Materiały źródłowe

• #1 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the hosts immune system becomes debilitated. […] Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. […] The pathogenic life cycle of M. tb is illustrated in Figure 2. TB is transmitted via M. tb-containing aerosol droplets, propelled by active TB patients when they cough, sneeze or talk. After the new host inhale the TB bacteria, they travel through the respiratory tract and reach the lung. At this point, the hosts innate immune system comes into play to quell the infection, whereupon the tubercle bacilli are internalised by alveolar macrophages. When the macrophages fail to inhibit or destroy the bacilli, the bacteria multiply within their intracellular environment, get released, then phagocytosed by other alveolar macrophages and the cycle continues.

• #2 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://www.mdpi.com/1422-0067/24/6/5202

  Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. […] The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host’s immune system becomes debilitated. […] Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. […] The pathogenic life cycle of M. tb is illustrated in Figure 2. TB is transmitted via M. tb-containing aerosol droplets, propelled by active TB patients when they cough, sneeze or talk. […] After the new host inhale the TB bacteria, they travel through the respiratory tract and reach the lung. At this point, the host’s innate immune system comes into play to quell the infection, whereupon the tubercle bacilli are internalised by alveolar macrophages.

• #3 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  TB damages tissues through delayed-type hypersensitivity (DTH), typically producing granulomatous necrosis with a caseous histologic appearance. Lung lesions are characteristically but not invariably cavitary, especially in immunosuppressed patients with impaired DTH. […] The course of TB varies greatly, depending on the virulence of the organism and the state of host defenses. The course may be rapid in members of isolated populations (eg, Native Americans) who, unlike many Europeans and their American descendents, have not experienced centuries of selective pressure to develop innate or natural immunity to the disease. The course is often more indolent in these European and American populations. […] The new anti-TB drugs bedaquiline, delamanid, and pretomanid and the fluoroquinolone moxifloxacin are oral drugs highly active against drug-resistant strains using shorter treatment duration than other regimens. They rapidly stop transmission and have higher rates of completion and cure and thus are likely to help control the epidemic of DR-TB. However, success will continue to depend on strong global commitments to provide access to molecular diagnostics and effective treatment as well as full treatment supervision.

• #4 Pathogenesis of Tuberculosis (TB) Infection

  https://www.labce.com/spg631661_pathogenesis_of_tuberculosis_tb_infection.aspx?srsltid=AfmBOooBMfPXjJ9XJWsHpzxlQK71CkL95esQoP4GmWDJuPiUY_7GzXsX

  The cycle of TB infection begins with dispersion of M. tuberculosis aerosols. A dose of one to 10 bacilli are dispersed throughout the air, making the risk of transmission likely. In the patients lung, the bacilli are phagocytized by alveolar macrophage cells, which then invade the underlying epithelium. Here, monocytes from nearby blood vessels form the beginning of a granuloma, as the immune system attempts to ward off the disease. This is a hallmark characteristic of tuberculosis. Within the granuloma, a core of infected macrophages is surrounded by foamy macrophages, mononuclear phagocytes, and lymphocytes. The result is a fibrous capsule with increased foamy macrophages, presumed to create the typical caseous debris (necrotic tissue resembling cheese) in the center of the granuloma. Although it appears contained immunologically, the caseous center tends to liquefy and cavitate as it empties thousands of M. tuberculosis bacilli into the airway.

• #5 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the hosts immune system becomes debilitated. […] Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. […] The pathogenic life cycle of M. tb is illustrated in Figure 2. TB is transmitted via M. tb-containing aerosol droplets, propelled by active TB patients when they cough, sneeze or talk. After the new host inhale the TB bacteria, they travel through the respiratory tract and reach the lung. At this point, the hosts innate immune system comes into play to quell the infection, whereupon the tubercle bacilli are internalised by alveolar macrophages. When the macrophages fail to inhibit or destroy the bacilli, the bacteria multiply within their intracellular environment, get released, then phagocytosed by other alveolar macrophages and the cycle continues.

• #6 Pathogenesis of Tuberculosis (TB) Infection

  https://www.labce.com/spg631661_pathogenesis_of_tuberculosis_tb_infection.aspx?srsltid=AfmBOooBMfPXjJ9XJWsHpzxlQK71CkL95esQoP4GmWDJuPiUY_7GzXsX

  The cycle of TB infection begins with dispersion of M. tuberculosis aerosols. A dose of one to 10 bacilli are dispersed throughout the air, making the risk of transmission likely. In the patients lung, the bacilli are phagocytized by alveolar macrophage cells, which then invade the underlying epithelium. Here, monocytes from nearby blood vessels form the beginning of a granuloma, as the immune system attempts to ward off the disease. This is a hallmark characteristic of tuberculosis. Within the granuloma, a core of infected macrophages is surrounded by foamy macrophages, mononuclear phagocytes, and lymphocytes. The result is a fibrous capsule with increased foamy macrophages, presumed to create the typical caseous debris (necrotic tissue resembling cheese) in the center of the granuloma. Although it appears contained immunologically, the caseous center tends to liquefy and cavitate as it empties thousands of M. tuberculosis bacilli into the airway.

• #7 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Tuberculosis may occur in 3 stages: Primary infection, Latent infection, Active infection. M. tuberculosis bacilli initially cause a primary infection, a small percentage of which eventually progress to clinical disease of variable severity. However, most (about 95%) primary infections are asymptomatic. An unknown percentage of primary infections resolve spontaneously, but the majority are followed by a latent (dormant) phase. A variable percentage (5 to 10%) of latent infections subsequently reactivate with symptoms and signs of disease. Infection is usually not transmissible in the primary stage and is never contagious in the latent stage. […] Infection requires inhalation of particles small enough to traverse the upper respiratory defenses and deposit deep in the lungs, usually in the subpleural airspaces of the middle or lower lobes. Larger droplets tend to lodge in the more proximal airways and typically do not result in infection. Infection usually begins from a single droplet nucleus, which typically carries few organisms. Perhaps only a single organism may suffice to cause infection in susceptible people, but less susceptible people may require repeated exposure to develop infection.

• #8 Chapter 2 of the Canadian Tuberculosis Standards: Transmission and pathogenesis of tuberculosis – Canada.ca

  https://www.canada.ca/en/public-health/services/diseases/tuberculosis/health-professionals/canadian-tuberculosis-standards/transmission-pathogenesis.html

  With few exceptions, infection with Mycobacterium tuberculosis (M. tuberculosis) is acquired by inhalation of small droplet nuclei (1-5 microns in diameter) that contain just a few mycobacteria and that are capable of reaching the alveoli. […] Through innate immune mechanisms, alveolar macrophages eradicate the bacteria in some individuals; in others, the bacteria are able to replicate and establish TB infection. Bacterial factors and host genetic factors that promote or limit acquisition of infection are not well understood. […] The pathogenesis and transmission of TB are inter-related. M. tuberculosis is almost exclusively a human pathogen and how it interacts with the human host determines its survival. From the perspective of the bacterium, a successful host-pathogen interaction is one that results in ongoing pathogen transmission.

• #9 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Tuberculosis may occur in 3 stages: Primary infection, Latent infection, Active infection. M. tuberculosis bacilli initially cause a primary infection, a small percentage of which eventually progress to clinical disease of variable severity. However, most (about 95%) primary infections are asymptomatic. An unknown percentage of primary infections resolve spontaneously, but the majority are followed by a latent (dormant) phase. A variable percentage (5 to 10%) of latent infections subsequently reactivate with symptoms and signs of disease. Infection is usually not transmissible in the primary stage and is never contagious in the latent stage. […] Infection requires inhalation of particles small enough to traverse the upper respiratory defenses and deposit deep in the lungs, usually in the subpleural airspaces of the middle or lower lobes. Larger droplets tend to lodge in the more proximal airways and typically do not result in infection. Infection usually begins from a single droplet nucleus, which typically carries few organisms. Perhaps only a single organism may suffice to cause infection in susceptible people, but less susceptible people may require repeated exposure to develop infection.

• #10 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Tuberculosis may occur in 3 stages: Primary infection, Latent infection, Active infection. M. tuberculosis bacilli initially cause a primary infection, a small percentage of which eventually progress to clinical disease of variable severity. However, most (about 95%) primary infections are asymptomatic. An unknown percentage of primary infections resolve spontaneously, but the majority are followed by a latent (dormant) phase. A variable percentage (5 to 10%) of latent infections subsequently reactivate with symptoms and signs of disease. Infection is usually not transmissible in the primary stage and is never contagious in the latent stage. […] Infection requires inhalation of particles small enough to traverse the upper respiratory defenses and deposit deep in the lungs, usually in the subpleural airspaces of the middle or lower lobes. Larger droplets tend to lodge in the more proximal airways and typically do not result in infection. Infection usually begins from a single droplet nucleus, which typically carries few organisms. Perhaps only a single organism may suffice to cause infection in susceptible people, but less susceptible people may require repeated exposure to develop infection.

• #11 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  To initiate infection, M. tuberculosis bacilli must be ingested by alveolar macrophages. Bacilli that are not killed by the macrophages actually replicate inside them, ultimately killing the host macrophage (with the help of CD8 lymphocytes); inflammatory cells are attracted to the area, causing a focal pneumonitis that coalesces into the characteristic tubercles seen histologically. […] In the early weeks of infection, some infected macrophages migrate to regional lymph nodes (eg, hilar, mediastinal), where they access the bloodstream. Organisms may then spread hematogenously to any part of the body, particularly the apical-posterior portion of the lungs, epiphyses of the long bones, kidneys, vertebral bodies, and meninges. Hematogenous dissemination is less likely in patients with partial immunity due to vaccination or to prior natural infection with M. tuberculosis or environmental mycobacteria.

• #12 Tuberculosis – Wikipedia

  https://en.wikipedia.org/wiki/Tuberculosis

  TB infection begins when a M. tuberculosis bacterium, inhaled from the air, penetrates the lungs and reaches the alveoli. Here it encounters an alveolar macrophage, a cell which is part of the body’s immune system, which attempts to destroy it. However, M. tuberculosis is able to neutralise and colonise the macrophage, leading to persistent infection. […] The defence mechanism of the macrophage begins when a foreign body, such as a bacterial cell, binds to receptors on the surface of the macrophage. The macrophage then stretches itself around the bacterium and engulfs it. Once inside this macrophage, the bacterium is trapped in a compartment called a phagosome; the phagosome subsequently merges with a lysosome to form a phagolysosome. […] The M. tuberculosis bacterium is able to subvert the normal process by inhibiting the development of the phagosome and preventing it from fusing with the lysosome. The bacterium is able to survive and replicate within the phagosome; it will eventually destroy its host macrophage, releasing progeny bacteria which spread the infection.

• #13 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  To initiate infection, M. tuberculosis bacilli must be ingested by alveolar macrophages. Bacilli that are not killed by the macrophages actually replicate inside them, ultimately killing the host macrophage (with the help of CD8 lymphocytes); inflammatory cells are attracted to the area, causing a focal pneumonitis that coalesces into the characteristic tubercles seen histologically. […] In the early weeks of infection, some infected macrophages migrate to regional lymph nodes (eg, hilar, mediastinal), where they access the bloodstream. Organisms may then spread hematogenously to any part of the body, particularly the apical-posterior portion of the lungs, epiphyses of the long bones, kidneys, vertebral bodies, and meninges. Hematogenous dissemination is less likely in patients with partial immunity due to vaccination or to prior natural infection with M. tuberculosis or environmental mycobacteria.

• #14 Tuberculosis – Wikipedia

  https://en.wikipedia.org/wiki/Tuberculosis

  TB infection begins when a M. tuberculosis bacterium, inhaled from the air, penetrates the lungs and reaches the alveoli. Here it encounters an alveolar macrophage, a cell which is part of the body’s immune system, which attempts to destroy it. However, M. tuberculosis is able to neutralise and colonise the macrophage, leading to persistent infection. […] The defence mechanism of the macrophage begins when a foreign body, such as a bacterial cell, binds to receptors on the surface of the macrophage. The macrophage then stretches itself around the bacterium and engulfs it. Once inside this macrophage, the bacterium is trapped in a compartment called a phagosome; the phagosome subsequently merges with a lysosome to form a phagolysosome. […] The M. tuberculosis bacterium is able to subvert the normal process by inhibiting the development of the phagosome and preventing it from fusing with the lysosome. The bacterium is able to survive and replicate within the phagosome; it will eventually destroy its host macrophage, releasing progeny bacteria which spread the infection.

• #15 Pathogenesis of tuberculosis and other mycobacteriosis | Enfermedades Infecciosas y Microbiología Clínica (English Edition)

  https://www.elsevier.es/en-revista-enfermedades-infecciosas-microbiologia-clinica-english-428-articulo-pathogenesis-tuberculosis-other-mycobacteriosis-S2529993X17303052

  The evolution between Mycobacterium tuberculosis infection and active tuberculosis is multifactorial and involves different biological scales. The synthesis of ESAT-6 or the induction of alveolar macrophage necrosis are key, but to understand it, it is necessary to consider the dynamics of endogenous and exogenous reinfection, drainage of lung parenchyma and respiratory mechanics, local fibrosis processes and blood supply. […] When the viable bacillus is phagocytised by the AM, it spreads its pathogenic capacity by secreting 6kDa early secretory antigenic target (ESAT-6). This peptide is essential to prevent the phagosomelysosome union and apoptosis and eventually allows entry of the bacillus into the cytoplasm. […] The dendritic cells process M. tuberculosis and present epitopes that mostly correspond to the most abundant antigens secreted: ESAT-6 and the antigen 85 complex (Ag85 A, B or C).

• #16 Pathogenesis of tuberculosis and other mycobacteriosis | Enfermedades Infecciosas y Microbiología Clínica (English Edition)

  https://www.elsevier.es/en-revista-enfermedades-infecciosas-microbiologia-clinica-english-428-articulo-pathogenesis-tuberculosis-other-mycobacteriosis-S2529993X17303052

  The evolution between Mycobacterium tuberculosis infection and active tuberculosis is multifactorial and involves different biological scales. The synthesis of ESAT-6 or the induction of alveolar macrophage necrosis are key, but to understand it, it is necessary to consider the dynamics of endogenous and exogenous reinfection, drainage of lung parenchyma and respiratory mechanics, local fibrosis processes and blood supply. […] When the viable bacillus is phagocytised by the AM, it spreads its pathogenic capacity by secreting 6kDa early secretory antigenic target (ESAT-6). This peptide is essential to prevent the phagosomelysosome union and apoptosis and eventually allows entry of the bacillus into the cytoplasm. […] The dendritic cells process M. tuberculosis and present epitopes that mostly correspond to the most abundant antigens secreted: ESAT-6 and the antigen 85 complex (Ag85 A, B or C).

• #17 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  Although it is observed that TNF suppression can cause more rapid progression to TB disease, many aspects of the diverse functions of this proinflammatory factor have yet to be elucidated. […] The hallmark of mycobacterial infection is the tuberculoma or granuloma. […] In the pre-antibiotic era TB patients were often treated with cod-liver oil and sunshine, both sources of 25-hydroxyvitamin-D, which has immunomodulatory properties. […] Vitamin D deficiency has been implicated to play a role in increased susceptibility to active TB disease in numerous studies.

• #18 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  However, in the setting of impaired immunity, the disease immediately progresses into active TB with clinical symptoms. […] The granuloma is the cardinal feature of pulmonary TB, which is an amorphous collection of macrophages and other immune cells aimed at restricting the bacterial spread. In immunocompetent individuals, although the granuloma is unable to eliminate the pathogen, it restrains the bacilli and halts the progression to the active disease. […] However, the bacteria still survive, avoiding death by blocking the phagolysosome fusion and subverting the hosts immune response. This process establishes a hospitable niche for M. tb where it can survive for decades, outwitting the immune system and persisting in a non-replicating or slowly replicating state. […] Even though the main cause of TB reactivation is ascribed to HIV co-infection, other conditions may also switch the quiescent infection to an active one. These triggering factors include malnutrition, immune suppressive medications, chemotherapy, uncontrolled diabetes mellitus, sepsis, drug or alcohol addiction, chronic renal failure, smoking and malignancy.

• #19 Pathogenesis of Tuberculosis (TB) Infection

  https://www.labce.com/spg631661_pathogenesis_of_tuberculosis_tb_infection.aspx?srsltid=AfmBOooBMfPXjJ9XJWsHpzxlQK71CkL95esQoP4GmWDJuPiUY_7GzXsX

  The cycle of TB infection begins with dispersion of M. tuberculosis aerosols. A dose of one to 10 bacilli are dispersed throughout the air, making the risk of transmission likely. In the patients lung, the bacilli are phagocytized by alveolar macrophage cells, which then invade the underlying epithelium. Here, monocytes from nearby blood vessels form the beginning of a granuloma, as the immune system attempts to ward off the disease. This is a hallmark characteristic of tuberculosis. Within the granuloma, a core of infected macrophages is surrounded by foamy macrophages, mononuclear phagocytes, and lymphocytes. The result is a fibrous capsule with increased foamy macrophages, presumed to create the typical caseous debris (necrotic tissue resembling cheese) in the center of the granuloma. Although it appears contained immunologically, the caseous center tends to liquefy and cavitate as it empties thousands of M. tuberculosis bacilli into the airway.

• #20 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  However, in the setting of impaired immunity, the disease immediately progresses into active TB with clinical symptoms. […] The granuloma is the cardinal feature of pulmonary TB, which is an amorphous collection of macrophages and other immune cells aimed at restricting the bacterial spread. In immunocompetent individuals, although the granuloma is unable to eliminate the pathogen, it restrains the bacilli and halts the progression to the active disease. […] However, the bacteria still survive, avoiding death by blocking the phagolysosome fusion and subverting the hosts immune response. This process establishes a hospitable niche for M. tb where it can survive for decades, outwitting the immune system and persisting in a non-replicating or slowly replicating state. […] Even though the main cause of TB reactivation is ascribed to HIV co-infection, other conditions may also switch the quiescent infection to an active one. These triggering factors include malnutrition, immune suppressive medications, chemotherapy, uncontrolled diabetes mellitus, sepsis, drug or alcohol addiction, chronic renal failure, smoking and malignancy.

• #21 Pathophysiology And Treatment of Tuberculosis According to Who

  https://www.ijpsjournal.com/article/Pathophysiology+And+Treatment+of+Tuberculosis+According+to+Who++

  The evolution between Mycobacterium tuberculosis infection and active tuberculosis is multi factorial and involves different biological scales. The synthesis of ESAT-6 or the induction of alveolar macrophage necrosis are key, but to understand it, it is necessary to consider the dynamics of endogenous and exogenous reinfection, drainage of lung parenchyma and respiratory mechanics, local fibrosis processes and blood supply. Severe immunosuppression can only explain 10% of active tuberculosis cases, while the remainder are attributable to comorbidities, a proinflammatory environment and an unknown genetic propensity. The pathogenic capacity of environmental mycobacteria is discrete linked to deficits in the innate and acquired immune response. […] The pathogenic life cycle of M.tb is transmitted via M. tb containing aerosol droplets, propelled by active TB patients when they cough,sneeze or talk. The granuloma is the cardinal feature of pulmonary TB, which is amorphous collection of macrophages and other immune cell aimed at restricting the bacterial spread. In immune competent individuals, although the granuloma is unable to eliminate the pathogen, it restrain the bacilli and halts the progression to the active disease. As the granuloma matures, macrophages differentiate into foamy macrophages and other various morphotypes. The centre of the granuloma may necrotisc as a results of the necrotic lysis of the host immune cells forming what is referred to as caseum. Indeed, the accumulating soft necrotic debris, located in the core of the granuloma, resembles cheese. Foamy macrophages, which are charaterised by accumulated lipid droplets, distribute around the necrotic foci of the granuloma. In this case, the patient is still non infectious and asmptomatic. One of the challenges facing the current TB therapy is targeting this tenacious pathogen inside the granuloma. At the this point, the hosts innate immune system comes into play to quell the infection, the tubercle bacilli, are internalized by alveolar macrophages. When the macrophages fail to inhibit or destroy the bacillus , the bacteria multiply within their intracellular environment , get released, then phagocytosed by other alveolar macrophages and the cycle continues. Lymphocytes are the recruited to the infection sites, initiaging a cell-mediated immune response, in which a pile of immune cells arrives, attempting to sequester the bacterial and limit further multiplication.

• #22 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  In this section the different phases of infection with Mycobacterium tuberculosis will be reviewed. […] Transmission of TB is by inhalation of infectious droplet nuclei containing viable bacilli (aerosol spread). […] For reasons not clearly understood, the majority of individuals infected with M. tuberculosis (~90 %) do not develop disease. […] Susceptibility to TB is influenced by environmental, host and pathogen factors. […] The key players in the innate defence against M. tuberculosis are the alveolar macrophages and dendritic cells. […] PRR-mediated phagocytosis of the pathogen by macrophages is an essential feature of the innate immune response. […] Dendritic cells are an important mediator between the innate and adaptive immune response which in addition to phagocytosis, present live mycobacteria to nave T cells after migrating to regional lymph nodes.

• #23 Pathogenesis of tuberculosis and other mycobacteriosis | Enfermedades Infecciosas y Microbiología Clínica (English Edition)

  https://www.elsevier.es/en-revista-enfermedades-infecciosas-microbiologia-clinica-english-428-articulo-pathogenesis-tuberculosis-other-mycobacteriosis-S2529993X17303052

  The evolution between Mycobacterium tuberculosis infection and active tuberculosis is multifactorial and involves different biological scales. The synthesis of ESAT-6 or the induction of alveolar macrophage necrosis are key, but to understand it, it is necessary to consider the dynamics of endogenous and exogenous reinfection, drainage of lung parenchyma and respiratory mechanics, local fibrosis processes and blood supply. […] When the viable bacillus is phagocytised by the AM, it spreads its pathogenic capacity by secreting 6kDa early secretory antigenic target (ESAT-6). This peptide is essential to prevent the phagosomelysosome union and apoptosis and eventually allows entry of the bacillus into the cytoplasm. […] The dendritic cells process M. tuberculosis and present epitopes that mostly correspond to the most abundant antigens secreted: ESAT-6 and the antigen 85 complex (Ag85 A, B or C).

• #24 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Latent TB infection occurs after most primary infections. In about 95% of cases, after about 3 weeks of uninhibited growth, the immune system suppresses bacillary replication, usually before symptoms or signs develop. Foci of bacilli in the lung or other sites resolve into epithelioid cell granulomas, which may have caseous and necrotic centers. Tubercle bacilli can survive in this material for years; the balance between the hosts resistance and microbial virulence determines whether the infection ultimately resolves without treatment, remains dormant, or becomes active. […] Conditions that impair cellular immunity (which is essential for defense against TB) significantly facilitate reactivation. Thus, patients coinfected with HIV and not receiving appropriate antiretroviral therapy (ART) have about a 10% annual risk of developing active disease.

• #25 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Latent TB infection occurs after most primary infections. In about 95% of cases, after about 3 weeks of uninhibited growth, the immune system suppresses bacillary replication, usually before symptoms or signs develop. Foci of bacilli in the lung or other sites resolve into epithelioid cell granulomas, which may have caseous and necrotic centers. Tubercle bacilli can survive in this material for years; the balance between the hosts resistance and microbial virulence determines whether the infection ultimately resolves without treatment, remains dormant, or becomes active. […] Conditions that impair cellular immunity (which is essential for defense against TB) significantly facilitate reactivation. Thus, patients coinfected with HIV and not receiving appropriate antiretroviral therapy (ART) have about a 10% annual risk of developing active disease.

• #26 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  In this section the different phases of infection with Mycobacterium tuberculosis will be reviewed. […] Transmission of TB is by inhalation of infectious droplet nuclei containing viable bacilli (aerosol spread). […] For reasons not clearly understood, the majority of individuals infected with M. tuberculosis (~90 %) do not develop disease. […] Susceptibility to TB is influenced by environmental, host and pathogen factors. […] The key players in the innate defence against M. tuberculosis are the alveolar macrophages and dendritic cells. […] PRR-mediated phagocytosis of the pathogen by macrophages is an essential feature of the innate immune response. […] Dendritic cells are an important mediator between the innate and adaptive immune response which in addition to phagocytosis, present live mycobacteria to nave T cells after migrating to regional lymph nodes.

• #27 Pathogenesis Involved in Tuberculosis

  https://www.longdom.org/open-access/pathogenesis-involved-in-tuberculosis-96859.html

  Mycobacterium Tuberculosis (MTB) bacteria directly cause the infectious disease Tuberculosis (TB). […] When mycobacteria enter the lung’s alveolar air sacs, they invade and multiply inside the endosomes of alveolar macrophages, which results in the initiation of TB infection. […] Only 10% of people with M. tuberculosis have latent TB infections, which are asymptomatic and have a 10% lifetime chance of progressing into active tuberculous disease. […] The risk of acquiring active TB in people with HIV increases to over 10% year. […] The mortality rate for active TB individuals might reach 66% if effective treatment is not provided. […] The granuloma may inhibit mycobacteria from spreading and provide a local environment for immune system cell interaction and this indicates that the bacteria employ the granulomas to evade the host’s immune system.

• #28 Pathogenesis Involved in Tuberculosis

  https://www.longdom.org/open-access/pathogenesis-involved-in-tuberculosis-96859.html

  Mycobacterium Tuberculosis (MTB) bacteria directly cause the infectious disease Tuberculosis (TB). […] When mycobacteria enter the lung’s alveolar air sacs, they invade and multiply inside the endosomes of alveolar macrophages, which results in the initiation of TB infection. […] Only 10% of people with M. tuberculosis have latent TB infections, which are asymptomatic and have a 10% lifetime chance of progressing into active tuberculous disease. […] The risk of acquiring active TB in people with HIV increases to over 10% year. […] The mortality rate for active TB individuals might reach 66% if effective treatment is not provided. […] The granuloma may inhibit mycobacteria from spreading and provide a local environment for immune system cell interaction and this indicates that the bacteria employ the granulomas to evade the host’s immune system.

• #29 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Latent TB infection occurs after most primary infections. In about 95% of cases, after about 3 weeks of uninhibited growth, the immune system suppresses bacillary replication, usually before symptoms or signs develop. Foci of bacilli in the lung or other sites resolve into epithelioid cell granulomas, which may have caseous and necrotic centers. Tubercle bacilli can survive in this material for years; the balance between the hosts resistance and microbial virulence determines whether the infection ultimately resolves without treatment, remains dormant, or becomes active. […] Conditions that impair cellular immunity (which is essential for defense against TB) significantly facilitate reactivation. Thus, patients coinfected with HIV and not receiving appropriate antiretroviral therapy (ART) have about a 10% annual risk of developing active disease.

• #30 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  Latent TB infection occurs after most primary infections. In about 95% of cases, after about 3 weeks of uninhibited growth, the immune system suppresses bacillary replication, usually before symptoms or signs develop. Foci of bacilli in the lung or other sites resolve into epithelioid cell granulomas, which may have caseous and necrotic centers. Tubercle bacilli can survive in this material for years; the balance between the hosts resistance and microbial virulence determines whether the infection ultimately resolves without treatment, remains dormant, or becomes active. […] Conditions that impair cellular immunity (which is essential for defense against TB) significantly facilitate reactivation. Thus, patients coinfected with HIV and not receiving appropriate antiretroviral therapy (ART) have about a 10% annual risk of developing active disease.

• #31 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  However, in the setting of impaired immunity, the disease immediately progresses into active TB with clinical symptoms. […] The granuloma is the cardinal feature of pulmonary TB, which is an amorphous collection of macrophages and other immune cells aimed at restricting the bacterial spread. In immunocompetent individuals, although the granuloma is unable to eliminate the pathogen, it restrains the bacilli and halts the progression to the active disease. […] However, the bacteria still survive, avoiding death by blocking the phagolysosome fusion and subverting the hosts immune response. This process establishes a hospitable niche for M. tb where it can survive for decades, outwitting the immune system and persisting in a non-replicating or slowly replicating state. […] Even though the main cause of TB reactivation is ascribed to HIV co-infection, other conditions may also switch the quiescent infection to an active one. These triggering factors include malnutrition, immune suppressive medications, chemotherapy, uncontrolled diabetes mellitus, sepsis, drug or alcohol addiction, chronic renal failure, smoking and malignancy.

• #32 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  When the host is immunocompromised, the dormant bacilli, originally enclosed in the granuloma, will reactivate and replicate, accompanied by the granuloma liquifying and cavitating. […] The caseous material serves as a fertile source of nutrients that promotes the growth of the pathogen to an overwhelming burden. […] As lung histology during the active disease indicates the coexistence of granulomas at different stages of development, granuloma progression is thought to correlate with TB reactivation. […] The pathogenic life cycle of M. tb is illustrated in Figure 2. TB is transmitted via M. tb-containing aerosol droplets, propelled by active TB patients when they cough, sneeze or talk. After the new host inhale the TB bacteria, they travel through the respiratory tract and reach the lung. At this point, the hosts innate immune system comes into play to quell the infection, whereupon the tubercle bacilli are internalised by alveolar macrophages. When the macrophages fail to inhibit or destroy the bacilli, the bacteria multiply within their intracellular environment, get released, then phagocytosed by other alveolar macrophages and the cycle continues. […] However, in the setting of impaired immunity, the disease immediately progresses into active TB with clinical symptoms.

• #33 Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10049048/

  When the host is immunocompromised, the dormant bacilli, originally enclosed in the granuloma, will reactivate and replicate, accompanied by the granuloma liquifying and cavitating. […] The caseous material serves as a fertile source of nutrients that promotes the growth of the pathogen to an overwhelming burden. […] As lung histology during the active disease indicates the coexistence of granulomas at different stages of development, granuloma progression is thought to correlate with TB reactivation. […] The pathogenic life cycle of M. tb is illustrated in Figure 2. TB is transmitted via M. tb-containing aerosol droplets, propelled by active TB patients when they cough, sneeze or talk. After the new host inhale the TB bacteria, they travel through the respiratory tract and reach the lung. At this point, the hosts innate immune system comes into play to quell the infection, whereupon the tubercle bacilli are internalised by alveolar macrophages. When the macrophages fail to inhibit or destroy the bacilli, the bacteria multiply within their intracellular environment, get released, then phagocytosed by other alveolar macrophages and the cycle continues. […] However, in the setting of impaired immunity, the disease immediately progresses into active TB with clinical symptoms.

• #34 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  TB damages tissues through delayed-type hypersensitivity (DTH), typically producing granulomatous necrosis with a caseous histologic appearance. Lung lesions are characteristically but not invariably cavitary, especially in immunosuppressed patients with impaired DTH. […] The course of TB varies greatly, depending on the virulence of the organism and the state of host defenses. The course may be rapid in members of isolated populations (eg, Native Americans) who, unlike many Europeans and their American descendents, have not experienced centuries of selective pressure to develop innate or natural immunity to the disease. The course is often more indolent in these European and American populations. […] The new anti-TB drugs bedaquiline, delamanid, and pretomanid and the fluoroquinolone moxifloxacin are oral drugs highly active against drug-resistant strains using shorter treatment duration than other regimens. They rapidly stop transmission and have higher rates of completion and cure and thus are likely to help control the epidemic of DR-TB. However, success will continue to depend on strong global commitments to provide access to molecular diagnostics and effective treatment as well as full treatment supervision.

• #35 Tuberculosis (TB) – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

  To initiate infection, M. tuberculosis bacilli must be ingested by alveolar macrophages. Bacilli that are not killed by the macrophages actually replicate inside them, ultimately killing the host macrophage (with the help of CD8 lymphocytes); inflammatory cells are attracted to the area, causing a focal pneumonitis that coalesces into the characteristic tubercles seen histologically. […] In the early weeks of infection, some infected macrophages migrate to regional lymph nodes (eg, hilar, mediastinal), where they access the bloodstream. Organisms may then spread hematogenously to any part of the body, particularly the apical-posterior portion of the lungs, epiphyses of the long bones, kidneys, vertebral bodies, and meninges. Hematogenous dissemination is less likely in patients with partial immunity due to vaccination or to prior natural infection with M. tuberculosis or environmental mycobacteria.

• #36 Tuberculosis – Wikipedia

  https://en.wikipedia.org/wiki/Tuberculosis

  If TB bacteria gain entry to the blood stream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the tissues. This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis. […] People with this disseminated TB have a high fatality rate even with treatment (about 30%). […] In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with caseous necrotic material. During active disease, some of these cavities are joined to the air passages (bronchi) and this material can be coughed up. It contains living bacteria and thus can spread the infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.

• #37 Tuberculosis – Wikipedia

  https://en.wikipedia.org/wiki/Tuberculosis

  If TB bacteria gain entry to the blood stream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the tissues. This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis. […] People with this disseminated TB have a high fatality rate even with treatment (about 30%). […] In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with caseous necrotic material. During active disease, some of these cavities are joined to the air passages (bronchi) and this material can be coughed up. It contains living bacteria and thus can spread the infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.

• #38

  https://link.springer.com/article/10.1186/s43556-022-00106-y

  The Mtb H37Rv genome consists of 4.4106bp (65.6% GC), encoding ~4000 predicted proteins. […] These annotated proteins are involved in multiple cellular metabolic pathways, including DNA or RNA methylation, RNA processing, protein processing, lipid synthesis, membrane assembly, cell division, and cytoplasmic and membrane transfer steps of peptidoglycan synthesis, in which numerous metabolic pathways are closely related to the pathogenicity of Mtb. […] A unique feature of the Mtb genome is that over 200 proteins (6% of the total) participate in the metabolism of fatty acids, among which approximately 100 are predicted to function in the -oxidation of fatty acids. […] This large number of Mtb enzymes may be related to the ability of this pathogen to grow in specific tissues of the infected host, in which fatty acids act as the major carbon source.

• #39

  https://link.springer.com/article/10.1186/s43556-022-00106-y

  The Mtb H37Rv genome consists of 4.4106bp (65.6% GC), encoding ~4000 predicted proteins. […] These annotated proteins are involved in multiple cellular metabolic pathways, including DNA or RNA methylation, RNA processing, protein processing, lipid synthesis, membrane assembly, cell division, and cytoplasmic and membrane transfer steps of peptidoglycan synthesis, in which numerous metabolic pathways are closely related to the pathogenicity of Mtb. […] A unique feature of the Mtb genome is that over 200 proteins (6% of the total) participate in the metabolism of fatty acids, among which approximately 100 are predicted to function in the -oxidation of fatty acids. […] This large number of Mtb enzymes may be related to the ability of this pathogen to grow in specific tissues of the infected host, in which fatty acids act as the major carbon source.

• #40

  https://link.springer.com/article/10.1186/s43556-022-00106-y

  The Mtb H37Rv genome consists of 4.4106bp (65.6% GC), encoding ~4000 predicted proteins. […] These annotated proteins are involved in multiple cellular metabolic pathways, including DNA or RNA methylation, RNA processing, protein processing, lipid synthesis, membrane assembly, cell division, and cytoplasmic and membrane transfer steps of peptidoglycan synthesis, in which numerous metabolic pathways are closely related to the pathogenicity of Mtb. […] A unique feature of the Mtb genome is that over 200 proteins (6% of the total) participate in the metabolism of fatty acids, among which approximately 100 are predicted to function in the -oxidation of fatty acids. […] This large number of Mtb enzymes may be related to the ability of this pathogen to grow in specific tissues of the infected host, in which fatty acids act as the major carbon source.

• #41 Pediatric Tuberculosis: Overview of Tuberculosis, TB Risk Factors, Mechanism of TB Infection

  https://emedicine.medscape.com/article/969401-overview

  Tuberculosis (TB) occurs when individuals inhale bacteria aerosolized by infected persons. The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses. […] Among the several virulence factors in the mycobacterial cell wall are the cord factor, lipoarabinomannan (LAM), and a highly immunogenic 65-kd M tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro. LAM is a heteropolysaccharide that inhibits macrophage activation by interferon (IFN)-gamma and induces macrophages to secrete TNF-alpha, which causes fever, weight loss, and tissue damage. […] Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli. However, these nave macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.

• #42 Pediatric Tuberculosis: Overview of Tuberculosis, TB Risk Factors, Mechanism of TB Infection

  https://emedicine.medscape.com/article/969401-overview

  Tuberculosis (TB) occurs when individuals inhale bacteria aerosolized by infected persons. The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses. […] Among the several virulence factors in the mycobacterial cell wall are the cord factor, lipoarabinomannan (LAM), and a highly immunogenic 65-kd M tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro. LAM is a heteropolysaccharide that inhibits macrophage activation by interferon (IFN)-gamma and induces macrophages to secrete TNF-alpha, which causes fever, weight loss, and tissue damage. […] Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli. However, these nave macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.

• #43 Key mechanism in tuberculosis survival discovered

  https://www.drugtargetreview.com/news/47893/key-mechanism-in-tuberculosis-survival-discovered/

  A new study has revealed that M. tuberculosis uses a unique type of antacid which gives immune cells indigestion, enabling the bacteria to survive. […] A study has discovered a key mechanism the Mycobacterium tuberculosis (TB) bacteria uses that prevents immune cells from killing them. […] Previous studies have shown that M. tuberculosis can survive for years despite encapsulation inside phagosomes within macrophages. […] They uncovered two enzymes critical to the production of 1-TbAd, but not the mechanism by which the molecule helped the bacterium survive. […] As the phagosome needs to be acidic for fusion, the researchers hypothesised that 1-TbAd played a role in preventing acidification of the phagosome. […] This suggests that the molecule works as an antacid and prevents the phagosome from reaching the level of acidity required to fuse with the lysosome.

• #44 Key mechanism in tuberculosis survival discovered

  https://www.drugtargetreview.com/news/47893/key-mechanism-in-tuberculosis-survival-discovered/

  The researchers investigated the adenosine compound, to understand whether it acts through a receptor. […] The lipid part is needed to cross the membranes and get into the phagosomes and lysosomes, explained Buter. […] Tests with macrophages infected with M. tuberculosis show that the phagosomes only increase significantly in the presence of the enzyme Rv3378c needed to produce 1-TbAd. […] This suggests that 1-TbAd could be used as an anti-malarial drug but also targeting the production of 1-TbAd could kill M. tuberculosis inside the macrophages. […] The researchers say that the enzyme Rv3378c would be an interesting target for drug discovery, as it is unique to the tuberculosis bacterium.

• #45 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  In this section the different phases of infection with Mycobacterium tuberculosis will be reviewed. […] Transmission of TB is by inhalation of infectious droplet nuclei containing viable bacilli (aerosol spread). […] For reasons not clearly understood, the majority of individuals infected with M. tuberculosis (~90 %) do not develop disease. […] Susceptibility to TB is influenced by environmental, host and pathogen factors. […] The key players in the innate defence against M. tuberculosis are the alveolar macrophages and dendritic cells. […] PRR-mediated phagocytosis of the pathogen by macrophages is an essential feature of the innate immune response. […] Dendritic cells are an important mediator between the innate and adaptive immune response which in addition to phagocytosis, present live mycobacteria to nave T cells after migrating to regional lymph nodes.

• #46 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  In this section the different phases of infection with Mycobacterium tuberculosis will be reviewed. […] Transmission of TB is by inhalation of infectious droplet nuclei containing viable bacilli (aerosol spread). […] For reasons not clearly understood, the majority of individuals infected with M. tuberculosis (~90 %) do not develop disease. […] Susceptibility to TB is influenced by environmental, host and pathogen factors. […] The key players in the innate defence against M. tuberculosis are the alveolar macrophages and dendritic cells. […] PRR-mediated phagocytosis of the pathogen by macrophages is an essential feature of the innate immune response. […] Dendritic cells are an important mediator between the innate and adaptive immune response which in addition to phagocytosis, present live mycobacteria to nave T cells after migrating to regional lymph nodes.

• #47 Frontiers | Editorial: Emerging concepts in Mycobacterium tuberculosis pathogenesis: Host-pathogen interaction and stress adaption mechanisms

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1148756/full

  Editorial on the Research Topic Emerging concepts in Mycobacterium tuberculosis pathogenesis: Host-pathogen interaction and stress adaption mechanisms […] The study of host-pathogen interactions is a dynamic and constantly evolving field. Such studies are vital for understanding infectious agent behavior under normal conditions and exposed to host and environmental stresses. The pathogen Mycobacterium tuberculosis (M. tb) has caused numerous human deaths since prehistoric times. Its stress adaptation mechanisms enable it to subvert host immune challenges. Many M. tb encoded effectors exploit host pathophysiology for their benefit. A mechanistic understanding of these effectors will facilitate the design of novel intervention strategies. […] Tumor necrosis factor-alpha (TNF-α) plays an important role in preventing and treating M. tb infection and pathogenesis. Pathogenic mycobacteria can regulate host cell TNF-α production, aiding their evasion of anti-TB immune stress. M. tb-infected macrophages displayed increased expression of the E3 ubiquitin ligase FBXW7. Specific suppression of FBXW7 with siRNA greatly increased TNF-α expression and eventually cleared infection. In turn, FBXW7 overexpression in RAW264.7 macrophages significantly reduced TNF-α production. Finally, FBXW7 has been shown to reduce TNF-α in a K63-linked ubiquitin signalling dependent manner. In summary, this study revealed that FBXW7 plays a key role in granuloma production that is crucial for M. tb pathogenesis. It induces macrophage polarization towards the M2 phenotype and controls TNF-α production via a ubiquitination cascade (Song et al., 2022).

• #48 Frontiers | Editorial: Emerging concepts in Mycobacterium tuberculosis pathogenesis: Host-pathogen interaction and stress adaption mechanisms

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1148756/full

  Editorial on the Research Topic Emerging concepts in Mycobacterium tuberculosis pathogenesis: Host-pathogen interaction and stress adaption mechanisms […] The study of host-pathogen interactions is a dynamic and constantly evolving field. Such studies are vital for understanding infectious agent behavior under normal conditions and exposed to host and environmental stresses. The pathogen Mycobacterium tuberculosis (M. tb) has caused numerous human deaths since prehistoric times. Its stress adaptation mechanisms enable it to subvert host immune challenges. Many M. tb encoded effectors exploit host pathophysiology for their benefit. A mechanistic understanding of these effectors will facilitate the design of novel intervention strategies. […] Tumor necrosis factor-alpha (TNF-α) plays an important role in preventing and treating M. tb infection and pathogenesis. Pathogenic mycobacteria can regulate host cell TNF-α production, aiding their evasion of anti-TB immune stress. M. tb-infected macrophages displayed increased expression of the E3 ubiquitin ligase FBXW7. Specific suppression of FBXW7 with siRNA greatly increased TNF-α expression and eventually cleared infection. In turn, FBXW7 overexpression in RAW264.7 macrophages significantly reduced TNF-α production. Finally, FBXW7 has been shown to reduce TNF-α in a K63-linked ubiquitin signalling dependent manner. In summary, this study revealed that FBXW7 plays a key role in granuloma production that is crucial for M. tb pathogenesis. It induces macrophage polarization towards the M2 phenotype and controls TNF-α production via a ubiquitination cascade (Song et al., 2022).

• #49 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  Although it is observed that TNF suppression can cause more rapid progression to TB disease, many aspects of the diverse functions of this proinflammatory factor have yet to be elucidated. […] The hallmark of mycobacterial infection is the tuberculoma or granuloma. […] In the pre-antibiotic era TB patients were often treated with cod-liver oil and sunshine, both sources of 25-hydroxyvitamin-D, which has immunomodulatory properties. […] Vitamin D deficiency has been implicated to play a role in increased susceptibility to active TB disease in numerous studies.

• #50 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  Although it is observed that TNF suppression can cause more rapid progression to TB disease, many aspects of the diverse functions of this proinflammatory factor have yet to be elucidated. […] The hallmark of mycobacterial infection is the tuberculoma or granuloma. […] In the pre-antibiotic era TB patients were often treated with cod-liver oil and sunshine, both sources of 25-hydroxyvitamin-D, which has immunomodulatory properties. […] Vitamin D deficiency has been implicated to play a role in increased susceptibility to active TB disease in numerous studies.

• #51 Pathogenesis – Tuberculosis in Adults and Children – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK344406/

  Although it is observed that TNF suppression can cause more rapid progression to TB disease, many aspects of the diverse functions of this proinflammatory factor have yet to be elucidated. […] The hallmark of mycobacterial infection is the tuberculoma or granuloma. […] In the pre-antibiotic era TB patients were often treated with cod-liver oil and sunshine, both sources of 25-hydroxyvitamin-D, which has immunomodulatory properties. […] Vitamin D deficiency has been implicated to play a role in increased susceptibility to active TB disease in numerous studies.

• #52 Pathophysiology And Treatment of Tuberculosis According to Who

  https://www.ijpsjournal.com/article/Pathophysiology+And+Treatment+of+Tuberculosis+According+to+Who++

  TB is the infectious disease in which the phenomenon of drug resistance was first described in 1948, during the very first human trial of TB therapy. As each new anti-TB drug has been introduced into clinical practice, widespread emergence of resistant strains has been described, usually within a decade. M. tuberculosis develops drug resistance through genetic mutations (there are no reports of resistance developed by the acquisition of new DNA). Although there is an ever-expanding list of genes that have been linked to resistance, allelic exchange experiments have confirmed the causality between mutation and drug resistance for only a subset of mutated genes. In these genes, the two major mechanisms of drug resistance are target modification (for example, a mutant bacterial RNA polymerase that eludes the action of rifampicin) or a defective enzyme that converts a pro-drug into an active drug (for example, a mutant bacterial catalase that fails to activate isoniazid).

• #53 Pathophysiology And Treatment of Tuberculosis According to Who

  https://www.ijpsjournal.com/article/Pathophysiology+And+Treatment+of+Tuberculosis+According+to+Who++

  TB is the infectious disease in which the phenomenon of drug resistance was first described in 1948, during the very first human trial of TB therapy. As each new anti-TB drug has been introduced into clinical practice, widespread emergence of resistant strains has been described, usually within a decade. M. tuberculosis develops drug resistance through genetic mutations (there are no reports of resistance developed by the acquisition of new DNA). Although there is an ever-expanding list of genes that have been linked to resistance, allelic exchange experiments have confirmed the causality between mutation and drug resistance for only a subset of mutated genes. In these genes, the two major mechanisms of drug resistance are target modification (for example, a mutant bacterial RNA polymerase that eludes the action of rifampicin) or a defective enzyme that converts a pro-drug into an active drug (for example, a mutant bacterial catalase that fails to activate isoniazid).

• #54 Pathophysiology And Treatment of Tuberculosis According to Who

  https://www.ijpsjournal.com/article/Pathophysiology+And+Treatment+of+Tuberculosis+According+to+Who++

  TB is the infectious disease in which the phenomenon of drug resistance was first described in 1948, during the very first human trial of TB therapy. As each new anti-TB drug has been introduced into clinical practice, widespread emergence of resistant strains has been described, usually within a decade. M. tuberculosis develops drug resistance through genetic mutations (there are no reports of resistance developed by the acquisition of new DNA). Although there is an ever-expanding list of genes that have been linked to resistance, allelic exchange experiments have confirmed the causality between mutation and drug resistance for only a subset of mutated genes. In these genes, the two major mechanisms of drug resistance are target modification (for example, a mutant bacterial RNA polymerase that eludes the action of rifampicin) or a defective enzyme that converts a pro-drug into an active drug (for example, a mutant bacterial catalase that fails to activate isoniazid).

• #55

  https://biomedgrid.com/fulltext/volume7/mechanism-of-drug-resistance-in-mycobacterium.001181.php

  Mycobacterium tuberculosis the causative agent of tuberculosis has many intrinsic features which enable it to evade the activity of antibiotics. […] An attempt was made in this write up to elucidate the various mechanism of drug resistance in M. tuberculosis, including its innate impermeable cell wall and mutation of specific genes. Drug resistance in Mycobacterium tuberculosis is not a product of a single homogeneous genetic unit. Rather it is as a result of frequent mutation in various genes which encode for resistance to antibiotics. […] The complexity of the mechanisms used by M. tuberculosis in drug resistance has led scientists to studying M. tuberculosis at the molecular level. Various researchers have been able to identify some molecular features which have been attributed to drug resistance in the organism. When considering the mechanisms of drug resistance in M. tuberculosis, it is imperative to understand the interplay between the molecular mechanisms, adaptive features and the innate attribute which play crucial role in resistant-MTB strain.

• #56 Pathophysiology And Treatment of Tuberculosis According to Who

  https://www.ijpsjournal.com/article/Pathophysiology+And+Treatment+of+Tuberculosis+According+to+Who++

  The evolution between Mycobacterium tuberculosis infection and active tuberculosis is multi factorial and involves different biological scales. The synthesis of ESAT-6 or the induction of alveolar macrophage necrosis are key, but to understand it, it is necessary to consider the dynamics of endogenous and exogenous reinfection, drainage of lung parenchyma and respiratory mechanics, local fibrosis processes and blood supply. Severe immunosuppression can only explain 10% of active tuberculosis cases, while the remainder are attributable to comorbidities, a proinflammatory environment and an unknown genetic propensity. The pathogenic capacity of environmental mycobacteria is discrete linked to deficits in the innate and acquired immune response. […] The pathogenic life cycle of M.tb is transmitted via M. tb containing aerosol droplets, propelled by active TB patients when they cough,sneeze or talk. The granuloma is the cardinal feature of pulmonary TB, which is amorphous collection of macrophages and other immune cell aimed at restricting the bacterial spread. In immune competent individuals, although the granuloma is unable to eliminate the pathogen, it restrain the bacilli and halts the progression to the active disease. As the granuloma matures, macrophages differentiate into foamy macrophages and other various morphotypes. The centre of the granuloma may necrotisc as a results of the necrotic lysis of the host immune cells forming what is referred to as caseum. Indeed, the accumulating soft necrotic debris, located in the core of the granuloma, resembles cheese. Foamy macrophages, which are charaterised by accumulated lipid droplets, distribute around the necrotic foci of the granuloma. In this case, the patient is still non infectious and asmptomatic. One of the challenges facing the current TB therapy is targeting this tenacious pathogen inside the granuloma. At the this point, the hosts innate immune system comes into play to quell the infection, the tubercle bacilli, are internalized by alveolar macrophages. When the macrophages fail to inhibit or destroy the bacillus , the bacteria multiply within their intracellular environment , get released, then phagocytosed by other alveolar macrophages and the cycle continues. Lymphocytes are the recruited to the infection sites, initiaging a cell-mediated immune response, in which a pile of immune cells arrives, attempting to sequester the bacterial and limit further multiplication.

• #57 Understanding the Pathophysiology of Tuberculosis: Mechanisms and Implications | HealthOK Global

  https://healthokglobal.com/pathophysiology-of-tuberculosis

  Several factors influence the pathophysiology of TB, including the virulence of the Mycobacterium tuberculosis strain, the host’s immune status, and genetic predisposition. […] Understanding the pathophysiology of tuberculosis is essential for developing effective strategies to combat this infectious disease. […] By exploring the mechanisms involved in TB infection, immune response, and granuloma formation, we can better appreciate the complexities of TB and work towards improved treatments and preventive measures.

• #58 Mycobacterium tuberculosis : Pathogenesis and therapeutic targets – ScienceOpen

  https://www.scienceopen.com/document?vid=1145e9d0-a834-4d75-9c2b-72cf8f692dcc

  Mtb’s adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti-TB drug development efforts. […] Our review provides valuable insights for future antituberculosis drug development efforts.

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