We continue to see significant advances in the treatment of cancer including specifically targeted chemotherapy, radiation, and hematopoetic stem cell transplantation that have allowed for increased survival among cancer patients. Despite such advances, these treatments come with a wide range of side effects, one of which includes decreased ability of the patient to respond to infections. This, coupled with prolonged hospitalizations, makes the cancer patient at increased risk for health-care associated infections and such infections contribute to significant mortality among cancer patients. The bacterium Pseudomonas aeruginosa (PA) is a common infection among patients with weakened immune systems. P. aeruginosa is responsible for a variety of infections including pneumonia, urinary tract infection, and bacteremia especially in immunocompromised cancer patients. In addition, PA has become more difficult to treat as it becomes increasingly resistant to most, if not all, available antibiotics. This study seeks to improve treatment options for PA infections in patients with cancer by exploring the role that known and novel virulence factors play in the severity of PA bloodstream infections. Using animal modeling and advanced microscopy, we will explore the role that various bacterial secreted proteins play in the ability of PA to resist clearance by the liver. The liver plays a critical role in the clearance of bacterial pathogens from the bloodstream. P. aeruginosa employs a secretion system known as the type III secretion system (T3SS) to intoxicate and kill host cells. We will examine the role that type III secretion plays in bacterial survival in the liver during disseminated infection. In addition, using the sequenced genomes from 102 clinical strains of PA isolated from the bloodstream of patients, we will undertake a search for new T3SS proteins important for bacterial persistence during bloodstream infection. Genes encoding candidate T3S proteins will be deleted from highly virulent strains and examined for infection severity in animal models. By identifying novel T3S proteins with a role in PA bloodstream infections, we will gain a better understanding of which infected patients may be at greater risk for disseminated infection. In addition, these proteins serve as new targets for novel antibacterial drug development. Overall, insights into the mechanisms of bloodstream infection by PA offered by this study will help to improve quality of life and survival among patients undergoing treatment for cancer.
|Effective start/end date||7/1/17 → 9/9/19|
- American Cancer Society (130602-PF-17-107-01-MPC)
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