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Review
. 2013 May 16:3:17.
doi: 10.3389/fcimb.2013.00017. eCollection 2013.

Host-Brucella interactions and the Brucella genome as tools for subunit antigen discovery and immunization against brucellosis

Gabriel Gomez  1 , Leslie G Adams, Allison Rice-Ficht, Thomas A Ficht
Affiliations
Review

Host-Brucella interactions and the Brucella genome as tools for subunit antigen discovery and immunization against brucellosis

Gabriel Gomez et al. Front Cell Infect Microbiol. .

Abstract

Vaccination is the most important approach to counteract infectious diseases. Thus, the development of new and improved vaccines for existing, emerging, and re-emerging diseases is an area of great interest to the scientific community and general public. Traditional approaches to subunit antigen discovery and vaccine development lack consideration for the critical aspects of public safety and activation of relevant protective host immunity. The availability of genomic sequences for pathogenic Brucella spp. and their hosts have led to development of systems-wide analytical tools that have provided a better understanding of host and pathogen physiology while also beginning to unravel the intricacies at the host-pathogen interface. Advances in pathogen biology, host immunology, and host-agent interactions have the potential to serve as a platform for the design and implementation of better-targeted antigen discovery approaches. With emphasis on Brucella spp., we probe the biological aspects of host and pathogen that merit consideration in the targeted design of subunit antigen discovery and vaccine development.

Keywords: Brucellosis; antigen discovery; intracellular pathogens; reverse vaccinology; subunit vaccine; vaccines.

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Figures

Figure 1
Figure 1
Brucella invasion and intracellular trafficking in host mammalian cells. Smooth Brucella is internalized in a vacuole following interactions with host cell lipid rafts, PrPc, and SR-A. Brucella derived β-1,2-glucans act by remodeling surface vacuolar lipid-rich domains. The vacuole then fuses transiently with host cell lysosomes for replication- competent bacteria. These transient interactions lead to activation of acid-dependent genes, including type 4 secretion system. Type 4 secretion system substrate proteins are translocated to the cytosol of the host cell where they purportedly act to support trafficking and interactions with the endoplasmic reticulum in order to reach the replicative vacuole. In contrast, internalization and intracellular trafficking of rough Brucella is poorly characterized but a role for Brucella Omp22 and Omp25 has been demonstrated. The events that occur after internalization are not clear but ultimately lead to lysosomal degradation.
Figure 2
Figure 2
Vaccine candidate selection approach. An important aspect of a vaccine candidate is antigenicity. In silico analysis of available genomic sequences can aid in the selection of open reading frames that code for desired properties such as T and B cell epitopes, subcellular localization (i.e., outer membrane proteins), and a lack of homology to host proteins. Secondly, antigens with evidence for a role in pathogenesis are often targeted in the identification of vaccine candidates. Identification of factors important for invasion, survival, and replication can be performed via mutagenesis studies in the mouse or cell culture systems. Additionally, comparative transcriptomic and proteomic studies of wild type and mutant pathogen strains can be carried out to identify potential virulence factors. Lastly, the priming of an immune response to a specific antigen relies on its availability. In order to identify antigenic targets present during infection, infection-dependent gene expression studies may reveal suitable targets.
Figure 3
Figure 3
Model for antigen presentation during Brucella infection. Upon internalization of Brucella, the conditions in the vacuole trigger changes in the gene expression profiles. Interactions or fusion with the lysosomes result in changes that support intracellular replication or lead to Brucella degradation, respectively. Peptides that result from degradation are presented via MHCII to helper T cells or, presumptively, to cytotoxic T cells via the vacuolar pathway of cross-presentation. Intracellular Brucella proteins are processed for presentation via MHCI molecules. Proteins are processed into peptides by host proteosomes in the cytosol. Peptides are loaded into MHCI molecules in the endoplasmic reticulum and packaged in the golgi apparatus for transportation to the surface of the host cell for presentation and activation of T cells.
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