A viral etiology for amyotropic lateral sclerosis (ALS) has long been postulated. Poliovirus is considered a putative agent for ALS because there is selective involvement of motor neurons in both diseases and because patients with ALS have a greater incidence than the general population of having had poliomyelitis in childhood. Also, it has now been demonstrated that enteroviruses are capable of persisting in the central nervous system (CNS) of man, i.e., in children with immunodeficiencies. The objective of this research is a continuation of our studies of persistent poliovirus infections of the CNS of immunocompromised mice. Investigations will concentrate on three areas: (1) Further analysis of the mechanisms of viral dissemination. (2) Characterizing the immune response as it relates to viral clearance and persistence, and development of a host that is tolerant to the infection. (3) Examination of the viral molecular, biological, and immunological correlates of CNS persistence. The study of viral dissemination will employ axonal transport inhibitors, viral assays, and electron microscopic immunohistochemical staining to follow the spread of infection. Immunohistochemical staining will also be used to determine the location of virus during the persistent infection. The role of humoral and cellular immunity in CNS viral clearance is being analyzed by depletion studies with anti-IgM or anti-thymocyte sera, transfer experiments with antibody and cells, and studies in B-cell deficient (CBA/N) or T-cell deficient (Nude) mice. The cellular immune response to infection is being measured by a lymphocyte transformation assay. The gentic control of the antibody response is also being investigated in inbred and congenic mice. Studies of the molecular correlates of persistence will include mapping of the previously observed new RNase Tl-resistant oligonucleotides seen during the persistent infection on the viral genome by RNase III digestion. Experiments will also be performed to biologically and immunologically characterize highly paralytic isolates of the attenuated W-2 strain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021756-03
Application #
3403297
Study Section
Virology Study Section (VR)
Project Start
1986-02-01
Project End
1989-11-30
Budget Start
1988-02-01
Budget End
1989-11-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Jubelt, B; Ropka, S L; Goldfarb, S et al. (1991) Susceptibility and resistance to poliovirus-induced paralysis of inbred mouse strains. J Virol 65:1035-40
Wang, K; Sun, L; Jubelt, B et al. (1990) Cell-mediated immune responses to poliovirus II. Survey of delayed hypersensitivity and T-cell proliferative responses in inbred mouse strains. Viral Immunol 3:111-7
Pevear, D C; Oh, C K; Cunningham, L L et al. (1990) Localization of genomic regions specific for the attenuated, mouse-adapted poliovirus type 2 strain W-2. J Gen Virol 71 ( Pt 1):43-52
Jubelt, B; Wilson, A K; Ropka, S L et al. (1989) Clearance of a persistent human enterovirus infection of the mouse central nervous system by the antiviral agent disoxaril. J Infect Dis 159:866-71
Jubelt, B; Ropka, S L; Goldfarb, S J et al. (1989) Anti-thymocyte serum delays clearance of poliovirus from the mouse central nervous system. J Neuroimmunol 22:223-32
Wang, K G; Sun, L Z; Jubelt, B et al. (1989) Cell-mediated immune responses to poliovirus. I. Conditions for induction, characterization of effector cells, and cross-reactivity between serotypes for delayed hypersensitivity and T cell proliferative responses. Cell Immunol 119:252-62
Jubelt, B; Lipton, H (1987) Lansing poliovirus infection in mice: antibody demonstrable by enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation but not by neutralization. J Neuroimmunol 14:109-21
Jubelt, B; Cashman, N R (1987) Neurological manifestations of the post-polio syndrome. Crit Rev Neurobiol 3:199-220