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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2019.00331

Editorial: Cellular and Molecular Mechanisms of Mycobacterium tuberculosis Virulence

 Jianjun Sun1*, Partricia A. Champion2* and  FABIANA BIGI3*
  • 1Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, United States
  • 2Department of Biological Sciences, University of Notre Dame, United States
  • 3National Institute of Agricultural Technology, Argentina

Mycobacterium tuberculosis (Mtb) is the bacterial pathogen that causes the majority of human tuberculosis (TB), the leading infectious disease in the world (1). Mtb invades the human host by aerosol and establishes infection in lung by using virulence factors to combat host immunity. Over the past several decades, significant progress has been made in our understanding of Mtb pathogenesis. However, the mechanisms of Mtb virulence remain largely unknown. Moreover, the emergence of multidrug resistant Mtb strains and co-infection of Mtb with HIV have posed new challenges in TB control. There is an urgent need to enhance our understanding of Mtb pathogenesis and to develop effective countermeasures against TB. This frontiers research topic reports recent new findings that cover diverse aspects of cellular and molecular mechanisms of Mtb virulence.A new role of the well-known virulence factor ESAT-6 in regulating macrophage differentiation ESAT-6 (6-kDa early secreted antigenic target), a well-documented Mtb virulence factor, is essential for Mtb pathogenesis, including phagosomal rupture, mycobacterial cytosolic translocation and cell-to-cell spreading (2-10). ESAT-6 appears to function as an important modulator of host inflammatory responses by manipulating several intracellular signaling pathways in macrophages, T cells and epithelial cells (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Here, Refai et al. report a new role of ESAT-6 in macrophage differentiation and polarization. They found that during early infection, ESAT-6 induced differentiation of M0 and M2 macrophages toward the pro-inflammatory M1 phenotype to promote granuloma formation. Subsequently, ESAT-6 drove the phenotype switch from M1 to anti-inflammatory M2 macrophages to maintain the infection during the later persistent phases.RD4: A number of regions of difference (RD) among mycobacterial species have been identified by comparative genomic studies (21)(22)(23)(24)(25). RD1, which is present in the Mtb complex and in a related species Mycobacterium marinum, but absent from the Mycobacterium bovis Bacille CalmetteGuérin (BCG) genome, encodes an ESX-1 type VII secretion system that has been extensively investigated as a major virulence factor (26,27). However, other regions of difference between mycobacterial pathogens and attenuated BCG strain have been characterized to a lesser extent. Ru et al. investigated the potential role of RD4 in virulence. RD4 is larger in M. marinum than in Mtb, but absent in M. bovis, including BCG, suggesting a gradual decay of RD4 in mycobacterial genomes in the order of M. marinum, Mtb, and M. bovis. The knock-in strains of BCG and M. marinum containing the entire or partial RD4 regions exhibited alterations of wild type virulence in both mouse and zebrafish models of infection. Thus, RD4 appears to be a new locus contributing to the mycobacterial virulence.CitE: Bacterial citrate lyase, which is important for both metabolism and virulence, is comprised of three subunits, CitD (), CitF () and CitE () (28,29). The Mtb genome encodes 2 paralogous CitE subunits (CitE1 and CitE2), but their role in Mtb virulence has not been explored. Arora et al. biochemically and functionally characterized the CitE enzymatic subunits. The purified CitE1 and CitE2 proteins degraded acetyl-CoA and propionyl-CoA in vitro and the genes encoding both enzymes were up-regulated when Mtb was exposed to oxidative stress. Moreover, deletion of the citE genes from the Mtb genome reduced the resistance to oxidative stress, intracellular replication in macrophages and growth in a guinea pig infection model. This study suggests that CitE may be a potential target for TB drug development.A novel phylogenetic clade associated hypervirulent strain: Rajwani et al. analyzed the phylogenetic relatedness of a hypervirulent Mtb strain (H112) with global collection of M. tuberculosis genomes and identified a novel phylogenetic clade that share single-nucleotidepolymorphisms (SNPs) in key virulence-associated loci, including the mce1 locus and the phoP gene. This clade includes four hypervirulent strains isolated from geographically diverse regions. The common SNPs and structural variations within the clade may be considered as potential genetic determinants of hypervirulence for future studies.While Mtb is the most common cause of human TB, M. bovis can cause TB in both humans and cattle, making it a zoonotic threat to both food safety and public health (30)(31)(32). Moreover, the knowledge obtained in the studies of M. bovis infection is valuable for understanding of Mtb infection due to their close relationship. In the comparative proteomic study done by Li et al., they identified proteins that were differentially regulated in human macrophages following infection with M. bovis, including proteins in several pathways that are similar to Mtb infections, such as phagosome maturation pathway and TNF signaling pathway. In addition, a number of proteins and enzymes that are mainly involved in metabolic pathways, endocytosis and endosome trafficking events were found to be uniquely affected by M. bovis infection.Drug-resistance is mainly caused by mutations in Mtb genome, particularly by single nucleotide polymorphisms in genes whose protein products are directly targeted by anti-TB drugs (33,34). Hameed et al. provided a comprehensive review on the major molecular targets that are related to drug resistance mechanisms of Mtb.The mutations in the thyA (encoding thymidylate synthase A) and folC (encoding FolCdihydrofolate synthase) genes have been associated with resistance to Para-Aminosalicylic acid (PAS) (35-37), a second-line anti-TB drug. Methionine is structurally related to anti-folate drugs and is shown to antagonize PAS. However, the mechanism for methionine-based antagonism remains undefined. Using both targeted and untargeted approaches, Howe et al. found that MetM, a putative amino acid transporter, plays a crucial role in the synthesis of folate precursors, which antagonizes PAS activity.Drug induced reversion of antibiotic resistance has drawn recent attention as a prospective approach to combat drug resistance (38). FS-1, a new anti-TB drug, induces antibiotic resistance reversion in Mtb. In the report done by Ilin et al., FS-1 was used in combination with standard anti-TB antibiotics on guinea pigs infected with an XDR-Mtb strain. The genetic changes in Mtb genomes following infection were analyzed and FS-1 was found to cause a counter-selection of drug resistant variants that sped up the recovery of the infected animals from XDR-TB. While the drug-resistance mutations remained intact in more sensitive isolates, reversion of drug resistance was associated with a general increase in genetic heterogeneity of the Mtb population.The articles in this research topic present new findings regarding the cellular and molecular mechanisms of Mtb virulence, including characterization of new roles for known virulence factors, identification of new virulence factors, and the elucidation of drug-resistance mechanisms and reversion. This research topic, together with many recent publications, enhances our understanding of the mechanism of Mtb virulence and pathogenesis.

Keywords: Mycobacterium tuberculosis, Drug Resistance, Virulence, Pathogenesis, host-pathogen interaction

Received: 28 Aug 2019; Accepted: 06 Sep 2019.

Copyright: © 2019 Sun, Champion and BIGI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Jianjun Sun, The University of Texas at El Paso, Department of Biological Sciences and Border Biomedical Research Center, El Paso, United States, jsun@utep.edu
Mx. Partricia A. Champion, University of Notre Dame, Department of Biological Sciences, Notre Dame, 46556, Indiana, United States, pchampion@nd.edu
Mx. FABIANA BIGI, National Institute of Agricultural Technology, Buenos Aires, Buenos Aires, Argentina, bigi.fabiana@inta.gob.ar