Metabolite changes in blood predict the onset of tuberculosis

Weiner, January; Maertzdorf, Jeroen; Sutherland, Jayne S.; Duffy, Fergal J.; Thompson, Ethan; Suliman, Sara; McEwen, Gayle; Thiel, Bonnie; Parida, Shreemanta K.; Żyła, Joanna; Hanekom, Willem A.; Mohney, Robert P.; Boom, W. Henry; Mayanja‐Kizza, Harriet; Howe, Rawleigh; Dockrell, Hazel M.; Ottenhoff, Tom H. M.; Scriba, Thomas J.; Zak, Daniel E.; Walzl, Gerhard; Kaufmann, Stefan H. E.

doi:10.1038/s41467-018-07635-7

Cited by 129 publications

(129 citation statements)

References 43 publications

(41 reference statements)

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“…However, the vast majority of people will not develop active TB in their lifetime [2,3]. The most likely reason is that their immune system can control the TB progression, which highlights the role of host factors [4][5][6][7][8]. The morbidity and mortality caused by TB is further enhanced by immune-compromising conditions, such as coinfection with HIV, development of drug resistant Mtb strains, and the coexistence of other chronic diseases, such as diabetes, malaria, and severe viral infections [9].…”

Section: Introductionmentioning

confidence: 99%

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

et al. 2020

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Tuberculosis (TB) is one of the leading causes of mortality and morbidity, particularly in developing countries, presenting a major threat to the public health. The currently recommended long term treatment regimen with multiple antibiotics is associated with poor patient compliance, which in turn, may contribute to the emergence of multi-drug resistant TB (MDR-TB). The low global treatment efficacy of MDR-TB has highlighted the necessity to develop novel treatment options. Host-directed therapy (HDT) together with current standard anti-TB treatments, has gained considerable interest, as HDT targets novel host immune mechanisms. These immune mechanisms would otherwise bypass the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (Mtb), which may be mutated to cause antibiotic resistance. Additionally, host-directed therapies against TB have been shown to be associated with reduced lung pathology and improved disease outcome, most likely via the modulation of host immune responses. This review will provide an update of host-directed therapies and their mechanism(s) of action against Mycobacterium tuberculosis.

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Section: Introductionmentioning

confidence: 99%

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

et al. 2020

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“…At the early stage of infection, it is possible that Mtb is rapidly eradicated before stable LTBI develops, but the proportion of individuals who become transiently infected, sometimes accompanied by a short episode of clinical symptoms remains unclear (51,57,59). Recent evidence suggests LTBI is succeeded by incipient TB, in which the host remains healthy, but becomes alerted and Mtb regains its metabolic and replicative activities (59)(60)(61)(62). Subsequently, subclinical TB evolves in which first signs of pathology occur although clinically the patient appears healthy.…”

Section: Immunopathology Of Tuberculosismentioning

confidence: 99%

Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology

Kaufmann

2020

Front. Immunol.

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Tuberculosis (TB) remains a major health threat. Although a vaccine has been available for almost 100 years termed Bacille Calmette-Guérin (BCG), it is insufficient and better vaccines are urgently needed. This treatise describes first the basic immunology and pathology of TB with an emphasis on the role of T lymphocytes. Better understanding of the immune response to Mycobacterium tuberculosis (Mtb) serves as blueprint for rational design of TB vaccines. Then, disease epidemiology and the benefits and failures of BCG vaccination will be presented. Next, types of novel vaccine candidates are being discussed. These include: (i) antigen/adjuvant subunit vaccines; (ii) viral vectored vaccines; and (III) whole cell mycobacterial vaccines which come as live recombinant vaccines or as dead whole cell or multi-component vaccines. Subsequently, the major endpoints of clinical trials as well as administration schemes are being described. Major endpoints for clinical trials are prevention of infection (PoI), prevention of disease (PoD), and prevention of recurrence (PoR). Vaccines can be administered either pre-exposure or post-exposure with Mtb. A central part of this treatise is the description of the viable BCG-based vaccine, VPM1002, currently undergoing phase III clinical trial assessment. Finally, new approaches which could facilitate design of refined next generation TB vaccines will be discussed.

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“…In a prospective study in Sub‐Saharan Africa, kynurenine increased a few months prior to time of active TB. [ 60 ] In a different setting, of 351 cerebrospinal fluid metabolites studied by Van Laarhoven et al., tryptophan was amongst the top five differing between patients and controls. TB patients had lower cerebrospinal fluid tryptophan, but very low levels also correlated with survival.…”

Section: Ido Activity Is Elevated During Human Tuberculosismentioning

confidence: 99%

Evolutionary Views of Tuberculosis: Indoleamine 2,3‐Dioxygenase Catalyzed Nicotinamide Synthesis Reflects Shifts in Macrophage Metabolism

et al. 2020

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Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno-foetal tolerance, increasing human reproductive fitness. IDO mediates immune suppression through depletion of tryptophan required by T lymphocytes and other mechanisms. IDO is expressed by alternatively activated macrophages, suspected to play a key role in tuberculosis (TB) pathogenesis. Unlike its human host, Mycobacterium tuberculosis can synthesize tryptophan, suggesting possible benefit to the host from infection with the microbe. Intriguingly, nicotinamide analogues are used to treat TB. In reviewing this field, it is postulated that flux through the nicotinamide synthesis pathway reflects switching between aerobic glycolysis and oxidative phosphorylation in M. tuberculosis-infected macrophages. The evolutionary cause of such shifts may be ancient mitochondrial behavior related to reproductive fitness. Evolutionary perspectives on the IDO pathway may elucidate why, after centuries of co-existence with the Tubercle bacillus, humans still remain susceptible to TB disease.

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Metabolite changes in blood predict the onset of tuberculosis

Cited by 129 publications

References 43 publications

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology

Evolutionary Views of Tuberculosis: Indoleamine 2,3‐Dioxygenase Catalyzed Nicotinamide Synthesis Reflects Shifts in Macrophage Metabolism

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