Progressive Multifocal Leukoencephalopathy (PML) is a life-threatening demyelinating brain disease in immune-compromised individuals caused by the JC polyomavirus (JCV), a ubiquitous human-only pathogen. No anti-JCV agents are available. PML is a significant complication for patients receiving long-term natalizumab, a humanized antibody against ?4 integrins that dramatically reduces relapses in multiple sclerosis (MS) patients. PML is being diagnosed with increasing frequency in patients treated with other immunomodulatory agents (e.g., Rituxamab, Efalixumab, Fingolimod, and dimethyl fumarate) as well. Drug withdrawal is often complicated by Immune Reconstitution Inflammatory Syndrome (IRIS), a severe inflammatory reaction with paradoxical worsening of demyelination that carries a high mortality rate. Lack of a tractable animal model for PML is a widely recognized hurdle to defining pathogenesis of demyelination in PML and PML-IRIS. Using mouse polyomavirus (MPyV), we developed a robust model of polyomavirus-associated demyelinating leukoencephalitis (brain white matter inflammation), with viral infection and T cell infiltration localized to subcortical white matter.
For Specific Aim 1, we hypothesize that MPyV replicates predominantly in astrocytes early in infection, with neuroinflammation rather than viral infection causing oligodendrocyte loss; with ?4 integrin blockade, however, oligodendrocyte dropout is delayed and results from MPyV replication extending to oligodendrocytes. To test this hypothesis, we developed a novel floxed MPyV mutant to conditionally restrict viral replication in Cre recombinase-expressing astrocytes or oligodendrocytes, and will use a mouse line with ablation of the ?4 integrin gene in hematopoietic cells. Histologic and immunohistologic evaluation of MPyV-infected brains will be complemented by MRI diffusion tensor imaging to detect and quantify multifocal lesions and axon organizational integrity in whole brain scans.
For Specific Aim 2 we hypothesize that IFN-?, produced by MPyV-specific CD8 T cells, mediates a demyelinating leukoencephalitis in early infection, but confers protection in persistent infection. To test this hypothesis, we will use transgenic mice to conditionally ablate IFN-? signaling in astrocytes and oligodendrocytes, and mice made chimeric with IFN-?-sufficient/-deficient, MPyV-specific TCR transgenic CD8 T cells.
For Specific Aim 3 we hypothesize that the PD-1:PD-L1 pathway balances MPyV-specific CD8 T cell-mediated control of CNS infection against their ability to promote neuroinflammation and demyelination. Anti-MPyV CD8 T cells infiltrating the brain are stably maintained and uniformly upregulate PD-1 inhibitory receptors. To test this hypothesis, we will study the in vivo function and fate of PD-1-/- T cells in brains of MPyV-infected mice, and apply chronic intracerebroventricular infusion of anti-PD-L1. This model of polyomavirus-associated CNS disease may provide insights for strategies to prevent or stem progression of this devastating demyelinating leukoencephalitis associated with immunomodulatory therapies for MS and other autoimmune/inflammatory diseases.
Progressive Multifocal Leukoencephalopathy (PML) is a life-threatening white matter brain disease caused by JC virus (JCV), a ubiquitous human-only pathogen. PML is a well-documented complication of natalizumab, an immune modulating therapy that dramatically reduces multiple sclerosis relapses; the list of immunotherapeutic agents linked to PML is increasing. No anti-JCV agents are available. Using a mouse virus in the same family as JCV, we developed a tractable animal model of CNS infection to define the mechanisms causing glial cell death in the pathogenesis of PML. Findings from this mouse model may offer insight into strategies to control the onset/progression of PML and the neuroinflammation after immune reconstitution in PML patients.
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| Maru, Saumya; Jin, Ge; Schell, Todd D et al. (2017) TCR stimulation strength is inversely associated with establishment of functional brain-resident memory CD8 T cells during persistent viral infection. PLoS Pathog 13:e1006318 |
| Qin, Qingsong; Lauver, Matthew; Maru, Saumya et al. (2017) Reducing persistent polyomavirus infection increases functionality of virus-specific memory CD8 T cells. Virology 502:198-205 |
