McFadden, Grant: Professor
Dr. Grant McFadden’s scientific expertise is on the nature of how viral pathogens interact with the host immune system. Over the past two decades his lab has studied a variety of strategies that poxviruses in particular have evolved to evade, subvert, suppress or micro-manipulate the various host defense pathways. This work has generated several hundred scientific articles or reviews from the lab on the subject of virus-host interactions. He is best known as a key originator of the more general discipline of “anti-immunology”, or the study of pathogen evasion of the immune system. His lab’s work has spun off a variety of new initiatives, including the co-founding (with Dr. A. Lucas) of a biotech company (VIRON Therapeutics) in Canada. VIRON is the first company to be devoted to developing anti-immune molecules from viruses as novel drugs to treat immune-based and inflammatory diseases in humans. Their lead compound (VT 111), a viral serpin, is extremely promising as a very effective means of controlling inflammation and is now in Phase II human clinical trials. search Interests:
The McFadden lab has also studied the mechanisms that determine the tropism and host range of viruses for host species, and they are examining the molecular basis operative when poxviruses cause zoonotic infections in man. As a side-product of this research, they are developing specific viruses as novel candidates for the oncolytic treatment of human cancers, and have already successfully treated neural gliomas in mouse models of glioblastoma using this strategy. This work has led to further collaborations with companies interested in pathogen countermeasures (Myriad Corp) and oncolytic virotherapy (Wellstat Corp). All of these projects have convinced Dr. McFadden that the continued study of pathogens, and in particular the study of the fundamental mechanisms that regulate their emergence and thus dictate how they leap from one host species to another, is itself a new and emerging discipline whose time has arrived.
As a leading poxvirus investigator, biotech entrepreneur and international expert in bio-terrorism, Dr. McFadden is a scientific thinker in great demand. His laboratory studies how proteins created by viruses work to help those viruses evade detection by the immune systems of their hosts. The work aims to understand the precise mechanisms that allow viruses to live in the body, often for many years, without succumbing to attack by the inflammatory process associated with the normal immune response to a foreign invader.
It is an approach that has led to the development of a number of potential new anti-inflammatory agents. It builds on a seminal finding by University of Florida cardiologist and scientist, Dr. Alexandra Lucas, who in 1996 was the first to demonstrate that viral proteins work like a drug to inhibit the reformation of arterial plaque – the build-up that leads to clogged arteries – after angioplasty, a medical expansion procedure used to improve blood flow in diseased arteries. This unique finding led Drs. Lucas and McFadden to establish a Canadian-based biotech company called Viron Therapeutics Inc., which is currently exploring expansion options in Florida.
Poxviruses infect a broad spectrum of vertebrate hosts but the basis for the host range specificity exhibited by individual virus isolates is poorly understood. Myxoma virus (MV) is a poxvirus that causes lethal infection only in rabbits, but the mechanism underlying the strict MV species tropism is not known. Like all poxviruses, myxoma virus expresses a wide array of immunomodulatory proteins, but relatively few of these are actually rabbit-specific when tested in vitro. In fact, at least one such species-nonspecific immunomodulatory protein derived from myxoma virus, SERP-1, is currently in human clinical trials as an anti-inflammatory drug. The lab has investigated the molecular basis for tropism specificity of poxviruses, using the MV model system.
The McFadden lab has shown that MV infection of nonpermissive primary mouse embryo fibroblasts (pMEFs) evokes the activation of interferon (IFN) regulatory factor-3 (IRF3) and induces type I IFN, which aborts the virus infection. The McFadden lab discovered that disruption of signal transducer and activator of transcription 1 (STAT1)-mediated IFN signaling breaks the cellular blockade to MV multiplication in non-rabbit cells. Moreover, STAT1 deficiency renders mice highly susceptible to lethal MV infection. This work has prompted the McFadden lab to investigate the use of myxoma virus as an oncolytic virus to treat human cancers that exhibit defective interferon responses. Most recently, they have shown that the ability of human cancer cells to support the productive replication of MV is related to the activation state of the Akt signaling pathway of the cell. Thus, the ability to regulate the host cell Akt signaling pathway makes it possible to alter the permissiveness of human cancer cells for infection by MV.
The study of host tropism by poxviruses thus offers the potential for development of novel platforms for replication-restricted vaccine vectors and oncolytic viruses, but it also likely to produce novel insights into how and why poxviruses can occasionally leap from a long-term evolutionary host species to cause zoonotic infections in humans. In fact, there is a real need to better understand the dynamics of how “emerging” viruses in general can occasionally leap into non-evolutionary hosts to cause novel disease. There is a growing consensus that, unlike many other viruses where tropism is dependant upon the expression of specific cellular receptors, poxviruses can bind and enter almost all mammalian cells. In contrast, it is the specific the ability of any individual poxvirus to micro-manipulate signaling pathways of the infected cell that determines whether the infection will be permissive or not.
Ph.D., McGill University (Biochemistry), Montreal, Quebec
Postdoctoral Training, The University of Western Ontario, London, Ontario
American Society of Microbiology, Fellow
ASM Division E. Lecture Award, New Orleans
Allan Granoff Lecturer Award, St. Jude’s Hospital
Hellmuth Prize for Research Excellence
Marcel-Piche Lectureship, Clinical Research Institute of Montreal
Bill Joklik Lectureship, Am. Society for Virology
Co-founder, Viron Therapeutics, Inc.
2005 Prix Gallien Award winner, (to Viron Therapeutics, Inc.)
Canada Research Chair in Molecular Virology
Royal Society of Canada, Fellow
Canadian Academy of Health Sciences, Fellow
Howard Hughes Medical Institute International Scholarship
Key Research Issues:
Discover novel viral proteins that inhibit inflammatory processes.
Analyze the role of intracellular signaling in poxvirus tropism.
Develop poxviruses for oncolytic therapeutics.