The principal objective of these studies is to determine host and viral factors that influence the genetically-controlled resistance of inbred mouse strains to street rabies virus (SRV). Studies concerning the importance of interferon induced within the central nervous system (CNS) during infection as a mechanism responsible for resistance have been completed. The interferon was characterized as a typical viral-induced pH 2.0 stable type l interferon with alpha and beta specificity. Furthermore, it was determined that the high concentrations of interferon-alpha/beta that were induced by SRV in the CNS of susceptible A/WySnJ mice were ineffective in inhibiting viral relication. The 100% survival of SRV-infected resistant SJL/J mice following neutralization of interferon within their CNC with high concentrations of rabbit anti-mouse interferon-alpha/beta suggested that the minimal amount of interferon present in the CNS during infection was not the mechanism responsible for their innate resistance to ip-inoculated SRV. Studies concerning the significance of cellular immunity have progressed with the development of a 8 hr assay that measures specific cytotoxic T-cell killing. Maximum killing occurs following a 5 day in vitro incubation of 1X108 spleen cells with 1X106 137Cs-irradiated rabies virus-infected stimulator cells; effector to target (E:T) ratios of 10 and 5 result in >70% and >40% specific lysis, respectively. The assay has been simplified by using P815, EL-4 and mouse neuroblastoma target cells persistently- infected with ERA virus. We have demonstrated specific T-cell cytotxicity with lymphocytes from susceptible A/WySnJ and C57Bl/6J mice and resistant DBA/2J and BALB/cByJ mice. Preliminary results suggest that maximum cytotoxic T-cell activity occurs seven days after ip-infection with ERA virus grown in CER cells. Mice infected with similar concentrations of SRV, CVS, and ERA viruses inoculated ip. as 10% mouse brain suspensions have minimal T-cell activity. We have been unable to demonstrate specific T-cell killing in an 8 hr assay with uncultured lymphocytes. The emphasis of these studies will be to continue to investigate the importance of cytotoxic T cells in murine resistance to SRV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000072-18
Application #
3818099
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1988
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