Use of Soluble Extracellular Regions of MmpL (SERoM) as Vaccines for Tuberculosis

Emily J Strong,Nicholas P West

doi:10.1038/s41598-018-23893-3

Emily J Strong, Nicholas P West

Open Access

https://doi.org/10.1038/s41598-018-23893-3

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Journal: Scientific Reports	Publication Date: Apr 4, 2018
Citations: 3	License type: open-access

Affiliation: University of Queensland

Abstract

The current vaccine for tuberculosis (TB) is a live attenuated strain of Mycobacterium bovis (BCG) and while effective at reducing the potential for disseminated TB in young children its disease protection rates in adults is highly variable while it confers little protection against latent TB. With these limitations a new vaccine is desperately needed. We investigated the efficacy of three members of the mycobacterial membrane protein Large (MmpL) family as potential subunit vaccines for TB. MmpLs are large, multifunctional integral membrane proteins, and as such are recalcitrant to purification. Here, we describe a strategy of producing synthetic antigens comprised of the soluble, extracellular regions of MmpL (SERoM)-1, MmpL8 and MmpL10 (SERoM-8 and 10 respectively) as potential vaccine candidates. SERoM-1 and SERoM-8 were determined to be highly immunogenic by IFN-γ ELISpot assays, with 0.1% of all splenocytes from SERoM-1 vaccinated mice producing IFN-γ when re-stimulated with MmpL1. A combined SERoM-1, −8 and −10 vaccine demonstrated significant protection against M. tuberculosis challenge in a murine model of TB, resulting in approximately 10-fold reduction in bacterial numbers following challenge in both the lungs and spleens compared to adjuvant only vaccinated mice. These protective effects were comparable to that achieved with BCG.

Highlights

The only vaccine ever licensed to protect against TB is the attenuated M. bovis Bacillus Calmette-Guérin (BCG) live vaccine
This study reveals that SERoM1 and SERoM8 are immunogenic proteins, with SERoM1 providing protective efficacy against M. tuberculosis infection
The amino acids mapping to these regions for MmpL1 are inclusive of residue 40 to 192 (R1) and residue 396 to 759 (R2); for MmpL8, residue 65 to 219 (R1) and residue 423 to 872 (R2); and for MmpL10, residue 1 to 170 (R1) and residue 379 to 804 (R2)

Summary

Introduction

The only vaccine ever licensed to protect against TB is the attenuated M. bovis Bacillus Calmette-Guérin (BCG) live vaccine. The MmpL proteins possess extended surface domains which are involved in the translocation of cell wall outer components and sequestration of essential nutrients from the host Their extracellular location and important functionality make them strong potential vaccine candidates. MmpL1 is a functional, single open reading frame in M. tuberculosis but contains a stop codon insertion resulting in a truncated transcript in M. bovis, the parental stain of the BCG vaccine. In a murine infection it was observed that MmpL8 may play a role in the suppression of Th1 immunity[13] These findings indicate a strong requirement for their in vivo expression and forms the basis for our interest in investigating their potential as subunit vaccine candidates. In Addition to B-cell epitopes, MmpLs contain strong T-cell epitopes within the predicted host exposed region of the protein[21]

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Results

Conclusion