Viral infection in the developing central nervous system (CNS) is frequently associated with long-term consequences which may include behavioral and physiological changes. Neurological disorders involving previous viral infection in children are only recently being explored;those infections which have the ability to persist or remain latent in the CNS may cause disease in a number of different ways. Viral replication during acute infection may directly destroy target cells which may include stem cells, neurons, astrocytes, or oligodendrocytes. Viruses that persist may sporadically replicate and slowly harm the CNS by chronically activating the innate and adaptive immune response. Immune effector cells migrating into the brain may directly kill cells expressing viral proteins, thereby potentially causing CNS disease. These scenarios demonstrate the importance of understanding not only how a virus infects the CNS, but also how the immune system responds to infection in an organ which is considered to be very delicate and irreparable. Enteroviruses (EV) mirror just such a scenario in which infection is frequently associated with CNS disease, particularly in the very young. Acute infection may cause meningitis and encephalitis. In fact, the majority of aseptic meningitis cases in the US are directly associated with EV infection. However, EV are also known to persist in host tissues, sometimes years after initial infection. The persistence of EV in organs other than the CNS may explain its direct association with a number of chronic diseases including myocarditis, diabetes, and chronic inflammatory myopathy. Within the CNS, persistent or latent EV infection has been suggested for such chronic CNS disorders as post-poliovirus syndrome, amyotrophic lateral sclerosis and a number of demyelinating conditions. We have recently the studied the acute and chronic effects of coxsackievirus B3 (CVB3) infection in our neonatal mouse model utilizing novel recombinant viruses expressing molecular markers and T-cell epitopes. Extraordinary detrimental effects on neurogenesis and CNS development have been identified following infection. This proposal will examine the ability of CVB3 to (1) infect all stem cells in the CNS (2) diminish neurogenesis in the developing CNS (3) stimulate immune activation in the CNS during acute/latent infection and after virus reactivation, and (4) contribute to pathology in the CNS. These studies may ultimately help to understand how viruses cause CNS disease following childhood infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054108-04
Application #
7817095
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Wong, May
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$291,384
Indirect Cost
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Sin, Jon; Mangale, Vrushali; Thienphrapa, Wdee et al. (2015) Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis. Virology 484:288-304
Robinson, Scott M; Tsueng, Ginger; Sin, Jon et al. (2014) Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog 10:e1004045
Puccini, Jenna M; Ruller, Chelsea M; Robinson, Scott M et al. (2014) Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system. Lab Invest 94:161-81
Sin, Jon; Puccini, Jenna M; Huang, Chengqun et al. (2014) The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development. PLoS Pathog 10:e1004249
Ruller, Chelsea M; Tabor-Godwin, Jenna M; Van Deren Jr, Donn A et al. (2012) Neural stem cell depletion and CNS developmental defects after enteroviral infection. Am J Pathol 180:1107-20
Tabor-Godwin, Jenna M; Tsueng, Ginger; Sayen, M Richard et al. (2012) The role of autophagy during coxsackievirus infection of neural progenitor and stem cells. Autophagy 8:938-53
Banerjee, Anirban; Kim, Brandon J; Carmona, Ellese M et al. (2011) Bacterial Pili exploit integrin machinery to promote immune activation and efficient blood-brain barrier penetration. Nat Commun 2:462
Tsueng, Ginger; Tabor-Godwin, Jenna M; Gopal, Aparajita et al. (2011) Coxsackievirus preferentially replicates and induces cytopathic effects in undifferentiated neural progenitor cells. J Virol 85:5718-32
Rhoades, Ross E; Tabor-Godwin, Jenna M; Tsueng, Ginger et al. (2011) Enterovirus infections of the central nervous system. Virology 411:288-305
Tabor-Godwin, Jenna M; Ruller, Chelsea M; Bagalso, Nolan et al. (2010) A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS. J Neurosci 30:8676-91

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