We propose to examine the molecular pathways that mediate the species specificity and tropism of one particular poxvirus, namely myxoma virus (MV). MV is a rabbit-specific poxvirus that induces distinctly different disease profiles depending on the specific rabbit species but is nonpathogenic for every other host species, including man. Our lab has extensively studied MV and the disease it causes in rabbits, called myxomatosis, as a model system to investigate the fundamental principles of poxvirus pathogenesis, particularly by exploiting our large and growing collection of targeted MV gene knockout constructs. Several years ago, we unexpectedly discovered that primary mouse cells, which are normally nonpermissive for MV infection, could be rendered fully permissive by interrupting the cellular interferon (IFN) responses. This work then led to the discovery that the majority of human cancer cells tested were fully permissive for MV and that MV is remarkably effective as oncolytic therapy for the treatment of human cancer xenografts in a variety of animal models. We also discovered that two viral host range factors (M-T5 and M063) were also critical for permissive MV replication in many human cancer cells and we could manipulate viral permissiveness and oncolysis through these viral proteins and their host cell protein targets. Finally, our most recent observation related to this proposal is that primary human cells are protected from MV infection synergistically by IFN and tumor necrosis factor (TNF). We propose to: 1- Evaluate the roles of viral host range factors in MV tropism for human cancer cells. We propose to analyze the interactions of MV host range proteins with host cell signaling molecules (like Akt) by mutagenesis, siRNA knockdowns, signaling inhibitors and protein microarrays. We will test a number of adjunct strategies, like signaling modifier drugs used for cancer chemotherapy in man, to increase MV oncolytic potential for a wider spectrum of human cancer cells. 2- Investigate the role of host IFN and TNF responses in MV tropism. We will study MV knockout viruses that are deleted in several key viral host range genes to investigate their roles in inhibiting IFN or TNF responses, and modulating MV tropism and oncolysis. This new information will allow for more rational approaches to optimizing MV virotherapy against a wider spectrum of human cancers, and for controlling MV replication in primary noncancerous human cells.

Public Health Relevance

Previously, our studies on poxvirus pathogenesis were more focused on studying the basic mechanisms by which one particular rabbit-specific poxvirus called myxoma virus (MV) causes disease in the rabbit host. Recently, we discovered that MV also infects and kills a wide spectrum of human cancer cells and we have now used MV to successfully treat several types of cancers in animal models. In this proposal, we will study two key viral host range factors and their cellular signaling pathway targets in order to assist the preclinical development of MV as a new oncolytic therapeutic for cancer in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080607-04
Application #
8231980
Study Section
Virology - B Study Section (VIRB)
Program Officer
Challberg, Mark D
Project Start
2009-03-16
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$353,852
Indirect Cost
$108,827
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Liu, Jia; McFadden, Grant (2015) SAMD9 is an innate antiviral host factor with stress response properties that can be antagonized by poxviruses. J Virol 89:1925-31
Boutard, Bérengère; Vankerckhove, Sophie; Markine-Goriaynoff, Nicolas et al. (2015) The α2,3-sialyltransferase encoded by myxoma virus is a virulence factor that contributes to immunosuppression. PLoS One 10:e0118806
McKenzie, Brienne A; Zemp, Franz J; Pisklakova, Alexandra et al. (2015) In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells. Neuro Oncol 17:1086-94
Bell, John; McFadden, Grant (2014) Viruses for tumor therapy. Cell Host Microbe 15:260-5
Lamb, Stephanie A; Rahman, Masmudur M; McFadden, Grant (2014) Recombinant myxoma virus lacking all poxvirus ankyrin-repeat proteins stimulates multiple cellular anti-viral pathways and exhibits a severe decrease in virulence. Virology 464-465:134-45
Chan, Winnie M; McFadden, Grant (2014) Oncolytic Poxviruses. Annu Rev Virol 1:119-141
Haller, Sherry L; Peng, Chen; McFadden, Grant et al. (2014) Poxviruses and the evolution of host range and virulence. Infect Genet Evol 21:15-40
Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing et al. (2014) Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus. Cancer Res 74:7260-73
Lemos de Matos, Ana; McFadden, Grant; Esteves, Pedro J (2014) Evolution of viral sensing RIG-I-like receptor genes in Leporidae genera Oryctolagus, Sylvilagus, and Lepus. Immunogenetics 66:43-52
Doty, Rosalinda A; Liu, Jia; McFadden, Grant et al. (2013) Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma. Oncolytic Virother 2:1-17

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