Viral infection, immunity and disease in the brain
Our laboratory studies viral infections of the brain and the immune responses to those infections, with the goal of defining how viruses contribute to disease in humans, including cancer. Over the past decade, we have developed mouse models that have enabled mechanistic insights into viral replication and spread within neurons, and the roles played by soluble immune mediators, such as chemokines and cytokines, in viral clearance.
A primary objective of our work is to understand how the immune response contributes to viral clearance from the central nervous system without inducing brain damage, such as encephalitis or edema. Using a transgenic mouse model that restricts measles virus infection to CNS neurons, we have shown that both type I and type II interferons play a crucial role in clearance. Interferons, especially the type I interferons, alpha and beta, are used clinically to dampen virus infections that are associated with human cancer, such as hepatitis C. However, we do not fully understand how these immune molecules function in vivo; thus, a manipulable animal model system will be essential for understanding their mode of action, and how they may cause CNS pathology. Moreover, immunotherapy has particular appeal for the resolution of brain tumors that are otherwise not approachable with existing surgical, radiological or chemical strategies. However, immunotherapeutic side effects, such as edema, pose a particular concern in the brain. Therefore, clarifying how a CNS immune response can occur without induction of immunopathology—as in our model system—is directly relevant to the development of immune-mediated approaches to resolve CNS tumors.
Virginia Pearson, Visiting Scientist
Yianna Yiantsos, Undergraduate Intern
O’Donnell, L.A., K. M. Henkins, A. Kulkarni, C. M. Matullo, S. Balachandran, A. K. Pattisapu, G. F. Rall. Interferon gamma induces protective, non-canonical signaling pathways in primary neurons. J. Neurochem., 135: 309-322, 2015. PMID: 26190522 PubMed
Miller, K.D., Holmgren, A.M., S.E. Cavanaugh, G.F. Rall. Bone marrow stromal antigen-2 (Bst2)/tetherin is induced by type I interferon and viral infection, but is dispensable for protection against neurotropic viral challenge. J. Virology, 89: 11011-11018, 2015. PMID: 26311886 PubMed
Cavanaugh, S.E., A.M. Holmgren, G.F. Rall. Homeostatic interferon expression in neurons is sufficient for early control of viral infection. J. Neuroimmunol, 279: 11-19, 2015. PMC4325274 PubMed
Thapa, R.J., S. Nogusa, P. Chen, J.L. Maki, A. Lerro, M. Andrake, G.F. Rall, A. Degterev, S. Balachandran. Interferon-induced RIP1/RIP3-dependent necrosis requires PKR and is licensed by FADD and caspases. Proc. Natl. Acad. Sci., 110: E3109-118, 2013. PMC3746924 PubMed
O'Donnell, L.A., S. Conway, R.W. Rose, E. Nicolas, M. Slifker, S. Balachandran, G.F. Rall. STAT-1 independent control of a neurotropic measles virus challenge in primary neurons and infected mice. J. Immunol., 188 (4): 1915-1923, 2012. PMCID: PMC3273675 PubMed
Gomme, E.A., C. Wirblich, S. Addya, G.F. Rall, M.J. Schnell. Immune clearance of attenuated rabies virus results in neuronal survival with altered gene expression. PLoS Pathogens, 8 (10): e1002971, 2012. PMCID: PMC3469654 PubMed
Matullo, C.M., K.J. O’Regan, M. Curtis, G.F. Rall. CNS Recruitment of CD8+ T Lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge. PLoS Pathogens, 7 (12): e1002462, 2011. PMCID: PMC3245314 PubMed
Matullo, C.M., K.J. O'Regan, M. Curtis, H. Hensley, G.F. Rall. Lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation. J. Virol., 84: 312-320, 2010. PMCID: PMC2798401 PubMed
Rose, R.W., A. Vorobyeva, J.D. Skipworth, E. Nicolas, G.F. Rall. Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J. Neuroimmunol, 192: 145-156, 2007. PMCID: PMC2180831 PubMed
Makhortova, N., P. Askovich, C. E. Patterson, L. A. Gechman, N. P. Gerard, G. F. Rall. Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology, 362: 235-244, 2007. PMCID: PMC1945128 PubMed
Glenn.Rall@fccc.edu
Office Phone: 215-728-3617
Lab Phone: 215-728-3677
Fax: 215-728-2412
Office: R493
Glenn.Rall@fccc.edu
Office Phone: 215-728-3617
Lab Phone: 215-728-3677
Fax: 215-728-2412
Office: R493
Viral infection, immunity and disease in the brain
Our laboratory studies viral infections of the brain and the immune responses to those infections, with the goal of defining how viruses contribute to disease in humans, including cancer. Over the past decade, we have developed mouse models that have enabled mechanistic insights into viral replication and spread within neurons, and the roles played by soluble immune mediators, such as chemokines and cytokines, in viral clearance.
A primary objective of our work is to understand how the immune response contributes to viral clearance from the central nervous system without inducing brain damage, such as encephalitis or edema. Using a transgenic mouse model that restricts measles virus infection to CNS neurons, we have shown that both type I and type II interferons play a crucial role in clearance. Interferons, especially the type I interferons, alpha and beta, are used clinically to dampen virus infections that are associated with human cancer, such as hepatitis C. However, we do not fully understand how these immune molecules function in vivo; thus, a manipulable animal model system will be essential for understanding their mode of action, and how they may cause CNS pathology. Moreover, immunotherapy has particular appeal for the resolution of brain tumors that are otherwise not approachable with existing surgical, radiological or chemical strategies. However, immunotherapeutic side effects, such as edema, pose a particular concern in the brain. Therefore, clarifying how a CNS immune response can occur without induction of immunopathology—as in our model system—is directly relevant to the development of immune-mediated approaches to resolve CNS tumors.
Virginia Pearson, Visiting Scientist
Yianna Yiantsos, Undergraduate Intern
O’Donnell, L.A., K. M. Henkins, A. Kulkarni, C. M. Matullo, S. Balachandran, A. K. Pattisapu, G. F. Rall. Interferon gamma induces protective, non-canonical signaling pathways in primary neurons. J. Neurochem., 135: 309-322, 2015. PMID: 26190522 PubMed
Miller, K.D., Holmgren, A.M., S.E. Cavanaugh, G.F. Rall. Bone marrow stromal antigen-2 (Bst2)/tetherin is induced by type I interferon and viral infection, but is dispensable for protection against neurotropic viral challenge. J. Virology, 89: 11011-11018, 2015. PMID: 26311886 PubMed
Cavanaugh, S.E., A.M. Holmgren, G.F. Rall. Homeostatic interferon expression in neurons is sufficient for early control of viral infection. J. Neuroimmunol, 279: 11-19, 2015. PMC4325274 PubMed
Thapa, R.J., S. Nogusa, P. Chen, J.L. Maki, A. Lerro, M. Andrake, G.F. Rall, A. Degterev, S. Balachandran. Interferon-induced RIP1/RIP3-dependent necrosis requires PKR and is licensed by FADD and caspases. Proc. Natl. Acad. Sci., 110: E3109-118, 2013. PMC3746924 PubMed
O'Donnell, L.A., S. Conway, R.W. Rose, E. Nicolas, M. Slifker, S. Balachandran, G.F. Rall. STAT-1 independent control of a neurotropic measles virus challenge in primary neurons and infected mice. J. Immunol., 188 (4): 1915-1923, 2012. PMCID: PMC3273675 PubMed
Gomme, E.A., C. Wirblich, S. Addya, G.F. Rall, M.J. Schnell. Immune clearance of attenuated rabies virus results in neuronal survival with altered gene expression. PLoS Pathogens, 8 (10): e1002971, 2012. PMCID: PMC3469654 PubMed
Matullo, C.M., K.J. O’Regan, M. Curtis, G.F. Rall. CNS Recruitment of CD8+ T Lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge. PLoS Pathogens, 7 (12): e1002462, 2011. PMCID: PMC3245314 PubMed
Matullo, C.M., K.J. O'Regan, M. Curtis, H. Hensley, G.F. Rall. Lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation. J. Virol., 84: 312-320, 2010. PMCID: PMC2798401 PubMed
Rose, R.W., A. Vorobyeva, J.D. Skipworth, E. Nicolas, G.F. Rall. Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J. Neuroimmunol, 192: 145-156, 2007. PMCID: PMC2180831 PubMed
Makhortova, N., P. Askovich, C. E. Patterson, L. A. Gechman, N. P. Gerard, G. F. Rall. Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology, 362: 235-244, 2007. PMCID: PMC1945128 PubMed
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
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