Novel vaccine potential of Rv3131, a DosR regulon-encoded putative nitroreductase, against hyper-virulent Mycobacterium tuberculosis strain K

Kee Woong Kwon,Mi-Young Hahn,Sang-Nae Cho,Jong Seok Lee,Woo Sik Kim,Seung Jung Han,Ki Taek Nam,Hongmin Kim,Sung Jae Shin

doi:10.1038/srep44151

Kee Woong Kwon, Mi-Young Hahn + Show 7 more

Open Access

https://doi.org/10.1038/srep44151

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Abstract

Accumulating evidence indicates that latency-associated Mycobacterium tuberculosis (Mtb)-specific antigens from the dormancy survival regulator regulon (DosR) may be promising novel vaccine target antigens for the development of an improved tuberculosis vaccine. After transcriptional profiling of DosR-related genes in the hyper-virulent Beijing Mtb strain K and the reference Mtb strain H37Rv, we selected Rv3131, a hypothetical nitroreductase, as a vaccine antigen and evaluated its vaccine efficacy against Mtb K. Mtb K exhibited stable and constitutive up-regulation of rv3131 relative to Mtb H37Rv under three different growth conditions (at least 2-fold induction) including exponential growth in normal culture conditions, hypoxia, and inside macrophages. Mice immunised with Rv3131 formulated in GLA-SE, a well-defined TLR4 adjuvant, displayed enhanced Rv3131-specific IFN-γ and serum IgG2c responses along with effector/memory T cell expansion and remarkable generation of Rv3131-specific multifunctional CD4+ T cells co-producing TNF-α, IFN-γ and IL-2 in both spleen and lung. Following challenge with Mtb K, the Rv3131/GLA-SE-immunised group exhibited a significant reduction in bacterial number and less extensive lung inflammation accompanied by the obvious persistence of Rv3131-specific multifunctional CD4+ T cells. These results suggest that Rv3131 could be an excellent candidate for potential use in a multi-antigenic Mtb subunit vaccine, especially against Mtb Beijing strains.

Highlights

The phenotypic, genotypic and pathogenic variation among Mycobacterium tuberculosis (Mtb) strains should be taken into account, as these factors can contribute to vaccine efficacy[13,14], and different Mtb strains exhibit different levels of virulence[13]
Whole genome microarray analysis indicated that dormancy survival regulator (DosR) regulon-associated genes were highly up-regulated in Mtb K relative to H37Rv under normal in vitro culture conditions
There is accumulating evidence that the inclusion of latency-associated Ags, Ags encoded by the DosR regulon, will be important in the development of a more potent TB vaccine[6]

Summary

Introduction

The phenotypic, genotypic and pathogenic variation among Mtb strains should be taken into account, as these factors can contribute to vaccine efficacy[13,14], and different Mtb strains exhibit different levels of virulence[13]. One characteristic of Beijing strains is that this genotype is significantly associated with increased risk for relapse[21,22,23]; this high relapse rate might be related to the high expression of latency-associated genes, including the dormancy survival regulator (DosR) based on mice model study[18,24]. This DosR regulon, which is collectively transcribed by the DosR transcription factor, consists of ~50 genes (1.3% of the Mtb genome) classified into 9 functional categories[25] and plays an important role in Mtb adaptation in adverse conditions[7]. We investigated the immunogenicity and protective efficacy of Rv3131 formulated in GLA-SE (glucopyranosyl lipid adjuvant-stable emulsion), a well-defined TLR4 adjuvant, as a subunit vaccine platform against hyper-virulent Mtb K challenge

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