Pneumonia is a leading cause of mortality worldwide, affecting approximately 450 million people globally per year, and results in about 4 million deaths annually. Although the need for research directed toward development of new antibiotics is urgent, the need to study and better understand host immune responses has never been greater. Our previous studies identified and characterized a new member of animal heme-containing peroxidase (hPx) family, Vascular peroxidase 1 (VPO1). Like other members of the hPx family, VPO1 generates hypohalous acids and is able to kill bacteria. Our data show that VPO1-deficient mice have decreased survival in pneumonia. In addition to its catalytic domains, VPO1 has a unique N-terminus containing five leucine-rich repeats and four immunoglobulin domains, which bind with high specificity to lipopolysaccharide (LPS), and kill gram-negative bacteria. Furthermore, our data reveal that LPS causes stronger inflammatory responses in VPO1-deficient mice; VPO1 can inhibit LPS-mediated activation of Toll-like receptor 4. These results lead to our central hypothesis that VPO1 has a bifunctional role in innate immunity, both via bactericidal activities and inhibition of LPS-mediated inflammatory responses. Guided by strong preliminary data, we propose to pursue three Specific Aims: (1) define the molecular mechanisms of VPO1-mediated bactericidal activities; (2) evaluate functional roles of VPO1 in regulation of LPS-mediated inflammatory responses; (3) assess whether exogenous delivery of VPO1 restores host defense function in VPO1-deficient mice. Collectively, our proposed research will broadly impact the field by determining and characterizing a new host defense enzyme, VPO1, with dual function in bacterial killing and reduction of LPS-stimulated inflammation. These studies will uncover new molecular mechanisms of host-pathogen interaction and potentially provide a novel (beyond antibiotics) therapeutic strategy of immune-modulation to treat pneumonia and endotoxin septic shock.
. This project seeks to investigate the molecular mechanisms of VPO1-mediated bactericidal activities and the regulation of lipopolysaccharide-mediated inflammatory responses. The outcome will expand our current knowledge of lung innate immunity and fill the gap in which a novel heme peroxidase exists in lung alveoli. The identification and characterization of the new mediator in lung host defense, and elucidation of the molecular mechanisms of VPO1-mediated bacterial killing and regulation of lipopolysaccharide-mediated inflammatory responses will lead to development of a novel (beyond antibiotics) therapeutic strategy of immune-modulation to treat pneumonia and endotoxin septic shock
