BCG-Mediated Immunotherapy Against Bacteria

About This Grant

Abstract Up to 3.5 billion dollars is spent each year, in the US alone, to manage bladder infections and their recurrence. The intractability of these infections is attributable, in part, to the capacity of bladder bacteria to persist in the bladder long after infection resolution only to remerge as another flareup. In view of the fact that antibiotics are largely ineffective there is a dire need for alternate approaches to protect against these infections. We have found that a single bladder treatment of live attenuated Bacillus Calmette-Guerin (BCG), an FDA approved therapy for bladder cancer, along with a peptide capable of disrupting the superficial epithelium was highly efficacious in protecting against uropathogenic E.coli (UPEC) mediated infection. Since tumor fighting properties of BCG is associated with their persistence in the bladder and their capacity to recruit Th1 cells, the protection against UPEC is probably also mediated, at least in part, by Th1 cells. We hypothesize that we can prolong the duration of this protection by simultaneously inducing bladder recruitment of E.coli specific Th1 cells which typically have an indefinite life span. Thus, we believe that supplementing the BCG and epithelial disruptor peptide formulation with UPEC antigens would markedly prolong and enhance the protective capacity of BCG immunotherapy against UPEC bladder infections. The following specific aims are proposed: (i) Determine cellular targets of BCG uptake and persistence in the bladder, (ii) Identify the immunological basis of cross-protection induced by co-treatment with BCG bladder and epithelial disruptor peptide (iii) Evaluate the efficacy and durability of intravesical administration of an optimized formulation comprising of epithelial disruptor peptide/BCG/ UPEC antigens in combating recurrent bladder infections. It is expected that these studies will reveal a distinct, effective, and long-lasting strategy to combat intractable bladder infections. Since this strategy involves repurposing a currently utilized bladder therapy, its implementation could be relatively rapid.