up with the clinical need. Our lab investigates various approaches to combat infections based on understanding of host- S. aureus interaction. We seek to weaken the bacterial armor or boost host immunity to tilt the balance in favor of the host (Liu J Exp Med 2005, Liu Science 2008). We also investigate the use of commensals to prevent S. aureus colonization of the human mucosal surfaces (Park PLoS ONE 2011). Additionally, in collaboration with Dr. Ramachandran Murali, we are developing and testing novel inhibitors against Klebsiella pneumoniae carbapenemase.