THOMAS E. LANE
|Professor of Pathology
Neurobiology of Disease
Neural Stem Cells, Multiple Sclerosis, Virology
Work in my laboratory is divided into two main research areas: 1) define the functional contributions of chemokines and chemokine receptors in defense and disease following viral infection of the central nervous system (CNS) and 2) evaluate the therapeutic potential of mouse/human neural precursor cells (NPCs) in clinical recovery and remyelination in a model of viral-induced demyelination. My laboratory has a long-standing interest in understanding events that initiate and maintain inflammation within the CNS in response to viral infection. To this end, we have set forth on a directed path to determine the functional significance of chemokines and chemokine receptors in both host defense as well as disease development following instillation of a positive-strand RNA virus (mouse hepatitis virus – MHV) into the CNS of susceptible mice. Indeed, we have shown that blocking chemokine function via both antibody neutralization and genetic silencing in virally-infected mice resulted in increased mortality accompanied by reduced immune cell infiltration into the CNS. Subsequently, we have demonstrated that unique chemokine/chemokine receptor signaling pathways are critical for interrelated events required for optimal host defense following viral infection including linking innate and adaptive immune responses, regulating antiviral effector functions e.g. cytokine secretion/cytolytic activity by effector T cells, and promoting the directional migration of antigen-sensitized lymphocytes into the CNS. We have also focused on how chemokine signaling influences the biology of oligodendroglia with regards to protection from inflammatory cytokine-induced apoptosis.
Similar to the human demyelinating disease multiple sclerosis (MS), remyelination failure is also observed in MHV-infected mice. Therefore, an important and clinically-relevant question related to demyelinating diseases is to design therapies that promote remyelination of demyelinated axons. We have determined that surgical engraftment of mouse neural precursosr cells (NPCs) into mice persistently-infected with MHV results in survival and migration of engrafted NPCs accompanied by extensive remyelination. The use of a viral model of demyelination is relevant in that the etiology of MS remains enigmatic and viruses have long been considered important as a potential triggering agent in inducing demyelinating diseases. Moreover, numerous viruses are capable of persisting within the CNS therefore understanding if NPCs are capable of promoting repair within an environment in which a persistent virus is present resulting in chronic neuroinflammation/demyelination is critical. We have determined that transplanted cells migrate to areas of demyelination by responding to the specific chemokines expressed within areas of demyelination. We have now moved forward with our studies on NPC-mediated clinical/histological recovery to address whether allogeneic NPCs are antigenic and subject to immune-mediated rejection. We are also investigating the therapeutic potential of human NPCs (hNPCs) in mediating functional recovery following transplantation into MHV-infected mice.
Blanc, C.A., Grist, J.J., Rosen, H., Sears-Kraxberger, I., Steward, O., and Lane, T.E. (2015) S1P receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination. Am. J. Path, in press.
Chen, L., Coleman, R., Leang, R., Kopf, A., Walsh, C.M., Macklin, W., Loring, J.F., and Lane, T.E. (2014) Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis. Stem Cell Reports, 2(6):825-837.
Weinger, J.G., Plaisted, W.C., Maciejewski, S.M., Lanier, L.L., Walsh, C.M., and Lane, T.E. (2014) Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis. Stem Cells, Jun 4. Epub ahead of print.
Greenberg, M.L., Weinger, J.G., Matheu, M.P., Carbajal, K.S., Parker, I., Macklin, W.B., Lane*, T.E., and Cahalan*, M.D. (2014) Two-photon imaging demonstrates remyelination of spinal cord axons by engrafted neural precursor cells in a model of multiple sclerosis. PNAS, 111(22):E2349-2355.
Chucair-Elliott, A.J., Zhen, M., Kroll, C.M., Lane, T.E., and Carr, D.J.J. (2014) Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia, 2014 May 7. Epub ahead of print.
Weinger, J.G., Chen, L., Coleman, R., Leang, R., Plaisted, W., Loring, J.F., and Lane, T.E. (2013) Intraspinal transplantation of mouse and human neural precursor cells. Current Protocols in Stem Cell Biology 26,:Unit 2D.16.
Plaisted, W.C., Weinger, J.G., Walsh, C.M., and Lane, T.E. (2014) T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells. Virology, 449:235-243.
Villegas-Mendez, A., Findlay, E.G., Grady, L.M., de Souza, J.B., Saris, C.J., Lane, T.E., Riley, E.M., and Couper, K.N. (2013) WSX-1 signalling inhibits CD4⁺ T cell migration to the liver during malaria infection by repressing chemokine-independent pathways. PLoS One, 8(11): e78486.
Weinger, J.G., Marro, B.S., Hosking, M., and Lane, T.E. (2013) The chemokine receptor CXCR2 and coronavirus-induced neurologic disease. Virology 435(1): 110-117.
Nance, J.P., Vannella, K.M., Worth, D., David, C., Carter, D., Noor, S., Hubeau, C., Fitz, L., Lane, T.E., Wynn, T.A., and Wilson, E.H. (2012) Chitinase dependent control of protozoan cyst burden in the brain. PLoS Pathogens, 8(11): e1002990.
Tirotta, E., Duncker, P., Oak, J., Klaus, S., Tsukamoto, M.R., Gov, L., and Lane, T.E. (2012) Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis. J. Neuroimmunology, 254(1-2):110-116.
Zhao, J., Wohlford-Leanne, C., Zhao, J., Lane, T.E., McCray, P., and Perlman, S. (2012) Treatment with toll-lie receptor agonists protects aged mice from lethal respiratory viral infection. J. Virology, 86(21):11416-11424.
Weinger, J.G., Weist, B.M., Plaisted, W.C., Klaus, S.M., Walsh, C.M., and Lane, T.E. (2012) MHC mismatch results in neural progenitor cell rejection following spinal cord transplantation in a model of viral-induced demyelination. Stem Cells, 30(11):2584-2595.
Tirotta, E., Kirby, L.A., Hatch, M.N., and Lane, T.E. (2012) IFN-g-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling. Stem Cell Research, 9(3):208-217.
Marro, B.S., Hosking, M.P., and Lane, T.E. (2012) CXCR2 signaling and host defense following coronavirus-induced encephalomyelitis. Future Virology, 7(4):349-359.
Whitman, L.M., Blanc, C., Schaumburg, C.S., Rowitch, D.H., and Lane, T.E. (2012) Olig 1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination. Exp. Neuro., 235(1):380-387.
Liu, J.Z., Jellbauer, S., Poe, A., Ton, V., Pesciaroli, M., Kehl-Fie, T., Restrepo, N.A., Hosking, M., Edwards, R.A., Battistoni, A., Pasquali, P., Lane, T.E., Chazin, W.J., Vogl, T., Roth, J., Skaar, E.P., and Raffatellu, M. (2012) Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host Microbe 11(3): 227-239.