Mycobacterium tuberculosis Strains of the Modern Sublineage of the Beijing Family Are More Likely To Display Increased Virulence than Strains of the Ancient Sublineage

Abstract

dStrains of the Beijing genotype family of Mycobacterium tuberculosis are a cause of particular concern because of their increasing dissemination in the world and their association with drug resistance. Phylogenetically, this family includes distinct ancient and modern sublineages. The modern strains, contrary to the ancestral counterparts, demonstrated increasing prevalence in many world regions that suggest an enhanced bacterial pathogenicity. We therefore evaluated virulence of modern versus ancient Beijing strains with similar epidemiological and genotype characteristics. For this, we selected six strains that had very similar 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing profiles and belonged to the region of difference 181 (RD181) subgroup but differed using markers (mutT2 and mutT4 genes and NTF locus) that discriminate between modern and ancient Beijing sublineages. The strains were isolated from native patients in Brazil and Mozambique, countries with a low prevalence of Beijing strains. The virulence levels of these strains were determined in models of pulmonary infection in mice and in vitro macrophage infection and compared with that of a strain from Russia, part of the epidemic and hypervirulent Beijing clone B0/W148, and of the laboratory strain H37Rv. The results showed that two of the three modern Beijing strains were highly pathogenic, exhibiting levels of virulence comparable with that of the epidemic Russian strain. In contrast, all isolates of the ancient sublineage displayed intermediate or low virulence. The data obtained demonstrate that the strains of the modern Beijing sublineage are more likely to exhibit highly virulent phenotypes than ancient strains and suggest that genetic alterations characteristic of the modern Beijing sublineage favor selection of highly virulent bacteria. Despite extensive surveillance, tuberculosis (TB) remains a serious public health problem. In different parts of the world, there is concern about TB caused by the East Asian/Beijing lineage of Mycobacterium tuberculosis, demonstrating increasing prevalence in the global M. tuberculosis population (1). Clinical and epidemiological studies demonstrated that emergence of the Beijing strains could be associated with high levels of bacterial resistance to multiple drugs (2, 3) and enhanced pathogenicity of these strains, leading to increased transmissibility (4) and rapid progression from infection to active disease (5). However, the data on evaluation of the virulence of Beijing isolates were inconclusive, demonstrating a wide range of inflammatory and virulence phenotypes, as determined in animal models (6,7,8) and in vitro models of macrophage infection (9, 10).Such differences in the virulence of Beijing strains could be associated with genetic heterogeneity of the Beijing M. tuberculosis lineage. Indeed, bacterial genotyping and sequencing demonstrated that the Beijing lineage, having in common a characteristic spoligotype signature and lack of the region ...

Southern East Asian origin and coexpansion of Mycobacterium tuberculosis Beijing family with Han Chinese

“…The dominance of "modern" Beijing strains in both endemic and epidemic areas strongly suggest they are hypervirulent compared with the "ancient" genotype, which has been supported by several experimental studies using infection models. For example, a recent study showed "modern" Beijing caused more histopathological changes and mortality in mice (56). Most of all, three more recent studies all found that "modern" Beijing strains induced lower and/or delayed proinflammatory that may enable the bacteria to escape from host immune response (57)(58)(59).…”

Insights into the processes that drive the evolution of drug resistance in Mycobacterium tuberculosis

“…At last, the mutation type has been correlated with the genetic background of M. tuberculosis lineages in several studies (Hillemann et al., 2005; Mokrousov et al., 2006; Qian et al., 2002; Ribeiro et al., 2014). For instance, the kat G S315T is prevalent in lineage 2, conversely the inh A‐15 mutation is associated mostly with lineage 1 (Casali et al., 2014; Fenner et al., 2012; Gagneux, Burgos, et al., 2006; Mokrousov et al., 2002; Nguyen, Nguyen, et al., 2017).…”

“…Thus, lineage 2 could be better adapted to compensate for the loss or reduced activity of this catalase‐peroxidase enzyme in the context of isoniazid resistance. This hypothesis could also explain why the Beijing strains are generally strongly associated with resistance to isoniazid, regardless of the type of kat G resistant‐associated mutations and country (Fenner et al., 2012; Gagneux, Burgos, et al., 2006; Mokrousov et al., 2002; Ribeiro et al., 2014; van Soolingen et al., 2000). …”

Correlates between Models of Virulence for Mycobacterium tuberculosis among Isolates of the Central Asian Lineage: a Case for Lysozyme Resistance Testing?

“…Three CAS isolates of lineage 3 (37) were selected from clusters of similar yet nonidentical sizes based on 15-locus MIRU-VNTR analysis. We hypothesized that subtle epidemiological differences should translate into differential readouts in ex vivo and in vivo models of virulence (22,27) and that identification of corresponding VFs should be facilitated in silico through the elimination of lineage-defining regions of difference (RDs), SNPs, or LSPs. Of the 2,261 isolates identified in London in the year examined, the isolates of interest represented 0.57% (C72; n ϭ 13), 1.02% (C6; n ϭ 23), and 2.34% (C14; n ϭ 53) of the total population, with 95% confidence intervals of 0.32 to 1%, 0.66 to 1.55%, and 1.77 to 3.07%, respectively, suggesting a higher prevalence of C14 than of C72 or C6.…”

“…It has become clear, however, that the previously unrecognized genetic diversity among M. tuberculosis isolates has an impact on the outcome of infection (17-19), and different approaches have been undertaken towards a better understanding of what makes a strain virulent. Some studies have attempted to tie epidemiological data to mechanistic explanations; for example, emerging Beijing strains are believed to be more virulent or associated with increased progression to disease (18,(20)(21)(22), and their glycolipids are believed to contribute to their phenotype (23)(24)(25)(26). Outbreak strains were also found to have remarkable growth properties in animal models (27,28) or to induce a differential protective host response (29-31).…”