Identifying key determinants underlying variable efficacy of BCG substrains against Pulmonary TB.

Abstract

Protection conferred by BCG vaccine against adult pulmonary TB ranges from 0–80% based on large, well-controlled field trials. This variability is highly significant (P < 0.0001) and is regarded as being indicative of true biological differences in immunogenicity [1,2]. Out of many reasons responsible for the variable efficacy of BCG vaccine against Pulmonary TB, genetic variation between BCG substrains is considered an important factor [1,2]. These genetic variations exist because of the inability to preserve original stock and subsequent passaging globally, eventually resulting in a profusion of phenotypically different daughter strains that are collectively known as BCG [3]. Supporting this idea, BCG Pasteur strain (among most passaged BCGs) is less efficacious than BCG Tokyo (least passaged) as a vaccine against Pulmonary TB [2,11,40]. However, the molecular underpinning of these differences remains unknown. Several lines of evidence indicate that the redox metabolism of these strains differs, which contributes to variable efficacy. For example, BCG Pasteur has a higher antioxidant capacity than BCG Tokyo [2,9]. Also, modified BCG with reduced antioxidants has been shown to confer better protection [10]. In order to develop comprehensive insight and identify key modulators, which govern the differences, reported between BCG Pasteur (weak vaccine strain) and BCG Japan transcriptome, and thereby controlling its efficacy as well, we adopted a systems biology approach. We analyzed the transcriptome data of these strains and overlaid the expression changes on the global protein-protein interaction (PPI) map to generate weighted PPI networks of BCG Pasteur and Tokyo. This approach allowed us to confirm that several pathways converging at the level of redox metabolism likely drives variations in the efficacy of these strains as a vaccine. We identified four key nodes - whiB3, sigH, RegX3 and Rv1776c as major determinants of vaccine potential of these strains