Figures & data
Figure 1. Major hallmarks of TB pathology and immunity and their relation to biomarkers.
Center of figure depicts major steps from initial infection, to latency and active disease. Aerosols containing live Mtb bacilli, that are expectorated by a person with pulmonary TB, are inhaled by a healthy individual. Alveolar macrophages engulf the pathogen and leukocytes like dendritic cells transport bacilli from the alveoli to the draining lymph node, where T lymphocytes are primed [Citation14]. Some bacilli enter the lung parenchyma, eliciting inflammatory signals that attract mononuclear phagocytes and T lymphocytes to the site of Mtb deposition [Citation8]. Antigen-specific interactions between mononuclear phagocytes, dendritic cells and T lymphocytes orchestrate the formation of a solid granuloma to which further immune cells are attracted [Citation7]. The solid granuloma contains Mtb in a dormant stage and likely is autonomous [Citation15]. Yet, leukocytes can enter and leave granulomas thereby linking it with the general immune system via the blood stream. The solid granuloma is a characteristic feature of individuals with LTBI. In some of these individuals granulomas become necrotic and later caseous, which is characteristic of active TB. Simultaneously, Mtb progresses from a dormant to a metabolically active stage. Rupture of caseous granulomas into the alveolar space results in spread of the bacillus into the environment. Some individuals in which LTBI progresses into subclinical TB may occasionally be contagious without showing any clinical signs of disease. In contagious individuals volatile molecules are exhaled that likely originate from Mtb, and which can be used for TB diagnosis (left part of figure) using electronic noses or sniffer rats trained for bouquets of such molecules. In blood, effector cells with different phenotypes, including effector and memory T cells, can be identified (right part of figure). Active TB disease is preceded by an increase of regulatory and exhausted T cells that likely are critical for disease progression. The most commonly used source for biomarkers is the blood (far right part of figure). The IGRA determines IFN-gamma secretion by T cells from the blood in response to selected Mtb-specific antigens and is widely used to diagnose infection. However it cannot reliably distinguish between LTBI, subclinical TB or active TB disease. Transcriptomic biomarkers have been widely studied in TB by determining gene expression profiles in blood cells. Biosignatures comprising few transcriptomic markers can identify individuals with active TB disease with high sensitivity and specificity [Citation16]. Evidence has also been presented that a transcriptomic biosignature can be harnessed for prognosis of active TB, probably by detecting subclinical TB [Citation17]. In serum or plasma, metabolites and proteins can be harnessed for biomarker analysis [Citation18]. A biosignature composed of metabolites has been shown to accurately identify active TB patients and evidence has been obtained that metabolites can also be harnessed for a prognostic biosignature of active TB [Citation19]. Although current metabolite studies harness serum, urine may be considered as a noninvasive alternative. Principally the whole serum proteome can be employed for biomarker studies. Yet, immune mediators such as cytokines and chemokines that are released in response to infection and inflammation are more widely used [Citation20]. These include cytokines secreted by antigen-specific and activated T cells as well as cytokines released by mononuclear phagocytes in response to inflammatory stimuli. Abbreviations: TB, tuberculosis; LTBI, latent tuberculosis infection; Mtb, Mycobacterium tuberculosis; IGRA, interferon-gamma release assay.
![Figure 1. Major hallmarks of TB pathology and immunity and their relation to biomarkers.Center of figure depicts major steps from initial infection, to latency and active disease. Aerosols containing live Mtb bacilli, that are expectorated by a person with pulmonary TB, are inhaled by a healthy individual. Alveolar macrophages engulf the pathogen and leukocytes like dendritic cells transport bacilli from the alveoli to the draining lymph node, where T lymphocytes are primed [Citation14]. Some bacilli enter the lung parenchyma, eliciting inflammatory signals that attract mononuclear phagocytes and T lymphocytes to the site of Mtb deposition [Citation8]. Antigen-specific interactions between mononuclear phagocytes, dendritic cells and T lymphocytes orchestrate the formation of a solid granuloma to which further immune cells are attracted [Citation7]. The solid granuloma contains Mtb in a dormant stage and likely is autonomous [Citation15]. Yet, leukocytes can enter and leave granulomas thereby linking it with the general immune system via the blood stream. The solid granuloma is a characteristic feature of individuals with LTBI. In some of these individuals granulomas become necrotic and later caseous, which is characteristic of active TB. Simultaneously, Mtb progresses from a dormant to a metabolically active stage. Rupture of caseous granulomas into the alveolar space results in spread of the bacillus into the environment. Some individuals in which LTBI progresses into subclinical TB may occasionally be contagious without showing any clinical signs of disease. In contagious individuals volatile molecules are exhaled that likely originate from Mtb, and which can be used for TB diagnosis (left part of figure) using electronic noses or sniffer rats trained for bouquets of such molecules. In blood, effector cells with different phenotypes, including effector and memory T cells, can be identified (right part of figure). Active TB disease is preceded by an increase of regulatory and exhausted T cells that likely are critical for disease progression. The most commonly used source for biomarkers is the blood (far right part of figure). The IGRA determines IFN-gamma secretion by T cells from the blood in response to selected Mtb-specific antigens and is widely used to diagnose infection. However it cannot reliably distinguish between LTBI, subclinical TB or active TB disease. Transcriptomic biomarkers have been widely studied in TB by determining gene expression profiles in blood cells. Biosignatures comprising few transcriptomic markers can identify individuals with active TB disease with high sensitivity and specificity [Citation16]. Evidence has also been presented that a transcriptomic biosignature can be harnessed for prognosis of active TB, probably by detecting subclinical TB [Citation17]. In serum or plasma, metabolites and proteins can be harnessed for biomarker analysis [Citation18]. A biosignature composed of metabolites has been shown to accurately identify active TB patients and evidence has been obtained that metabolites can also be harnessed for a prognostic biosignature of active TB [Citation19]. Although current metabolite studies harness serum, urine may be considered as a noninvasive alternative. Principally the whole serum proteome can be employed for biomarker studies. Yet, immune mediators such as cytokines and chemokines that are released in response to infection and inflammation are more widely used [Citation20]. These include cytokines secreted by antigen-specific and activated T cells as well as cytokines released by mononuclear phagocytes in response to inflammatory stimuli. Abbreviations: TB, tuberculosis; LTBI, latent tuberculosis infection; Mtb, Mycobacterium tuberculosis; IGRA, interferon-gamma release assay.](/cms/asset/2615b03e-5161-48d1-bf90-17dc7a0826cf/ierv_a_1341316_f0001_oc.jpg)
Table 1. Major vaccine candidates currently in clinical trials.
