Brucellosis is a zoonotic infection caused by Brucella species. Two species, B. abortus and B. melitensis, are select agents and considered potential bioweapons, and there are no approved vaccines for use in humans. Approved vaccines do exist for livestock; however, they are only 60-70% effective, are infectious to humans, sometimes abortogenic, and the smooth vaccine can convolute diagnostic serology. Treatment of humans with brucellosis is complicated, requiring the administration of two antibiotics for extended periods of time. Such long-term antibiotic use has negative consequences upon the microbiome, now appreciated as critical in maintaining immune homeostasis and gut health. Development of antibiotic resistance is also a concern. As such, there is a clear need for new approaches for treatment of brucellosis, and this extends to a number of other bacterial diseases. We found that stimulation of innate immunity can reduce Brucella burden in the mouse model. In combination with other therapies, this treatment could eliminate infection. Bacteriophage (phage) therapy is a novel, highly specific alternative to antibiotics. We propose to use Brucella-specific phages, in combination with innate immune stimulation, as a novel countermeasure for brucellosis. Brucella can replicate intracellularly, sequestered away from phages. Thus, we will also encapsulate phage in liposomes for enhanced uptake into cells. We hypothesize that Stimulation of the innate immune system together with phage therapy, with or without liposome delivery, will result in synergistic and successful protection from Brucella infection. We will assess the effects of Brucella phages on Brucella replication in macrophages in vitro. The phages will be combined with innate immunostimulation, and encapsulated into liposomes. We will assess the effects of the novel phage preparations in the mouse model of brucellosis. At the completion of these studies, we will have proof of principle for an alternative treatment for brucellosis and possibly other diseases caused by intracellular bacterial pathogens. !
Brucellosis a Select Agent and zoonotic pathogen that is highly infectious. Though vaccines exist for animals, there are no vaccines for humans, and treatment of the human disease requires long-term high dose antibiotics, which have negative consequences. At the completion of this proposal we will have investigated the benefit of combining phage therapy and broad stimulation of innate immunity as a novel countermeasure for brucellosis as an alternative to antibiotics.
