Less may be more for Brucella bacteriophage therapy due to immune suppressive effects

Abstract We are studying the applicability of Brucella-specific phages to counter brucellosis. With antibiotic resistance on the rise and new realizations concerning the detrimental effects of long-term antibiotic use, phage therapy may become a useful approach against bacterial infection. However, phages are frequently less effective at countering bacterial infection in vivo than is expected considering their strong anti-bacterial effects in vitro. Furthermore, the effects of phage on mammalian cells are largely unknown. We have discovered that Brucella-specific phages are capable of activating some immune components, while suppressing others. Specifically, Brucella phages can activate bovine γδ T cells directly in vitro as measured by upregulation of IL-2R, but dampen the expression of TNF-α induced by E. coli LPS. A similar effect can be measured on human THP-1 macrophages. Also, in an in vitro model of intracellular Brucella infection, low phage MOI was capable of protecting cells from infection, but, unexpectedly, use of high phage MOI diminished protection. In vivo delivery of low phage MOI to the lung was more effective at diminishing Brucella burden than higher doses of phage. Finally, combining low dose phage with innate immune stimulation was more effective at reducing Brucella bacterial burden than either treatment alone. We hypothesize that some phage preparations induce an immune suppressive response that may counteract their anti-bacterial effects. Potentially combinatorial approaches may overcome this suppressive response. Our discovery of immune suppressive effects of Brucella bacteriophages is an important consideration for using phage as a treatment. This work is supported by NIH R21 AI144496-01.