Lane, Thomas, Ph.D.
Thomas E. Lane, Ph.D.
Director of the Center for Virus Research
Tom Lane has been working in the area of multiple sclerosis (MS) research for over twenty years. After completing his Ph.D. research in Microbiology and Immunology at the UCLA School of Medicine, he did his postdoctoral work in neurovirology at the Scripps Research Institute in La Jolla, CA. Dr. Lane joined the Biological Sciences faculty at UC Irvine in 1998 where he was a Professor of Molecular Biology & Biochemistry, Director of the MS Research Center and Associate Director of the Institute for Immunology. Dr. Lane was awarded a National Multiple Sclerosis Society (NMSS) Collaborative Center Award as well as a CIRM Early Translation Award dedicated to exploring the therapeutic potential of neural stem cells in treating demyelinating diseases. The majority of work performed in Dr. Lane’s laboratory is focused on understanding the immunopathological mechanisms contributing to both disease progression and repair using pre-clinical mouse models of MS. However, Dr. Lane is also interested in immunological deficits associated with spinal cord injury as well as the role of neuroinflammation in contributing to Alzheimer’s disease neuropathology. He is currently a Professor in the Department of Neurobiology & Behavior.
Research in Lay Terms
Our work focuses on defining the molecular and cellular mechanisms that govern neuroinflammation in response to CNS infection, injury, or following induction of a misdirected immune response to CNS antigens e.g. autoimmunity.
Work in the Lane laboratory is divided into two broad areas: 1) defining the functional role of host factors that contribute to defense and disease following viral infection of the central nervous system (CNS) and 2) evaluating strategies to promote remyelination in response to viral-induced demyelination. To accomplish these goals, we use intracranial (i.c.) infection of susceptible mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV, a positive-sense RNA virus member of the Coronaviridae) and this results in an acute encephalomyelitis characterized by replication in astrocytes, microglia and oligodendroglia with relative sparing of neurons. Virus-specific CD4+ and CD8+ T cells control viral replication through secretion of IFN- and cytolytic activity, respectively. Sterile immunity is not acquired and virus persists in white matter tracts of surviving mice that ultimately develop an immune-mediated demyelinating disease with clinical and histologic characteristics similar to the human demyelinating disease multiple sclerosis (MS).
Defining the functional role of chemokines/chemokine receptors following coronavirus induced neurologic disease: My laboratory has a long-standing interest in understanding events that initiate and maintain inflammation within the CNS in response to JHMV infection. To this end, we’ve focused upon determining the functional significance of chemokines and chemokine receptors in both host defense as well as disease development in JHMV-infected animals. Indeed, we were among the first laboratories to show that blocking chemokine function via either antibody neutralization or genetic silencing resulted in increased mortality accompanied by reduced immune cell infiltration into the CNS in response to acute JHMV-induced disease. Moreover, we demonstrated that targeting selected chemokines in mice persistently infected with JHMV attenuated the severity of neuroinflammation and demyelination resulting in improved motor skills associated with increased remyelination. Subsequently, we have shown that unique chemokine/chemokine receptor signaling pathways are critical for interrelated events required for optimal host defense following viral infection including recruiting myeloid cells to the CNS that contribute to increasing the permeability of the blood-brain-barrier (BBB) and linking innate and adaptive immune responses. More recently, we have focused on how chemokines/chemokine receptors influence neutrophil accumulation within the CNS of JHMV mice as well as regulating the biology of oligodendroglia in terms of maturing into myelin-producing oligodendrocytes and influencing remyelination.
Cell-replacement therapies to promote remyelination in JHMV-infected mice: An important and clinically-relevant question related to demyelinating diseases is defining mechanisms that promote remyelination of demyelinated axons. We have previously shown that surgical engraftment of syngeneic neural progenitor cells (NPCs) into mice persistently infected with JHMV results in survival and migration of engrafted NPCs accompanied by extensive remyelination. We are the only group, to my knowledge, examining the therapeutic potential of cell replacement strategies using a viral model of demyelination. This is important in that the etiology of MS remains enigmatic and viruses have long been considered important as a potential triggering agent in inducing demyelinating diseases such as MS. Moreover, numerous viruses are capable of persisting within the CNS therefore understanding if NPCs are capable of promoting repair within this environment 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 employed 2-photon microscopy to visualize how engrafted NPCs physically engage demyelinated axons initiating differentiation into oligodendrocytes that results in remyelination. From these studies, we’ve also demonstrated that axonal damage precedes immune-mediated demyelination following viral infection of the CNS. These findings argue that demyelination is not a prerequisite for axonopathy. Ongoing studies within the laboratory will define mechanisms by which viral infection of the CNS initiates damage to axons. We are also investigating the therapeutic potential of human NPCs (hNPCs) in mediating functional recovery following transplantation into JHMV-infected mice. Our data indicate that hNPCs are immunosuppressive as evidenced by the dramatic reduction in neuroinflammation accompanied by remyelination within the spinal cords of transplanted animals. These findings are provocative and indicate that hNPCs are therapeutic although rapidly rejected.
Using pre-clinical models of the human demyelinating disease multiple sclerosis (MS), we are examining mechanisms by which surgical engraftment of human neural progenitor cells (hNPCs) into the spinal cords results in remyelination of demyelinated axons. Our previous work has argued that hNPCs are immunomodulatory and that upon engraftment there is the emergence of regulatory T cells (Tregs) that secrete factors that both dampen ongoing immune-mediated demyelination as well as promote remyelination by enhancing the maturation of oligodendrocyte progenitor cells (OPCs) into mature myelin-producing oligodendrocytes.
In addition, we are now exploring the ability of SARS-CoV2 (COVID19) to infect and replicate in resident cells of the central nervous system (CNS) including microglia, neurons, and astrocytes to determine if there are potentially damaging effects that may contribute to neurologic disease in COVID19 patients. Along these lines, we are also infecting human brain organoids with SARS- CoV2 to assess neurologic damage as well as immune responses to better understand the consequences of viral infection of the CNS of COVID19 patients.
Mangale, V., A.R. Syage, H.A. Ekiz, D.D. Skinner, Y. Cheng, C.L. Stone, K. Green, R.M. O’Connell and T.E. Lane (2020). Microglia influence host defense and disease following coronavirus infection of the central nervous system. Glia, doi: 10.1002/glia.23844.
McIntyre, L.L., S.A. Greilach, O. Shivashankar, I. Sears-Kraxberger, B. Wi, J. Ayala-Angulo, E. Vu, Q. Pham, J. Silva, K. Dang, F. Rezk, O. Steward, M.D. Cahalan, T.E. Lane, and C.M. Walsh (2020). Regulatory T cells promote remyelination in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis following neural stem cell transplant. Neurobiology of Disease, 2020 Apr 7:104868. doi: 10.1016/j.nbd.2020.104868.
King, T., P. Mimche, C. Bray, B. Umaru, L. Brady, C. Stone, A. Tunon-Ortiz, C. Eboumbo Moukoko, T.E. Lane, L. Ayong and T. Lamb (2020). EphA2 mediates disruption of the blood-brain barrier in cerebral malaria. PLoS Pathogens, an 30;16(1):e1008261.
Ramstead, A.G., J.A. Wallace, S-H. Lee, K.M. Bauer, W. Tang, J.P. Snook, M.A. Williams, T.E. Lane, J.L. Round, and R. M. O’Connell (2020). Mitochondrial pyruvate carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria. Cell Reports, 3:30(9):2889-2899.
Brown, D.G., R. Soto, S. Yandamuri, C. Stone, L. Dickey, J.C. Gomes-Neto, E.D. Pastuzyn, R. Bell, C. Petersen, K. Buhrke, R.S. Fujinami, R.M. O’Connell, W.Z. Shepherd, T.E. Lane*, and J.L. Round* (2019). The gut microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling (*Co-corresponding authors), eLife, Jul 16;8. pii: e47117. doi: 10.7554/eLife.47117.
Marro, B.S., D.D. Skinner, J.J. Grist, L.L Dickey, E. Eckman, C. Worne, L. Liu, R.M. Ransohoff and T.E. Lane (2019). Disrupted CXCR2 signaling on oligodendroglia lineage cells enhances myelin repair in a viral model of multiple sclerosis. J. Virology, Jun 26. pii: JVI.00240-19. doi: 10.1128/JVI.00240-19.
Skinner, D.D. and T.E. Lane (2020). CXCR2 signaling and remyelination. DNA and Cell Biology, 39(1):3-7
Ongoing Collaborations within SCRC
1. Brian Cummings – infect iPSC-derived human brain organoids with SARS-CoV2 and assess cellular targets of replication, innate immune responses, and neuropathology
2. Leslie Thompson – infect enriched cultures of human iPSC-derived neurons and astrocytes with SARS-CoV2 and assess susceptibility to infection, ability to replicate virus, cytopathology and innate immune responses.
3. Matt Blurton-Jones – infect enriched cultures of human microglia with SARS-CoV2 and assess susceptibility to infection, ability to replicate virus, cytopathology and innate immune responses.
Was awarded the title of Chancellor’s Professor starting June 2020
Recent Grant Awards
1) NINDS-NIH, R35NS116835 “Defining mechanisms of disease and repair in a viral model of multiple sclerosis” 05/20-04/28
2) UC Irvine, CRAFT-COVID “A novel anti-viral inhibitor of SARS-CoV2” 06/20-05/21
3) UC Irvine, CRAFT-COVID, “Development and validation of an improved mouse model for investigation of Coronavirus infection and pathology” 07/20 – 06/21