The aim of this proposal is to evaluate the ability of recombinant attenuated Salmonella that express genes of Herpes simplex virus (HSV) to induce protective immunity against viral challenge in animal model systems. The vector system, although administered via the oral route, is expected to induce protective levels of antibody and perhaps cell mediated immunity at mucosal sites distant from the site of immunization and, in addition, should induce protective levels of systemic immunity. Effective immunity at mucosal sites may serve to prevent infection, an important objective for antiherpesvirus vaccines since infection is invariably followed by latency and the likelihood of recrudescent disease. To test the effectiveness of mucosal immunity, mice will be challenged via the respiratory and vaginal routes. Systemic immunity will be evaluated by control of subsequent zosteriform spread of virus following infection via the dermis. Various Salmonella vectors expressing HSV genes in different ways will be evaluated as vaccines and measurements will be made of the extent of the humoral and T cell mediated immune responses at mucosal sites, serum and lymphoid tissues. Evidence will be sought for correlations between in vitro parameters of immunity and the subsequent response to viral challenge in the different models. Especial emphasis will be directed at the cytotoxic T lymphocyte responses since it is hypothesized that for solid immunity to HSV this form of immunity must be included in the immune response. Our research will evaluate if a recombinant attenuated Salmonella vector system holds promise as a means of vaccinating against HSV in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033511-02
Application #
2068560
Study Section
Special Emphasis Panel (SRC (42))
Project Start
1993-08-01
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Davis, I A; Rouse, B T (2000) Identification of select lymphocyte homing molecules and vascular addressins in lymphotoxin-alpha deficient mice. Lab Anim 34:111-4
Rouse, B T; Nair, S; Rouse, R J et al. (1998) DNA vaccines and immunity to herpes simplex virus. Curr Top Microbiol Immunol 226:69-78
Kuklin, N A; Daheshia, M; Marconi, P C et al. (1998) Modulation of mucosal and systemic immunity by enteric administration of nonreplicating herpes simplex virus expressing cytokines. Virology 240:245-53
Davis, I A; Rouse, B T (1998) Immune responsiveness of lymphotoxin-alpha-deficient mice: two reconstitution models. Cell Immunol 189:116-24
Chun, S; Daheshia, M; Kuklin, N A et al. (1998) Modulation of viral immunoinflammatory responses with cytokine DNA administered by different routes. J Virol 72:5545-51
Kuklin, N A; Daheshia, M; Chun, S et al. (1998) Role of mucosal immunity in herpes simplex virus infection. J Immunol 160:5998-6003
Davis, I A; Knight, K A; Rouse, B T (1998) The spleen and organized lymph nodes are not essential for the development of gut-induced mucosal immune responses in lymphotoxin-alpha deficient mice. Clin Immunol Immunopathol 89:150-9
Kuklin, N A; Daheshia, M; Chun, S et al. (1998) Immunomodulation by mucosal gene transfer using TGF-beta DNA. J Clin Invest 102:438-44
Manickan, E; Karem, K L; Rouse, B T (1997) DNA vaccines -- a modern gimmick or a boon to vaccinology? Crit Rev Immunol 17:139-54
Kuklin, N; Daheshia, M; Karem, K et al. (1997) Induction of mucosal immunity against herpes simplex virus by plasmid DNA immunization. J Virol 71:3138-45

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