Partial Protection against Brucella Infection in Mice by Immunization with Nonpathogenic Alphaproteobacteria

Abstract

Previous findings indicate thatBrucellosis, an infectious disease affecting livestock and humans, is caused by different species of the genus Brucella, which belongs to the alpha-2 subgroup of the Proteobacteria. This subgroup also includes genera normally nonpathogenic for humans, such as Agrobacterium, Rhizobium, and Ochrobactrum (24). In contrast to Brucella species, which infect animals and humans, other alphaproteobacteria usually live in the soil (Ochrobactrum), establish symbiotic relationships with plants (Rhizobium, Mesorhizobium, and Sinorhizobium species) (19), or are phytopathogens (Agrobacterium) (29). These related alphaproteobacteria are not pathogenic for immunocompetent individuals or show only a limited pathogenicity. Human infections with Agrobacterium tumefaciens (Agrobacterium radiobacter) and Ochrobactrum anthropi have been reported almost exclusively to occur in immunocompromised patients or in those with debilitating underlying diseases or undergoing chemotherapy (2, 3, 21). There are no reports of human disease by Rhizobium and other nodule-forming bacteria.The close genetic and antigenic relationship between Brucella and nonpathogenic alphaproteobacteria (NPAP) has been revealed by several studies. A total of 1,902 Brucella suis open reading frames are conserved in Mesorhizobium loti, Sinorhizobium meliloti, and Agrobacterium tumefaciens, and 2,408 B. suis open reading frames are conserved in at least one of these three genomes (25). Similar relationships have been observed between NPAP and Brucella melitensis and Brucella abortus, since the genomes of the last two species are highly similar to that of B. suis (13,17).Few studies have investigated the immunological cross-reactivity between proteins from Brucella and those from related alphaproteobacteria. Velasco et al. (30) found an extensive cross-reactivity between cytosolic proteins from Brucella melitensis and those from Ochrobactrum anthropi and also some cross-reactions at the level of outer membrane proteins and lipopolysaccharide. More recently, we have shown the existence of cross-reactivities between Brucella and other NPAP, including Sinorhizobium meliloti and Agrobacterium tumefaciens (12). Moreover, we showed that some of these cross-reactivities could potentially be exploited for the development of serological tests for brucellosis based on antigens from NPAP.Live attenuated Brucella strains are still widely used for the vaccination of animals against brucellosis. While these vaccines have reduced virulence for animals, they still can produce disease in humans (4,5,6,27). Therefore, large-scale production of such vaccines requires biosafety level 3 facilities (11), which are seldom available in developing countries, where brucellosis is more prevalent. This is one of the reasons that has led many researchers to investigate alternative vaccination strategies for brucellosis, including the use of subunit vaccines based on recombinant proteins (1, 15) or the use of DNA

Immunization with Recombinant Brucella Species Outer Membrane Protein Omp16 or Omp19 in Adjuvant Induces Specific CD4 + and CD8 + T Cells as Well as Systemic and Oral Protection against Brucella abortus Infection

“…Furthermore, intragastric immunizations with different purified Ags and appropriate adjuvants were able to induce protective responses against different pathogens (20,30,32). Even though there are a significant number of recent studies evaluating oral Brucella challenge (14,29,31), to our knowledge there is only one report describing the use of a recombinant purified protein as an oral vaccine against Brucella (16). Therefore, a subunit vaccine that would also prevent oral infection would be of great value in the brucellosis field.…”

Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

“…Among three of these six subunit vaccines that use Freund's adjuvants, two of them use complete Freund's adjuvant for the primary immunization and incomplete Freund's adjuvant for the boost vaccination [ 40 , 41 ]. Three other vaccines are not categorized as subunit vaccines [ 43 – 45 ]. Among them is a vaccine that uses a DNA vaccine for priming and uses a recombinant protein adjuvanted by incomplete Freund's adjuvant for boosting [ 45 ].…”

“…Among them is a vaccine that uses a DNA vaccine for priming and uses a recombinant protein adjuvanted by incomplete Freund's adjuvant for boosting [ 45 ]. The NPAP Brucella vaccine is a killed vaccine that uses Freund's incomplete adjuvant [ 43 ]. The recombinant O. anthropi expressing Brucella Cu/Zn SOD is live vaccine that uses with CpG DNA adjuvant [ 44 ].…”