Main Interests:

Our research program is concerned with mucosal immunity and its role in host defense, and in the mechanisms by which pathogens subvert host defenses. One of our major areas of interest is molecular vaccines. We are investigating the use of live Salmonella enterica serovar Typhimurium strains as vehicles to deliver cloned antigens to the Peyer's patches in the gut in order to efficiently stimulate a mucosal IgA response. Because an immune response can be elicited to a selected antigen and not to the entire organism, problems associated with undesirable and potentially dangerous side effects of whole cell vaccines can be avoided. This approach also allows comparison of mucosal and systemic immune responses to different virulence factors singly, or in combination in the same background without the need for rigorous purification of native virulence factors from the parent organism.

We have recently shown that a potential virulence factor from Porphyromonas gingivalis, a putative pathogen in periodontal disease, can be expressed in an intact and biologically active form in S. enterica serovar Typhimurium vaccine strains. We can induce strong serum IgG and IgA responses to this antigen as well as mucosal IgA responses in saliva, gut and vaginal secretions. We have also shown strong secondary responses using the same vaccine construct. Furthermore, we have demonstrated the capacity to induce long-term immunological memory. Immune responses, as well as the capacity to mount a recall response persist for at least one year in mice, which represents half of their lifespan.

Many questions remain concerning the basic immunology of live oral vectors. Factors such as recombinant gene expression level and cellular localization can affect the characteristics of the immune response. The ability to control the characteristics of the immune response, the immunogenicity of the foreign antigen and the induction of long-term memory are all desirable goals for the design of any vaccine. These studies will aid in our understanding of the effects of vaccine parameters on immunogenicity, the pattern of the immune response and factors which affect induction of long term memory and recall.

Publications:

Kohler, J.J., Pathangey, L., Hasona, A., Progulske-Fox, A., & Brown, T.A. (2000). Long-term immunological memory induced by recombinant oral Salmonella vaccine vectors. Infect Immun, 68(7), 4370-3.

Kohler, J.J., Pathangey, L.B., Gillespie, S.R., & Brown, T.A. (2000). Effect of preexisting immunity to Salmonella on the immune response to recombinant Salmonella enterica serovar typhimurium expressing a Porphyromonas gingivalis hemagglutinin. Infect Immun, 68(6), 3116-20.

Kozarov, E., Miyashita, N., Burks, J., Cerveny, K., Brown, T.A., McArthur, W.P., & Progulske-Fox, A. (2000). Expression and immunogenicity of hemagglutinin A from Porphyromonas gingivalis in an avirulent Salmonella enterica serovar typhimurium vaccine strain. Infect Immun, 68(2), 732-9.

Kohler, J.J., Pathangey, L.B., & Brown, T.A. (1999). Oral immunization with recombinant Salmonellatyphimurium expressing a cloned Porphyromonas gingivalis hemagglutinin: effect of boosting on mucosal, systemic and immunoglobulin G subclass response. Oral Microbiol Immunol, 13(2), 81-8.

Brown, T.A. (1996). Immunity at mucosal surfaces. Adv Dent Res, 10(1), 62-5.

Dusek, D.M., Progulske-Fox, A., & Brown, T.A. (1995). Expression and immunogenicity of a cloned Porphyromonas gingivalis hemagglutinin in Salmonellatyphimurium. Adv Exp Med Biol, 371B, 1119-21.

Dusek, D.M., Progulske-Fox, A., & Brown, T.A. (1994). Systemic and mucosal immune responses in mice orally immunized with avirulent Salmonella typhimurium expressing a cloned Porphyromonas gingivalis hemagglutinin. Infect Immun, 62(5), 1652-7.

Dusek, D.M., Progulske-Fox, A., Whitlock, J., & Brown, T.A. (1993). Isolation and characterization of a cloned Porphyromonas gingivalis hemagglutinin from an avirulent strain of Salmonella typhimurium. Infect Immun, 61(3), 940-6.

Brown, T.A., Byres, L., Gardner , M., & Van Dyke, T.E. (1991). Subclass and molecular form of immunoglobulin A antibodies to Actinobacillus actinomycetemcomitans in juvenile periodontitis. Infect Immun, 59(3), 1126-30.

Brown, T.A., & Leak, I.G. (1989). A solid-phase immunoassay for detection of IgA1 protease activity on agar plates. J Immunol Methods, 123(2), 241-7.

Brown, T.A., Clements, M.L., Murphy, B.R., Radl, J., Haaijman, J.J., & Mestecky, J. (1987). Molecular form and subclass distribution of IgA antibodies after immunization with live and inactivated influenza A vaccines. Adv Exp Med Biol, 216B, 1691-700.

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