A TB Mini-Collection
Editors pick 10 (ish) recent papers showing the diversity of interesting work being done in the TB field at the moment.
One of the themes that comes up again and again while talking to researchers for World TB day is that so many important questions remain unanswered in this disease. For example:
- How is evolution driving altered virulence and drug resistance?
- How does Mycobacterium tuberculosis persist in a host for decades and what causes it to reactivate to symptomatic disease in some but not others?
- How does TB interact with the immune system and what are our prospects at a long-lasting, protective vaccine?
- Why does chemotherapy take months for clearance and how do we shorten this regimen and improve efficacy?
- Can we sensitively and accurately diagnose TB in resource limited settings?
- What can we do to increase access to medical care and treatment for those in developing countries?
Keeping these questions in mind, with the gracious help of fellow editors at our partner journals (thanks to Nature, Nature Medicine, Nature Immunology, Nature Structural and Molecular Biology, Nature Reviews Microbiology and Nature Genetics), we highlight here 10(ish) recent papers (from ours and others’ archives) that speak to some of the themes above. This list is obviously not meant to be exhaustive, but merely serves to show that the TB research community is carrying out some great interdisciplinary work in dissecting TB pathogenesis and discovering new bacterial paradigms while they’re at it.
- Supply et al. (2013), Nature Genetics, “Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis” and Boritsch et al. (2016), Nature Microbiology, “pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence”. In Supply et al., the authors show through whole genome sequencing that M. tuberculosis likely evolved to be more virulent from an ancestor of the less pathogenic M. canetti. In follow up work, Boristch et al. find that loss of a specific lipid synthesis cluster could account for the increase in M. tuberculosis virulence capacity compared to M. canetti.
- Sveinbjornsson et al. (2016), Nature Genetics, “HLA class II sequence variants influence tuberculosis risk in populations of European ancestry.” Here, the authors find that selection of specific HLA variants predispose certain European populations to TB infection, likely by altering the efficiency by which bacterial antigens can be presented to the immune system.
- Kimmey et al., (2015), Nature, “Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.” TB was long thought to be controlled through autophagy, as ATG5 mutant mice (a typical marker of autophagy) were extremely susceptible to infection. Stallings and colleagues discovered that here, unexpectedly, that ATG5 actually controls infection independent of autophagy by regulating neutrophil trafficking and tissue damage.
- Speaking of the complex relationship of TB and the immune system, Nature Immunology published a special focus issue on the immunology of the lung last year (http://www.nature.com/ni/focus/lung/index.html), which included a review on the immunological tug of war between opposing immune responses during TB infection (Orne et al., 2015, Nature Immunology, “The balance between protective and pathogenic immune responses in the TB-infected lung”)
- A recent review also tackles the complex metabolic crosstalk between TB and the host cell: Olive and Sassetti (2016), Nature Reviews Microbiology, “Metabolic crosstalk between host and pathogen: sensing, adapting and competing”
- Sun et al. (2015), Nature Structural and Molecular Biology, “The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.” In an odd way, TB had long been thought to lack overt virulence mechanisms (e.g., effectors) despite all evidence to the contrary. Neiderweis and colleagues here report the structure of a TB secreted necrotizing toxin (TNT) that can kill macrophages by hydrolyzing NAD+.
- Wang et al., (2015), Nature Immunology, “Mycobacterium tuberculosis suppresses innate immunity by coopting the host ubiquitin system.” Here, the authors show that a secreted phosphatase, PtpA, can be activated by interaction with host ubiquitin to desphorphorylate immune signaling Jnk and p38 enzymes.
- Andries et al., 2009, Science, “A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis” and Diacon et al., 2009, New England Journal of Medicine, “The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis”. While these papers are not that recent, it's worthwhile to include them in this list as bedaquiline (which inhibits ATP synthase) was the first anti-TB drug to be licensed in 40 years. Today, new TB drug development is gaining a foothold again.
- Prideaux et al., 2015, Nature Medicine, “The association between sterilizing activity and drug distribution into tuberculosis lesions.” But why does it take so long to treat TB even with good drugs? A study in human patients undergoing antibiotic therapy found that some TB drugs can penetrate the granuloma and kill TB, while other drugs (e.g., moxifloxacin) cannot make it into the site of active infection, which raises the risk of evolving drug resistance.
- Manina et al., Cell Host and Microbe, “Stress and Host Immunity Amplify Mycobacterium tuberculosis Phenotypic Heterogeneity and Induce Nongrowing Metabolically Active Forms”. But even with penetrating drugs, it takes months to cure TB. Why? There may be heterogeneous growth rates in any given population of bacteria and those that are less active may be phenotypically tolerant to drugs. McKinney and colleagues showed that the amount of growth heterogeneity can be exacerbated as stress increases, as is observed in vivo.