Prevention of Pseudomonas Infection with anti-PcrV

Spack, Edward

Abstract

We propose an innovative approach to prevent Pseudomonas aeruginosa infection by blockade of a critical Type III secretory protein with monoclonal antibodies. Pseudomonas causes disease by the release of exotoxins which destroy host tissue and paralyze the phagocytic mechanism of macrophages. To be active, many toxins require translocation from the interior of the bacteria directly into the eukaryotic cell. This translocation (type Ill secretory mechanism) is accomplished by a group of proteins which form a channel from the interior of the bacterium to the interior of the host cell. Preliminary work has shown that one of the type Ill secretory proteins, PcrV, is critical for translocation of toxins into the host cell. Blockade of this protein with active immunization or passive immunization with polyclonal antibodies prevents infection with P. aeruginosa in a murine model of pneumonitis. The overall goal of this Phase I proposal is to develop a murine monoclonal antibody to PcrV to prevent infection with P. aeruginosa. This work should establish proof of principle that a monoclonal antibody to PcrV can prevent infection, thus supporting the development of human monoclonal antibodies as a preventive therapy in patients at high risk for P. aeruginosa infection.

Proposed Commercial Applications

Pseudomonas aeruginasa is a major cause of hospital-acquired infection, accounting for 20% of nosocomial pneumonias,10-15% of nosocomial urinary tract infections and 10% of sepsis. In addition, P. aeruginosa infection is the major cause of mortality in cystic fibrosis. Current treatment is associated with a high rate of antibiotic resistance and a 25-50% failure rate. The proposed treatment provides a novel approach to the prevention of P. aervginosa infection in patients at high risk for this infection, including patients on ventilators, bum patients, patients with in-dwelling catheters, neutropenic patients, and patients with cystic fibrosis.