Human cytomegalovirus is an opportunistic pathogen that produces a devastating central nervous system disease in AIDS patients and is the most common infectious cause of congenital brain disorders. Though the importance of lymphocytes in clearing viral brain infection is well appreciated, recent data have suggested that infiltrating T lymphocytes may also play an integral role in repair of brain tissue damaged during viral infection. In this proposal, the central hypothesis to be tested is that cytomegalovirus infection of neural stem cells (NSCs) compromises their neuroreparative response to T lymphocyte-mediated clearance of viral brain infection. The proposed experiments are designed to study the effect of murine cytomegalovirus (MCMV) infection on the interplay between T-cells and NSCs in vivo. To test this hypothesis, we will (1) determine if NSCs respond to T lymphocyte-mediated viral clearance. This will be achieved by depleting CD8+, CD4+, and Treg (CD4+CD25+) lymphocyte subpopulations and examining the subsequent effect on NSC migration to sites of MCMV brain infection using real-time bio-luminescence imaging. We will also investigate how T-cell-mediated immune responses affect the production of select neurotrophins in the brains of infected animals. We will then (2) determine if MCMV infects endogenous NSCs in vivo and compromises their response to T lymphocytes. These studies will examine the effect of MCMV infection on the migration of luciferase-labeled NSCs towards IFNg3-induced chemokine production and determine if MCMV infected NSCs are themselves targets for CD8+ T-cell-mediated clearance. Finally, we will (3) determine if viral infection of NSCs alters their subsequent neurogenesis. These studies will investigate persistence of transplanted luciferase-labeled NSCs and evaluate how MCMV infection alters which neural cell markers (specific for neurons, oligodendrocytes, or astrocytes) are expressed following subsequent differentiation in vivo. In the final studies, we will determine if an anti-inflammatory environment fosters regenerative processes through overexpression of interleukin (IL)-10 and transforming growth factor (TGF)b2, followed by an assessment of neurogenesis. Taken together, the studies proposed in this competitive renewal application will provide new insights into the interactions between T lymphocytes and NSCs in the maintenance of healthy brain tissue following viral infection.

Public Health Relevance

Human cytomegalovirus is an opportunistic pathogen that produces a devastating central nervous system disease in AIDS patients and the murine models described in this grant application will help us to understand interactions between antiviral immune responses and brain repair. The prognosis for full recovery in patients suffering from chronic disability following viral encephalitis is poor and the experiments outlined in this proposal are timely because the use of neural stem cells to repair brain damage is currently being explored in numerous models of neurodegenerative diseases. Because it is believed that one function of neural stem cells is to repair inflamed and damaged brain tissue, these cells may offer an innovative approach to treat the neuropathological sequelae subsequent to neuroAIDS, as well as other viral encephalitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038836-14
Application #
8207288
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2000-01-01
Project End
2013-01-31
Budget Start
2012-01-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$323,706
Indirect Cost
$109,331
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Hu, Shuxian; Rotschafer, Jessica H; Lokensgard, James R et al. (2014) Activated CD8+ T lymphocytes inhibit neural stem/progenitor cell proliferation: role of interferon-gamma. PLoS One 9:e105219
Mutnal, Manohar B; Hu, Shuxian; Schachtele, Scott J et al. (2014) Infiltrating regulatory B cells control neuroinflammation following viral brain infection. J Immunol 193:6070-80
Schachtele, Scott J; Hu, Shuxian; Sheng, Wen S et al. (2014) Glial cells suppress postencephalitic CD8+ T lymphocytes through PD-L1. Glia 62:1582-94
Mutnal, Manohar B; Hu, Shuxian; Lokensgard, James R (2012) Persistent humoral immune responses in the CNS limit recovery of reactivated murine cytomegalovirus. PLoS One 7:e33143
Schachtele, Scott J; Mutnal, Manohar B; Schleiss, Mark R et al. (2011) Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol 17:201-11
Mutnal, Manohar B; Cheeran, Maxim C-J; Hu, Shuxian et al. (2011) Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain. PLoS One 6:e16211
Mutnal, Manohar B; Hu, Shuxian; Little, Morgan R et al. (2011) Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-?. J Neurovirol 17:424-37
Mutnal, Manohar B; Cheeran, Maxim C-J; Hu, Shuxian et al. (2010) Excess neutrophil infiltration during cytomegalovirus brain infection of interleukin-10-deficient mice. J Neuroimmunol 227:101-10
Cheeran, Maxim C-J; Lokensgard, James R; Schleiss, Mark R (2009) Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 22:99-126, Table of Contents
Cheeran, Maxim C-J; Mutnal, Manohar B; Hu, Shuxian et al. (2009) Reduced lymphocyte infiltration during cytomegalovirus brain infection of interleukin-10-deficient mice. J Neurovirol 15:334-42

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