Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>The Beijing family of<jats:named-content content-type="genus-species">Mycobacterium tuberculosis</jats:named-content>strains is part of lineage 2 (also known as the East Asian lineage). In clinical studies, we have observed that isolates from the sublineage RD207 of lineage 2 were more readily transmitted among humans. To investigate the basis for this difference, we tested representative strains with the characteristic Beijing spoligotype from four of the five sublineages of lineage 2 in the guinea pig model and subjected these strains to comparative whole-genome sequencing. The results of these studies showed that all of the clinical strains were capable of growing and causing lung pathology in guinea pigs after low-dose aerosol exposure. Differences between the abilities of the four sublineages to grow in the lungs of these animals were not overt, but members of RD207 were significantly more pathogenic, resulting in severe lung damage. The RD207 strains also induced much higher levels of markers associated with regulatory T cells and showed a significant loss of activated T cells in the lungs over the course of the infections. Whole-genome sequencing of the strains revealed mutations specific for RD207 which may explain this difference. Based on these data, we hypothesize that the sublineages of<jats:named-content content-type="genus-species">M. tuberculosis</jats:named-content>are associated with distinct pathological and clinical phenotypes and that these differences influence the transmissibility of particular<jats:named-content content-type="genus-species">M. tuberculosis</jats:named-content>strains in human populations.</jats:p>

Animal Models of Tuberculosis: Guinea Pigs

“…Key features of the pathology include human-like granulomas with central necrosis enclosed by lymphocytes, macrophages, and multinucleate giant cells and a fibrotic capsule. Cavitation is observed only rarely-for example, with certain strains of M. tuberculosis (Kato-Maeda et al 2012).…”

Persistent Infection by a Mycobacterium tuberculosis Strain That Was Theorized To Have Advantageous Properties, as It Was Responsible for a Massive Outbreak

“…Growth rates of the isolate from the case we report here (6613) and other Beijing strains analyzed previously (4)(5)(6)17). 6898 and 45261 correspond to Beijing virulent strains.…”

“…First, it is highly transmissible and responsible for severe outbreaks (2). Second, studies based on cellular and animal models reveal higher virulence for most Beijing strains (4)(5)(6). Third, Beijing strains are thought to have a hypermutator phenotype (7), which could increase the tendency to acquire variability and, more specifically, resistance mutations (8).…”

Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes

“…This variability may reflect the strains' ability to subvert innate (7,8) and/or adaptive (9, 10) immunity or their ability to exploit the host immune system by inducing a detrimental inflammatory response (11) leading to tissue damage (12,13) and formation of cavities that enable disease spread (14). Cytokines play a pivotal role in these events; insufficient production of proinflammatory cytokines may lead to uncontrolled mycobacterial growth, whereas overproduction may lead to tissue damage (15).…”