Murine resistance to intraperitoneally (i.p.)-inoculated street rabies virus (SRV) has been shown to be dominant and genetically controlled by the concurrent presence of each of two segregating genes. Trace experiments for infectious SRV indicated that susceptibility differences among genetically dissimilar strains of mice were associated with restriction of viral replication within the central nervous system (CNS). Limitation of viral replication appeared to correlate with the antibody response. The importance of the immune response was reaffirmed with cyclophosphamide studies in that all resistant SJL/J mice died following immunosuppressive treatment. In contrast, cyclophosphamide-treated SJL/J mice and immunodeficient athymic mice were protected when reconstituted with immune serum starting at 72hr after SRV inoculation, a time in which virus was not detected in the peritoneal cavity, but was present in the spinal cord. Passively transferred unfractionated immune cells also protected athymic mice. Specific cell eliminations with cytotoxic antibody and complement indicated B cells, but not T cells, were essential for protection. Additional studies showed that neutralizing antibody in the cerebrospinal fluid was unimportant in the resistance of mouse strains which remained CNS clinically asymptomatic. Furthermore, the CNS of mice inoculated i.p. 5 days previously with SRV was resistant to either intracerebral or intranasal rabies virus challenge. Survival of these mice correlated with the detection of neutralizing antibody in serum. A focal immunofluorescent assay (FIA) on live cells has been developed for quantification and biological cloning of street and laboratory-adapted strains of rabies viruses. Monoclonal antibodies, in conjunction with mutagenic agents and the FIA assays, are being utilized for selection of avirulent and virulent isolates of rabies viruses. Preliminary studies indicate that only monoclonal antibodies with neutralizing activity inhibit replication of rabies virus in vitro, and protect cyclophosphamide immunosuppressed SJL/J mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000072-14
Application #
4688344
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lodmell, Donald L; Esposito, Joseph J; Ewalt, Larry C (2004) Live vaccinia-rabies virus recombinants, but not an inactivated rabies virus cell culture vaccine, protect B-lymphocyte-deficient A/WySnJ mice against rabies: considerations of recombinant defective poxviruses for rabies immunization of immunocompromised Vaccine 22:3329-33
Lodmell, Donald L; Ewalt, Larry C (2004) Rabies cell culture vaccines reconstituted and stored at 4 degrees C for 1 year prior to use protect mice against rabies virus. Vaccine 22:3237-9
Lodmell, Donald L; Parnell, Michael J; Weyhrich, John T et al. (2003) Canine rabies DNA vaccination: a single-dose intradermal injection into ear pinnae elicits elevated and persistent levels of neutralizing antibody. Vaccine 21:3998-4002
Lodmell, Donald L; Parnell, Michael J; Bailey, John R et al. (2002) Rabies DNA vaccination of non-human primates: post-exposure studies using gene gun methodology that accelerates induction of neutralizing antibody and enhances neutralizing antibody titers. Vaccine 20:2221-8
Arai, Y T; Takahashi, H; Kameoka, Y et al. (2001) Characterization of Sri Lanka rabies virus isolates using nucleotide sequence analysis of nucleoprotein gene. Acta Virol 45:327-33
Lodmell, D L; Ewalt, L C (2001) Post-exposure DNA vaccination protects mice against rabies virus. Vaccine 19:2468-73
Lodmell, D L; Ray, N B; Ulrich, J T et al. (2000) DNA vaccination of mice against rabies virus: effects of the route of vaccination and the adjuvant monophosphoryl lipid A (MPL). Vaccine 18:1059-66
Lodmell, D L; Ewalt, L C (2000) Rabies vaccination: comparison of neutralizing antibody responses after priming and boosting with different combinations of DNA, inactivated virus, or recombinant vaccinia virus vaccines. Vaccine 18:2394-8