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Discordant Brucella melitensis antigens yield cognate CD8+ T cells in vivo.

ABSTRACT: Brucella spp. are intracellular bacteria that cause the most frequent zoonosis in the world. Although recent work has advanced the field of Brucella vaccine development, there remains no safe human vaccine. In order to produce a safe and effective human vaccine, the immune response to Brucella spp. requires greater understanding. Induction of Brucella-specific CD8+ T cells is considered an important aspect of the host response; however, the CD8+ T-cell response is not clearly defined. Discovering the epitope containing antigens recognized by Brucella-specific CD8+ T cells and correlating them with microarray data will aid in determining proteins critical for vaccine development that cover a kinetic continuum during infection. Developing tools to take advantage of the BALB/c mouse model of Brucella melitensis infection will help to clarify the correlates of immunity and improve the efficacy of this model. Two H-2(d) CD8+ T-cell epitopes have been characterized, and a group of immunogenic proteins have provoked gamma interferon production by CD8+ T cells. RYCINSASL and NGSSSMATV induced cognate CD8+ T cells after peptide immunization that showed specific killing in vivo. Importantly, we found by microarray analysis that the genes encoding these epitopes are differentially expressed following macrophage infection, further emphasizing that these discordant genes may play an important role in the pathogenesis of B. melitensis infection.

SUBMITTER: Durward MA

PROVIDER: S-EPMC2798188 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Discordant Brucella melitensis antigens yield cognate CD8+ T cells in vivo.

Durward Marina A MA Harms Jerome J Magnani Diogo M DM Eskra Linda L Splitter Gary A GA

Infection and immunity 20091102 1

Brucella spp. are intracellular bacteria that cause the most frequent zoonosis in the world. Although recent work has advanced the field of Brucella vaccine development, there remains no safe human vaccine. In order to produce a safe and effective human vaccine, the immune response to Brucella spp. requires greater understanding. Induction of Brucella-specific CD8+ T cells is considered an important aspect of the host response; however, the CD8+ T-cell response is not clearly defined. Discoverin ...[more]

PMID: 19884330

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Project description:Brucellosis remains a significant zoonotic threat worldwide. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure. After mucosal infection, brucellosis develops into a systemic disease. Mucosal vaccination could offer a viable alternative to conventional injection practices to deter disease. Using a nasal vaccination approach, the ?znuA B. melitensis was found to confer potent protection against pulmonary Brucella challenge, and reduce colonization of spleens and lungs by more than 2500-fold, with >50% of vaccinated mice showing no detectable brucellae. Furthermore, 10-fold more brucellae-specific, interferon-? (IFN-?)-producing CD8(+) T cells than CD4(+) T cells were induced in the spleen and respiratory lymph nodes. Evaluation of pulmonary and splenic CD8(+) T cells from mice vaccinated with ?znuA B. melitensis revealed that these expressed an activated effector memory (CD44(hi)CD62L(lo)CCR7(lo)) T cells producing elevated levels of IFN-?, tumor necrosis factor-?, perforin and granzyme B. To assess the relative importance of these increased numbers of CD8(+) T cells, CD8(-/-) mice were challenged with virulent B. melitensis, and they showed markedly increased bacterial loads in organs in contrast to similarly challenged CD4(-/-) mice. Only ?znuA B. melitensis- and Rev-1-vaccinated CD4(-/-) and wild-type mice, not CD8(-/-) mice, were completely protected against Brucella challenge. Determination of cytokines responsible for conferring protection showed the relative importance of IFN-?, but not interleukin-17 (IL-17). Unlike wild-type (wt) mice, IL-17 was greatly induced in IFN-?(-/-) mice, but IL-17 could not substitute for IFN-?'s protection, although an increase in brucellae dissemination was observed upon in vivo IL-17 neutralization. These results show that nasal ?znuA B. melitensis vaccination represents an attractive means to stimulate systemic and mucosal immune protection via CD8(+) T-cell engagement.

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Discordant Brucella melitensis antigens yield cognate CD8+ T cells in vivo.

Publications

Discordant Brucella melitensis antigens yield cognate CD8+ T cells in vivo.

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