In silico comparisons of lipid-related genes between Mycobacterium tuberculosis and BCG vaccine strains.

Alice Sarno,Sergio Arruda,Adriano Queiroz,Julia Bitencourt

doi:10.1590/1678-4685-gmb-2021-0024

Abstract

Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to prevent the tuberculosis (TB). Genomic heterogeneity between attenuated BCG strains and virulent Mycobacterium tuberculosis might help to explain this vaccine’s impaired capacity to induce long-term protection. Here, we investigate the lipid-related genes absent in attenuated BCG strains in order to correlate changes in both lipid metabolism and cell-wall lipid content to vaccine impairment. Whole genome sequences of M. tuberculosis H37Rv and the six most used BCG strains worldwide were aligned and the absent regions functionally categorized. Genomes of the BCG strains showed a total of 14 non-homologous lipid-related genes, including those belonging to mce3 operon, as well as the gene echaA1, which encodes an enoyl-CoA hydratase, and the genes encoding phospholipases PlcA, PlcB and PlcC. Taken together, the depletion of these M. tuberculosis H37Rv genomic regions were associated with marked alterations in lipid-related genes of BCG strains. Such alterations may indicate a dormant-like state and can be determining factors to the vaccine’s inability to induce long-term protection. These lipids can be further evaluated as an adjuvant to boost the current BCG-based vaccine.

Highlights

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a leading cause of death worldwide: In 2019 alone, 1.2 million deaths and 10 million new cases were reported
High homogeneity was observed between most BCG strains and M. tuberculosis H37Rv, with up to 94.6% of homologous regions identified in the BCG Moreau genome
The present study identified and categorized a comprehensive list of absent lipid-related genes shared by the most used BGC strains worldwide compared to the M. tuberculosis H37Rv genome

Summary

Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a leading cause of death worldwide: In 2019 alone, 1.2 million deaths and 10 million new cases were reported. One of the hypotheses to explain the variable protectiveness of BCG posits the genomic heterogeneity between vaccine and virulent M. bovis and M. tuberculosis strains (Behr 2002; Liu et al, 2009; Angelidou et al, 2020). Since it was first obtained and distributed, BCG has accumulated large sequence polymorphisms and has lost several virulence factor genes, including deletion of the region RD1, which encodes antigenic proteins ESAT-6 and CFP-10 (Mahairas et al, 1996; Lewis et al, 2003). The expression of RD1 in recombinant BCG does not result in a complete restoration of protection against TB, which could indicate that other mechanisms may be involved in virulence (Pym et al, 2003)

Methods

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Conclusion