The spectrum of latent tuberculosis: rethinking the biology and intervention strategies

Barry, Clifton E.; Boshoff, Helena I.; Dartois, Véronique; Dick, Thomas; Ehrt, Sabine; Flynn, Jo Anne L.; Schnappinger, Dirk; Wilkinson, Robert J.; Young, Douglas B.

doi:10.1038/nrmicro2236

Cited by 1,232 publications

(1,123 citation statements)

References 82 publications

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“…Several types can be found in humans including the caseous, non-necrotizing, and fibrotic granulomas [56]. However studying mechanisms underlying latency and reactivation of tuberculosis is hampered by the limitations of current animal models [57].…”

Section: Discussionmentioning

confidence: 99%

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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Animal models have long been used in tuberculosis research to understand disease pathogenesis and to evaluate novel vaccine candidates and anti-mycobacterial drugs. However, all have limitations and there is no single animal model which mimics all the aspects of mycobacterial pathogenesis seen in humans. Importantly mice, the most commonly used model, do not normally form granulomas, the hallmark of tuberculosis infection. Thus there is an urgent need for the development of new alternative in vivo models. The insect larvae, Galleria mellonella has been increasingly used as a successful, simple, widely available and cost-effective model to study microbial infections. Here we report for the first time that G. mellonella can be used as an infection model for members of the Mycobacterium tuberculosis complex. We demonstrate a dose-response for G. mellonella survival infected with different inocula of bioluminescent Mycobacterium bovis BCG lux, and demonstrate suppression of mycobacterial luminesence over 14 days. Histopathology staining and transmission electron microscopy of infected G. mellonella phagocytic haemocytes show internalization and aggregation of M. bovis BCG lux in granuloma-like structures, and increasing accumulation of lipid bodies within M. bovis BCG lux over time, characteristic of latent tuberculosis infection. Our results demonstrate that G. mellonella can act as a surrogate host to study the pathogenesis of mycobacterial infection and shed light on host-mycobacteria interactions, including latent tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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“…Tuberculosis is caused by the Mycobacterium tuberculosis complex of bacteria (MTBC), which all descend from a recent, common ancestor [53]. Human infection usually results in latent disease without clinical symptoms; it is thought that one-third of the global human population has been infected at some point in their lives [54]. The MTBC consists of multiple genetic lineages (figure 3a) [57], some of which are specific for animals, but occasionally infect humans.…”

Section: How Long Have Humans Been Afflicted By Tuberculosis?mentioning

confidence: 99%

How old are bacterial pathogens?

Achtman¹

2016

Proc. R. Soc. B.

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Only few molecular studies have addressed the age of bacterial pathogens that infected humans before the beginnings of medical bacteriology, but these have provided dramatic insights. The global genetic diversity of Helicobacter pylori , which infects human stomachs, parallels that of its human host. The time to the most recent common ancestor (tMRCA) of these bacteria approximates that of anatomically modern humans, i.e. at least 100 000 years, after calibrating the evolutionary divergence within H. pylori against major ancient human migrations. Similarly, genomic reconstructions of Mycobacterium tuberculosis , the cause of tuberculosis, from ancient skeletons in South America and mummies in Hungary support estimates of less than 6000 years for the tMRCA of M. tuberculosis . Finally, modern global patterns of genetic diversity and ancient DNA studies indicate that during the last 5000 years plague caused by Yersinia pestis has spread globally on multiple occasions from China and Central Asia. Such tMRCA estimates provide only lower bounds on the ages of bacterial pathogens, and additional studies are needed for realistic upper bounds on how long humans and animals have suffered from bacterial diseases.

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“…M ycobacterium tuberculosis, the deadliest human pathogenic bacterium, possesses the ability to persist within its host for decades 1 . Many other pathogenic bacteria have the ability to generate chronic or relapsing infections, and the problem of bacterial persistence is of general importance [2][3][4] .…”

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confidence: 99%

VapC20 of Mycobacterium tuberculosis cleaves the Sarcin–Ricin loop of 23S rRNA

et al. 2013

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The highly persistent and often lethal human pathogen, Mycobacterium tuberculosis contains at least 88 toxin-antitoxin genes. More than half of these encode VapC PIN domain endoribonucleases that inhibit cell growth by unknown mechanisms. Here we show that VapC20 of M. tuberculosis inhibits translation by cleavage of the Sarcin-Ricin loop (SRL) of 23S ribosomal RNA at the same position where Sarcin and other eukaryotic ribotoxins cleave. Toxin-inhibited cells can be rescued by the expression of the antitoxin, thereby raising the possibility that vapC20 contributes to the extreme persistence exhibited by M. tuberculosis. VapC20 cleavage is inhibited by mutations in the SRL that flank the cleavage site but not by changes elsewhere in the loop. Disruption of the SRL stem abolishes cleavage; however, further mutations that restore the SRL stem structure restore cleavage, revealing that the structure rather than the exact sequence of the SRL is important for this activity.

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The spectrum of latent tuberculosis: rethinking the biology and intervention strategies

Cited by 1,232 publications

References 82 publications

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

How old are bacterial pathogens?

VapC20 of Mycobacterium tuberculosis cleaves the Sarcin–Ricin loop of 23S rRNA

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