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Tryptophan metabolism is disrupted in aging and neurological disorders. Here, the authors show that histone deacetylase sirtuin 6 regulates tryptophan usage, and its absence results in neurotoxic products and impaired sleep that can be reversed by inhibiting the tryptophan processing enzyme TDO2.

In this instalment of Career pathways, Kivanç Birsoy and Sarah Lessard recount their roads to scientific research and reflect on how each step in their training prepared them for life as a group leader.

Frequent dispersal and short-lived local transmission clusters fuelled the 2013–2016 Ebola virus epidemic in Guinea, Liberia and Sierra Leone.

Sarah Fortune and colleagues report that Mycobacterium tuberculosis strains from lineage 2 acquire drug resistance in vitro more rapidly than strains from lineage 4 and show that this correlates with a higher in vivo mutation rate, as estimated from whole-genome sequencing of clinical isolates. They develop a stochastic mathematical model of the within-host evolution of drug resistance, using these mutation rate estimates to predict the rates of emergence of resistance in individuals with tuberculosis.

Sarah Fortune, Meindert Lamers and colleagues show that, unlike Escherichia coli, Mycobacterium tuberculosis uses an exonuclease domain in polymerase DnaE1 to proofread DNA replication. Importantly, this proofreading mechanism renders mycobacteria sensitive to nucleoside analogs, a class of small molecules used to treat viral infections and cancer.

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Fc engineering of a capsule-specific antibody identifies Fc variants which augment effector function and promote neutrophil-dependent control of Mycobacterium tuberculosis.

Alter and colleagues show that IgM titers in the plasma and bronchoalveolar lavage fluid represent markers of reduced Mtb burden in rhesus macaques vaccinated intravenously with Bacille Calmette–Guérin.

Sarah Fortune and colleagues report the whole-genome sequencing of Mycobacterium tuberculosis strains isolated from cynomolgus macaques with either active, latent or early reactivation disease. They estimate a similar mutation rate for these disease states in vivo, as well as for the bacterium in vitro. This suggests that M. tuberculosis has a greater mutational rate during latent and early reactivation disease than previously predicted and may be able to acquire drug resistance during these states.

Engineered kill-switch-encoding Mycobacterium tuberculosis infects, elicits immune responses and is cleared from immunocompetent and immunocompromised mice, providing a model of controlled tuberculosis infection.

Motion vision is critical for survival. Here the authors show that motion detection occurs already in bipolar cells of the mouse retina, which may contribute to motion processing throughout the visual system.

With forethought and support, science instructors can design effective massive open online courses.

Here, the authors conduct a paired genome analysis of humans and Mycobacterium tuberculosis in a cohort from Lima, Peru. Their research reveals that genetic variations in both the host and pathogen significantly influence the progression to tuberculosis.

Transcriptional plasticity (TP) governs gene expression variability, yet remains unexplored in prokaryotes. This study examines Mycobacterium tuberculosis genes’ TP via RNA-seq meta-analysis, uncovering genetic and functional traits impacting mycobacterial TP.

Analysis of Mycobacterium tuberculosis-specific antibody responses in previously exposed South African cohorts reveals that profile features associated with progression to active tuberculosis are affected by age and sex.

The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease with limited therapeutic options. Here, the authors identify the DNAJB1-PRKACA protein as a source for immunogenic neoepitopes and a potential target of T cell-based immunotherapy.

MS-based immunopeptidomics provides direct evidence for HLA peptide-antigen presentation, which is indispensable for therapeutic use. Here the authors present an ion mobility MS-based immunopeptidome workflow, largely expand benign reference databases and enables next generation tumor antigen discovery.

Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.

Screening Cas9 orthologues to improve CRISPR interference in mycobacteria identified four that are broadly functional for targeted gene knockdown, one of which (dCas9_Sth1) achieves a 20–100-fold knockdown of endogenous gene expression with minimal proteotoxicity.

Detecting and phenotyping Mycobacterium tuberculosis, especially in resource-limited settings, is important for global tuberculosis control. Here Liong et al. report a point-of-care diagnostic platform based on magnetic barcoding and nuclear magnetic resonance for the detection of mycobacterial nucleic acids.

New immune biomarkers of exposure to tuberculosis may require a rethink of evidence of Mycobacterium tuberculosis infection and control.

GM-CSF has been implicated in Mycobacterium tuberculosis (Mtb) host control. Here, the authors show that activation of GM-CSF discriminates Mtb-restrictive from -permissive macrophages while co-infection with HIV disrupts GM-CSF-mediated signaling, rendering macrophages susceptible to bacterial infection.

A genome-wide association study of Mycobacterium tuberculosis clinical isolates finds mutations in prpR that alter propionate metabolism and mediate multidrug tolerance.

In Mycobacterium tuberculosis, the activity of a protein lysine acetyltransferase (PAT) is allosterically regulated by cAMP binding to a domain fused to the catalytic domain. Now the crystal structures of the autoinhibited and cAMP-activated PAT, along with biochemical analysis, reveal how allosteric regulation between independent protein domains can evolve.

The polymerase and histidinol phosphatase (PHP) domain in the DNA polymerase DnaE1 is essential for mycobacterial high-fidelity DNA replication. Here, the authors determine the DnaE1 crystal structure, which reveals the PHP-exonuclease mechanism that can be exploited for antibiotic development.

Chinese government support and 'sea turtles' are spurring the sector, but investors lack exits.

Macrophages infected with virulent Mycobacterium tuberculosis die by necrosis. Remold and colleagues show that virulent M. tuberculosis promotes necrosis by damaging the plasma membrane and inhibiting its repair.

Tuberculosis (TB) is a heterogeneous disease: most infections are asymptomatic, but some infected individuals develop active symptomatic disease. This Review describes how features of the host immune response, granulomas and the mycobacteria contribute to the varied outcomes of TB infection.

Understanding how Mycobacterium tuberculosis is controlled by the body, leading to active disease in only a small fraction of infected individuals, is important for developing medical interventions to prevent and manage disease. Lin et al. now show that infected macaques with active tuberculosis have some sterile granulomas, suggesting immune-mediated control at certain sites of infection. Insight into the mechanisms underlying the heterogeneity of mycobacterial killing may inform vaccine development.

The integration of large, well-sampled collections of bacterial isolates with genomics and experimental methods provides opportunities for 'top-down' discovery of the genetic basis of phenotypes of interest. In a new report, the authors apply this approach to investigate the heterogeneity in manifestations of disease caused by Listeria monocytogenes and demonstrate that a previously uncharacterized cellobiose PTS system is involved in central nervous system infection.

Antibodies play an essential role in host defence against pathogens by binding to microorganisms and infected cells and exerting various effector functions. In this Review, Lu and colleagues summarize antibody isotypes and subclasses, modifications, receptor binding and signalling and effector functions in the context of infectious diseases.

Seq-Well provides similar scale and data quality to massively parallel, droplet-based single-cell RNA-seq methods in an easy to use, inexpensive and portable microwell format compatible with low-input samples.

Antibiotic persistence contributes to the survival of bacteria during antibiotic treatment. In this Consensus Statement, scientists working on the response of bacteria to antibiotics define antibiotic persistence and provide practical guidance on how to study bacterial persisters.

Resisters are individuals who show resistance to infection despite long-term, high exposure to Mycobacterium tuberculosis. In this Review, Simmons and colleagues discuss potential mechanisms underlying this resistance, such as those mediated by macrophages, T cells and B cells, and how an understanding of these mechanisms might aid in the development of therapies for tuberculosis.