Vincent A. Fischetti (born 1940) is a world renowned American microbiologist and immunologist. He is Professor of and Head of the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller University in New York City. His Laboratory is the oldest continuous laboratory at Rockefeller that started in 1926 and headed by 4 leading scientists over its near 100-year history: Homer Swift, Maclyn McCarty, Emil Gotschlich and now Vincent Fischetti. Keeping with the historical theme of infectious diseases, Fischetti's primary areas of research are bacterial pathogenesis, bacterial genomics, immunology, virology, microbiology, and therapeutics. He was the first scientist to clone and sequence a surface protein on gram-positive bacteria, the M protein from S. pyogenes, and determine its unique coiled-coil structure. He also was the first use phage lysins as a therapeutic and an effective alternative to conventional antibiotics.^[1][2]

Research

Fischetti became an assistant professor at Rockefeller University in 1973, an Associate Professor 1978, and a full Professor in 1990. He later served as the editor-in-chief of scientific journal, Infection and Immunity for 10 years and section editor of the Journal of Immunology for 5 years.^[3] In 1989, the journal Science published Fischetti's initial approaches to developing a Streptococcus pyogenes vaccine using an M-protein-based mucosal delivery approach, which he had developed and found effective at preventing non-type-specific streptococcal infections in mice. The Fischetti laboratory was also instrumental in our understanding of how surface proteins are anchored in the gram-positive bacterial cell wall. His lab identified the LPSTG signal sequence used by the transpeptidase sortase as the anchoring signal. By the late 1900s, he was exploring the impact of phage lysins, a novel form of antimicrobial ammunition, as an alternative to antibiotics, and found it to be a novel solution to target specific antibiotic resistant bacteria.^[4][5][6] In 2006, Fischetti was developing a lysin-based oral-nasal spray that can be delivered into the noses and mouths of hospital and nursing-home patients to prevent colonization by MRSA staphylococci.^[7] Tests on mice infected with MRSA found their survival rate was significantly improved, and human testing began in 2017.^[8] He has since accumulated 'near 40 patents' most dealing with methods to prevent bacterial infections. One such patent dealing with lysins to Acinetobacter was licensed by Bioharmony Therapeutics, Inc in 2019.^[9] Several other lysin patents were licensed by ContraFect, a biotech company based in Yonkers NY. ContraFect developed a Staphylococcal lysin that successfully completed FDA phase 1 and phase 2 human clinical trials, the only alternative to antibiotics to achieve these milestones. His postdoctoral students include microbiologist Olaf Schneewind, who identified sortase after leaving the Fischetti lab.^[10] Some of Fischetti's popular videos include those dealing with the topic: 'aged eggnog made with raw eggs is safer than drinking it fresh'.^{[11][12][13][14]}

Personal life and Career

Fischetti grew up in West Hempstead, Long Island, NY, and enrolled at Wagner College on a pre-dental track, before majoring in bacteriology and public health.^[2] He graduated in 1962, and went on to receive his master's degree in microbiology from Long Island University in 1967 and a Ph.D. degree with honors (Founders Day Award) in microbiology from New York University School of Medicine in 1970 under Alan Bernheimer.^[2] He later conducted postdoctoral research in the Maclyn McCarty laboratory at Rockefeller University with John Zabriskie and Emil Gotschlich. After receiving a Helen Hay Whitney Foundation fellowship he spent a year at Albert Einstein College of Medicine under Barry Bloom, working on the isolation of cytokines. Fischetti then returned to the McCarty lab at Rockefeller University to work on M protein. In 1974 he was appointed Assistant Professor and received his first NIH grant to study M protein, which began a project that was funded for 37 continuous years, 20 of which were 2 consecutive 10-year NIH MERIT awards (he was the first to receive consecutive MERIT awards).^[15]

Fischetti has been referred to as the "father of phage lysins" since his laboratory was the first to use phage lysins as therapeutics. But this finding occurred later in his career. His studies on the M protein of S. pyogenes revealed many basic discoveries regarding the way surface proteins on gram-positive bacteria were anchored to the peptidoglycan. These findings had critical implications for vaccine development for gram-positive pathogens including streptococci.

Fischetti published >250 articles, nearly 100 book chapters, and has coedited several books, the most popular of which is the ASM book Gram-Positive Pathogens, now in its 3rd edition. He has been the editor-in-chief of Infection and Immunity for 10 years and Section Editor of J. of Immunology for 5 years. He is a Fellow of the National Academy of Inventors because of his >40 issued patents. He is also a Fellow of the NY Academy of Sciences and received a Research Career Development Award from the NIH early in his career.

Major Contributions to Science

1. The Coiled Coil Structure of Streptococcal M Protein. His lab was the first to clone and then sequence the M protein making it the first surface protein on gram-positive to be cloned and sequenced. As such, the M protein was the archetypical molecule for surface proteins on gram-positive organisms. The Protein A sequence was published just before the M protein but there was a sequencing error near the C terminus that was corrected after the M protein sequence was published. Subsequent sequence data showed that the N-terminal region was the type-specific portion of the molecule and the C-terminal half was conserved among the many M proteins that are known. This latter information allowed for strains to be typed genetically based on the variability of the N-terminal sequence rather than the cumbersome and expensive serological typing scheme developed by Rebecca Lancefield. All this information about the M molecule had significant implications in vaccine development as well as streptococcal evolution. (https://doi.org/10.1073/pnas.78.8.4689)( https://doi.org/10.1016/S0021-9258(17)35993-8 )

2. Surface Protein Anchoring in Gram-Positive Pathogens. The Fischetti lab identified a motif (LPXTG) that was common among nearly all surface proteins on gram-positive bacteria. It was later proved that this motif was an anchoring signal for surface proteins on gram-positive bacteria. This information is now critical for the development of anti-infectives and vaccines. Also, by searching the bacterial sequence database for molecules with an LPXTG motif close to their C-terminii, the surface location of the molecules in the bacterial cell can be predicted. This finding lead to the identification of sortase, the transpeptidase responsible for the anchoring process. Inhibition of sortase activity by a small molecule can render the organism non-virulent and easily cleared by the immune system. (https://doi.org/10.1111/j.1365-2958.1990.tb02072.x)

3. Identification of Biologically Active Surface Proteins on S. pyogenes. Other than M protein, not much was known about the surface proteins on S. pyogenes that may be important in their pathogenesis. The Fischetti lab systematically identified several important molecules that could play a role in their pathogenesis and the antiphagocytic activity of the M protein. An important group of molecules were five contiguous glycolytic enzymes that are normally found in the cytoplasm but are located on the cell surface in a complex with the ability to produce ATP. Many of these same molecules are located on other pathogens such as S. aureus, S. pneumoniae, Candida and Trypanosomes and reported to be associated with autoimmune diseases. (https://doi.org/10.1084/jem.176.2.415)

4. Role of Bacteriophage in Disease and Bacterial Survival. Bacteriophages are prevalent in the environment and from bacterial genome sequence, it appears that they are also common inhabitants of nearly all bacteria. However, while phage carry virulence determinants on their genomes, their role in pathogenesis was poorly understood. For the first time the Fischetti lab showed that lysogenic bacteriophages are activated in vivo in the presence of a small molecule found in saliva. This implies that lysogenic phage could sense their environment and mobilize themselves or molecules for their survival. This is clearly seen in B. anthracis, where it was shown that when vegetative organisms enter the soil, they become lysogenized by soil phage, converting them to free living organisms able to survive in the soil. They also found that while lysogeny is defined as phage incorporation in the bacterial host DNA, there is a prevalence of plasmodial phage in the cytoplasm of pathogens (particularly B. anthracis and S. aureus) that contain virulence determinants that would be missed during normal bacterial genome sequencing. Thus, the Fischetti lab has identified a potential reservoir of virulence genes that have not been previously considered.(https://doi.org/10.1128/iai.71.7.3782-3786.2003)

5. Lysins as Novel Therapeutics. Given the increase in antibiotic resistance by pathogenic bacteria, new methods must be devised to control these pathogens. The Fischetti laboratory was the first to perform experiments to determine if phage lysins may be used therapeutically. Mice orally colonized with S. pyogenes were subsequently treated with one dose of lysin orally. After treatment, the mice were found to be decolonized of their streptococci. This was the first publication describing the therapeutic effects of phage lysins. During the ensuing years, the Fischetti laboratory developed phage lysins against all of the major gram-positive pathogens and now have lysins against both gram-negative pathogens, including the ESKAPE pathogens. A staphylococcal-specific lysin that the Fischetti lab developed is currently in phase 3 human clinical trials and if successful, could be the turning point for the widespread therapeutic use of lysins. (https://doi.org/10.1073/pnas.061038398) (https://doi.org/10.1016/j.tim.2005.08.007).

6. Lysibodies: Engineered Immunoglobulins to Control S. aureus. The cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a notoriously poor immune response. The Fischetti lab has been successful in engineering a hybrid IgG molecule called a “Lysibody” that is a human IgG1 directed to carbohydrate epitopes in the bacterial cell wall. Lysibodies are engineered immunoglobulin, combining in a single molecule a high-affinity carbohydrate-binding domain from enzymes of bacterial or bacteriophage origin (the Fab), and the Fc effector portion of human IgG1, forming a hybrid immunoglobulin with all the effector functions of normal human IgG. Currently, there are no vaccines or immunoglobulins against S. aureus since most antibodies are directed to protein targets that can vary among different strains, and their expression is also variable. A lysibody directed against methicillin resistant Staphylococcus aureus (MRSA) is currently in pre-clinical development to be used as prophylaxis in pre-surgical and dialysis patients and neonates to prevent MRSA and other staphylococcal infections.(https://doi.org/10.1073/pnas.1619249114)

7. The Trigger for Multiple Sclerosis. Multiple Sclerosis (MS) is a serious neurological disease that often affects young adults. Despite its impact on human health, the cause of this disease remains unknown. Over the past decade, Fischetti lab members (particularly Rashid Rumah) and their collaborators at Weill Cornell made a groundbreaking discovery, linking a gut-derived bacterial neurotoxin, called epsilon toxin (ETX), to MS. ETX is produced by the gut bacterium, Clostridium perfringens, and may be responsible for the MS trigger. In early 2023, we published a seminal paper in JCI (https://doi.org/10.1172/JCI163239) showing that ETX-producing C. perfringens bacteria could be identified in the intestines of 61% of MS patients compared to 13% of healthy individuals. Furthermore, MS patients who were ETX positive carried 1,500-fold more C. perfringens in their intestines than healthy individuals who were asymptomatic carriers. Lastly, we showed that ETX triggers MS-like brain lesions in experimental rodents that better approximate the regional brain distribution of human MS lesions, compared to more traditional animal models of MS. This agrees with earlier work where we showed that ETX binds to and damages both the blood brain barrier and brain myelin, further linking ETX to MS.(https://doi.org/10.1172/JCI163239) (https://doi.org/10.1371/journal.pone.0076359)

Companies Founded

Fischetti founded several biotech companies based on technology developed in his laboratory. The first, M6 Pharmaceuticals a David Blech company filed in 1994, developed mucosal anti-infective vaccines, but failed due to funding issues. It was reincarnated as Siga Technologies in 1995, and has now morphed into a company developing smallpox and monkeypox therapeutics. The third, Contrafect Corporation, was a biotech started by Robert Nowinski in 2008 on technology that did not fully materialize. ContraFect then licensed the Fischetti laboratory lysin technology in 2009 and is now developing lysin therapeutics as its sole technology. The fourth, Astoria Biologica, was founded in 2023 on technology conceived by an MD-PhD student working in both the Fischetti laboratory and Vartanian laboratory at Weill Cornell Medicine to develop therapeutics to treat and prevent multiple sclerosis.

Trainees

Trainees (43): Kevin Jones, Sheenah Mische, Deborah Bessen, Vijay Pancholi, Olaf Schneewind, Anu Vashishtha, Ambrose Cheung, Jasna Raconjac, Donata Medaglini, Ursula Fluckiger, Yoshi Shimoji, Claudia Rocha, Anne Bouvet, Patricia Fontan, Thomas Broudy, Daniel Nelson, Jutta Loeffler, Raymond Schuch, Sung Lee, Ann Derbis, Mathias Collin, Pauleen Yoong, Chad Euler, Patricia Ryan, Jonathan Schmitz, Assaf Raz, Mia Pastagia, Anu Daniel, Monica Fazzini, Greg Resch, Daniel Gilmer, Sherry Kan, Roberto Diez, Rashid Rumah, Rolf Lood, Brian Utter, Uri Sela, Douglas Deutsch, A. Tabata, Ryan Heselpoth, Juliette Wipf, Christopher Cheleuitte-Nieves, Edmondo Campisi

References

External links

• Research Links
• Search Results for author Fischetti VA on PubMed.
• Web Site: http://www.rockefeller.edu/vaf