Heads of Laboratories
Professor
Laboratory of Bacterial Pathogenesis and Immunology
vaf@rockefeller.edu
More than 90 percent of all infections begin at a mucous membrane site (oral, nasal, upper or lower respiratory, ocular, intestinal or urogenital). The Fischetti lab is working to understand the earliest events that occur when gram-positive bacteria interact with human tissues and cause disease. Its research is aimed at interfering with these events by: developing vaccines to induce a mucosal immune response; blocking the attachment of surface protein in the bacterial cell wall to prevent infection; and using phage lytic enzymes to both remove colonizing pathogenic bacteria to prevent infection and treat established infections.
Dr. Fischetti works with gram-positive bacteria, such as streptococci, that do not contain a second cell membrane outside of the cell wall. In the fight against infectious disease, Dr. Fischetti investigates two nonantibiotic treatment strategies. This two-pronged approach involves blocking bacteria from attaching to cells and exploring the use of phage lytic enzymes to remove pathogenic bacteria once they have colonized in the host.
To infect their host, bacteria use their surface molecules to attach and invade human tissues, particularly those that line the nose and throat. Knowledge of the process bacteria use to anchor these molecules in their cell wall could lead to strategies to prevent infection. The M protein is a surface protein that is the major virulence factor of group A streptococci because of its ability to impede attack by human white blood cells. Analysis of this molecule by Dr. Fischetti’s lab shows that the region used to attach the M protein to the cell surface is highly conserved in gram-positive bacteria, indicating that the mechanism for anchoring surface proteins in bacteria is also conserved. Since bacteria cannot cause infection without their surface proteins, a molecule that blocks surface protein attachment will be broadly applicable to different gram-positive bacteria.
Dr. Fischetti’s lab has also shown that the M protein can be used to deliver the molecules to the surface of gram-positive bacteria to be used as a vaccine. A vaccine that employs this approach could be used against a variety of harmful pathogens and is currently being tested in clinical trials. Dr. Fischetti has also identified a membrane-associated enzyme responsible for cleaving the highly conserved anchor region of surface proteins. Inhibition of this enzyme prevents both cell wall assembly and the proper attachment of most surface proteins, resulting in nearly naked bacteria. Studies are under way to further define the role of this enzyme in cell wall assembly and the protein attachment process to identify inhibitors that may be used as a new class of antibiotic.
As new antibiotics are proving futile against resistant strains of bacteria, the Fischetti lab is investigating the efficacy of lytic enzymes, which are found exclusively in viruses called bacteriophages (or phages), viruses that infect bacteria.
Dr. Fischetti’s lab has recombinantly produced lysins that will kill the major gram-positive pathogens — Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecalis and Bacillus anthracis — and has used these proteins to destroy their respective bacteria in animal models of disease. The enzymes are extremely potent; only very small amounts are needed to destroy millions of organisms within seconds of contact. They are also highly specific and unlike antibiotics, only kill the disease-causing bacteria without harming the beneficial bacteria. Dr. Fischetti’s studies have shown that when small amounts of the enzymes are administered to mice that have intentionally been infected with these bacteria, the disease-causing bacteria are rapidly destroyed. In an animal model of pneumococcus pneumonia, Dr. Fischetti has shown that systemic administration of the phage enzyme Cpl-1 can rescue mice infected with the pathogen and completely reverse lung tissue damage if given within 24 hours post-infection. Fischetti and his colleagues showed that when the enzyme is delivered to the brain of mice with pneumococcal meningitis, it effectively removes the organisms from the site. The lab has also shown that by removing colonizing S. pneumoniae from the nose of mice, they could completely prevent secondary ear infections triggered by influenza.
Using lytic enzymes as a tool, Dr. Fischetti’s lab developed a method of drilling through the thick cell walls of gram-positive bacteria while keeping them intact. The technique enabled the Fischetti lab to access the bacterial cytoplasm with labeled antibodies to study intracellular molecules that were previously inaccessible.
CAREER
Dr. Fischetti grew up in New York City, receiving his B.S. in bacteriology from Wagner College in 1962 and his M.S. in microbiology
from Long Island University in 1967. He received his Ph.D. in microbiology from New York University in 1970. Dr. Fischetti came to
Rockefeller as a postdoc in 1970 and became assistant professor in 1973, associate professor in 1978 and professor in 1990. In 1987
Dr. Fischetti received a 10-year National Institutes of Health MERIT Award that was renewed in 1997.
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