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.
