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Glenn F. Rall, PhD

Glenn Rall, PhD
About

Professor

Chief Academic Officer

 

Research Program

Lab Overview

The focus of the work in my laboratory is to explore how the immune response functions in the central nervous system following viral infection.  Specifically, we aim to define principles that govern T cell and interferon biology following neuronal infections with multiple RNA viruses, such as influenza A virus, measles virus, and the mouse pathogen, lymphocytic choriomeningitis virus.  Over the past 25 years, we have discovered novel roles for antiviral cytokines in neuronal survival, defined the mechanisms of trans-synaptic transport of viruses within the brain, and, perhaps most importantly, characterized how invasion of the brain by viruses can lead to both short-term and long-term disease. Because our observations define the “rules” that govern immunity in the brain, our work is therefore also relevant to the development of immunotherapeutic approaches to treat CNS tumors.  

 
Figure 1. Neurons become productively infected with influenza. Representative confocal microscopy images of uninfected (left) or IAV-WSN (MOI=1) infected (right) primary hippocampal neurons at 24 hours post infection (hpi). Cells were stained for nuclei with Hoechst (blue), influenza NP (green), and neurons for MAP2 (red). Magnification=40X.
Figure 2. Defining the heterotypic transfer of MV from neurons to astrocytes within the CNS. Once MV reaches the synaptic cleft, it induces fusion of neuronal cell membranes in a CD46-independent manner. In parallel, MV nucleoproteins are released into the synaptic cleft, which in turn interact with excitatory amino acid transporters (EAAT) on the astrocyte cell surface. Once the RNP is internalized, MV is reproduced efficiently and spreads to adjacent astrocytes, via fusion of the astrocytic cell membranes and independent of the known MV receptors. Our data show that astrocytes are the predominant cell type to which MV is transmitted during viral dormancy in the CNS.

 

Education and Training

Educational Background

  • Postdoctoral, Viral Immunology, The Scripps Research Institute, La Jolla, CA, 1990-95
  • PhD, Microbiology and Immunology, Vanderbilt University, Nashville, TN, 1990
  • BS, with Honors, Biology, Lafayette College, Easton, PA, 1985

Memberships

  • American Society of Microbiology
  • American Association of Immunology
  • American Society of Virology

Honors & Awards

  • The Marion Downs Lecturer, American Academy of Audiology
  • Fox Chase Cancer Center “Special Contributor”
  • The Sidney Pestka Lecturer, American Society for Microbiology, 2014
  • Dozor Lecturer, Ben-Gurion University, 2007
  • Autism Speaks Scientific Advisory Board Member of the Year, 2007
  • F.W. Kirby Scholar in Neurodegenerative Disease, 1998-present
Research Profile

Research Program

Research Interests

Viral infection, immunity, and disease in the brain

  • Elucidating how neurotropic viruses spread to, and across, synaptic junctions
  • Defining principles that govern unique aspects of the host immune response within the brain
  • Developing mouse models to study immunity to multiple pathogenic encounters
  • Evaluating long-term neuropathological consequences of viral infections

Lab Description

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 decades, 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 is 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 is directly relevant to the development of immune-mediated approaches to resolve CNS tumors.

Type I interferon synthesized by astrocytes limits influenza A virus replication in neurons and prevents egress from the CNS. The mechanisms that govern influenza A virus (IAV) reproduction and pathogenesis in tissues other than the airways and the lungs are not well understood.  This is particularly true in the case of the central nervous system (CNS), even though multiple neurotropic IAV strains can cause severe, even life-threatening, neurological consequences, including encephalitis and meningitis. In this manuscript, an essential role for type I interferons (IFNs) in controlling neurotropic IAV is shown, implicating astrocytes as a primary IFN-producing cell population during IAV CNS infection. Type I IFN receptor 1 knockout (IFNAR KO) mice are significantly more permissive to a neurovirulent strain, A/WSN/1933 (H1N1) (IAV-WSN), than wild type (WT) mice. Moreover, unlike WT mice, in which IAV-WSN remains localized to the CNS, IAV disseminates to other organs in IFNAR KO mice. IFNAR KO mice have negligible leukocyte recruitment into the brain, and leukocyte depletion does not lead to enhanced neuropathology in WT mice, indicating that a CNS-intrinsic immune mechanism drives IFN-mediated viral control during the early phase of infection. Further studies showed that astrocytes are a primary source of intraparenchymal type I IFN: IAV-infected astrocytes produce high levels of type I IFN, and supernatants from primary astrocyte cultures significantly limit IAV replication in neurons (Figure 1). Collectively, these data characterize IAV infection and distribution in the mouse brain, and support the conclusion that astrocyte-derived type I IFN directly controls IAV infection in neurons, leading to restriction of viral reproduction within the brain.

Anti-measles virus antibodies provide long term protection in the infected brain.  Although the contributions of interferons, cytokines, and T cells within the brain following neurotropic virus infection are well-known, how B cells and antibodies contribute to viral control is less well-studied.  Using a mouse model of neuron-restricted measles virus (MV) infection, we have previously shown that wild type mice become infected, but that virus is controlled by T cell-synthesized interferon-gamma.  Recently, we showed that, although IFN-gamma can suppress viral replication in these otherwise healthy mice, viral RNA can persist. When mice are immunosuppressed, viral replication can resume, leading to unique manifestations of central nervous system (CNS) disease. In this manuscript, we show that antibodies, produced by B cells following establishment of a persistent infection, reduce MV RNA levels in vitro and in vivo at timepoints congruent with persistent infection. We conclude that anti-MV antibodies contribute to overall control of MV infection at later stages of infection.

A non-canonical mode of trans-synaptic virus transmission from neurons to astrocytes. Viruses, including herpes-, entero-, and morbilliviruses, are the most common cause of infectious encephalitis in mammals worldwide. During most instances of acute viral encephalitis, neurons are typically the predominant infected cell type. Surprisingly, however, cellular tropism may change during long-term infections in the brain. For example, measles virus (MV), a neurotropic RNA virus, relocates from neurons to astrocytes during viral dormancy in the brains of experimentally infected mice. Consequently, to define how neurotropic viruses trigger neuropathology, it is crucial to define which central nervous system (CNS) cell populations are susceptible and permissive, and to define how viruses spread between these distinct cell populations. Using a MV transgenic mouse model that expresses human CD46 (hCD46), the MV vaccine strain receptor, under the control of a neuron-specific enolase promoter (NSE-hCD46+ mice), a novel mode of viral spread between heterotypic cell types of the CNS (specifically, neuron-to-astrocyte) was identified. Although hCD46 is required for initial neuronal infection, this receptor is dispensable for heterotypic spread to astrocytes, which instead depends on glutamate transporters and direct neuron-astrocyte contact. Moreover, in the presence of RNase A, astrocyte infection is reduced, suggesting that the infectious particle that crosses the neuron-astrocyte synaptic cleft is an infectious ribonucleoprotein (RNP)(Figure 2).  The characterization of this unique mode of intercellular transport offers insights into neurotropic viral biology, and may reveal unique targets to mitigate the life-threatening consequences of measles encephalitis.

Lab Staff

Christine Matullo, PhD

Lab Manager, Research Associate

Room: R493
215-728-3677

Riley M. Williams, PhD

Postdoctoral Associate

Room: R493
215-728-3677

Additional Staff

Virginia Pearson, Visiting Scientist

 

Publications

Selected Publications

Balachandran, S. G. F. Rall.  Benefits and perils of necroptosis in influenza virus infection.  J. Virol., 94: DOI: 10.1128/JVI.01101-19, 2020.  PMID:  32051270.

Miller, K. D., C. M. Matullo, K. A. Milora, R. M. Williams, K. J. O’Regan, G. F. Rall.  Immune mediated control of a dormant neurotropic RNA virus infection.  J. Virol. 93:e00241-19. https://doi.org/10.1128, 2019.

Milora, K. A., G. F. Rall.  Interferon control of neurotropic viral infections.  Trends in Immunology, 40: 842-856, 2019.  PMID: 31439415.

Solomos, A. C., K. J. O’Regan, G. F. Rall.  CD4+ T cells require either B cells or CD8+ T cells to control spread and pathogenesis of a neurotropic infection.  Virology, 499: 196-202, 2016. PMID: 27677156

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

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

 

Additional Publications

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