Glenn F Rall, PhD
Office Phone: 215-728-3617
Lab Phone: 215-728-3677
Our laboratory has three main research objectives, all pertaining to viral infections within the central nervous system (CNS) and the diseases that these infections can cause. The first objective is to define how viruses, such as measles, polio and others, are transported to and across the synapse, to result in infection of adjacent neurons. We recently identified a critical role for the neuronal neurotransmitter receptor, neurokinin-1, in trans-synaptic spread of measles virus (MV), and are currently defining interactions between MV components and neuronal molecular motors, such as dynein and kinesin. A major objective of these studies is to ascertain how neurotropic viruses cause disease; using both transgenic mouse models and primary neuronal cultures, we are currently testing whether engagement of crucial cellular factors might account for CNS diseases in the absence of overt neuronal destruction. For example, viral sequestration of neurotransmitter receptors by viral proteins may not only allow the virus to spread among neurons, but could also constitutively trigger neuronal signaling pathways that can lead to neuronal dysfunction.
A second objective of the lab is to characterize the activation, recruitment and function of the host immune response under conditions of CNS infection. Using a novel transgenic mouse model of MV infection of CNS neurons, we have recently defined the signals that recruit immune cells into the infected brain, and have initiated studies to esablish how neurons and T cells interact to result in viral clearance in the absence of neuronal loss. In addition, we have identified key differences between neurons and non-neuronal cells with regard to responsiveness to antiviral cytokines, such as interferons. Such cell-specific responses likely play a critical role in dictating how cells--including tumor cells, which are known to downregulate key immune response proteins--will respond to immune mediators, and may provide key insights into the mechanism underlying the unique cytokine-driven and noncytopathic manner by which the host response resolves some pathogenic challenges.
A third, somewhat new, project within the lab is to develop complex animal models to better understand the complexity of the human response when exposed to multiple pathogens simultaneously. Using our transgenic mouse in which a human MV receptor is restricted to CNS neurons, we developed a model that challenges such mice with MV (infecting neurons within the brain) and periperhally with the natural mouse pathogen, lymphocytic choriomeningitis virus (LCMV; that does not infect the CNS). We also demonstrted massive recrutiment of LCMV-specific T cells into the brain, where no LCMV is present. This "lymhocyte misrecrutiment" results in blood brain barrier damage, edema and death in greater than 50% of doubly challenged mice, as compared to no disease in animals challenged with either pathogen alone. Further exploration of how immune responses interact with each other should result in improved therapeutic modalities to treat immunogenic challenges, including pathogens, allergens and tumors.Description of research projects
Fox Chase Programs
- O'Donnell LA, Rall GF. "Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin" J Neuroimmune Pharmacol. 2010 Sep;5(3):443-55. PubMed
- Matullo CM, O'Regan KJ, Hensley H, Curtis M, Rall GF. Lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation. J Virol. 2010 Jan;84(1):312-20. PubMed
- Young VA, Rall GF. Making it to the synapse: measles virus spread in and among neurons. Curr Topics Microbiol Immunol. 2008;330:3-30. PubMed
- Rose RW, Skipworth JD, Nicolas E, Rall GF. Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J Neuroimmunol. 2007;192:145-156. PubMed
- Makhortova N, Askovich P, Patterson CE, Gechman LA, Gerard NP, Rall GF. Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology. 2007;362:235-244. PubMed