scholarly journals Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-directed Therapies.

2021 ◽  
Author(s):  
Robert E. E. Brown ◽  
Robert L Hunter
Keyword(s):  
Fatty Acid Synthase ◽  
Mycobacterial Antigen ◽  
Primary Tuberculosis ◽  
Human Lungs ◽  
Programmed Death ◽  
Bronchiolar Epithelium ◽  
Cox 2 ◽  
Early Lesion ◽  
Mycobacterial Antigens ◽  
Secreted Antigens

The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions undergo necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Here we extend these findings with the demonstration of mycobacterial antigen, but not AFB, of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis uses its secreted antigens to coordinate prolonged subclinical development of the early le-sions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas and fibrocaseous disease.

scholarly journals Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-directed Therapies

2021 ◽  
Author(s):  
Robert E. E. Brown ◽  
Robert L Hunter
Keyword(s):  
Fatty Acid Synthase ◽  
Mycobacterial Antigen ◽  
Primary Tuberculosis ◽  
Human Lungs ◽  
Programmed Death ◽  
Bronchiolar Epithelium ◽  
Cox 2 ◽  
Early Lesion ◽  
Mycobacterial Antigens ◽  
Secreted Antigens

The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions under necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Here we extend these findings with the demonstration of mycobacterial antigen, but not AFB, of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis use its secreted antigens to coordinate prolonged subclinical development of the early lesions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas and fibrocaseous disease

scholarly journals Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-Directed Therapies

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1572
Author(s):  
Robert E. Brown ◽  
Robert L. Hunter
Keyword(s):  
Fatty Acid Synthase ◽  
Programmed Death Ligand 1 ◽  
Primary Tuberculosis ◽  
Human Lungs ◽  
Programmed Death ◽  
Bronchiolar Epithelium ◽  
Cox 2 ◽  
Early Lesion ◽  
Mycobacterial Antigens ◽  
Secreted Antigens

The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions undergo necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Bacteria grow massively on the cavity wall where they can be coughed out to infect new people. Here we extend these findings with the demonstration of secreted mycobacterial antigens, but not acid fast bacilli (AFB) of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis uses its secreted antigens to coordinate prolonged subclinical development of the early lesions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas, and fibrocaseous disease.

scholarly journals Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Hostdirected Therapies

2021 ◽  
Author(s):  
Robert E. Brown ◽  
Robert L. Hunter
Keyword(s):  
Fatty Acid Synthase ◽  
Clinical Disease ◽  
Primary Tuberculosis ◽  
New Synthesis ◽  
Programmed Death ◽  
Cord Factor ◽  
Bronchiolar Epithelium ◽  
Early Lesion ◽  
Mycobacterial Antigens ◽  
Secreted Antigens

Research on the pathogenesis of tuberculosis in recent years has focused largely on the granulomatous stage of primary tuberculosis. However, post-primary tuberculosis that accounts for 80% of clinical disease is seldom studied because of the paucity of animal models and human tissues. The early lesion of post-primary tuberculosis is a subclinical obstructive lobular pneumonia that develops asymptomatically for months accumulating secreted mycobacterial antigens in alveolar macrophages and highly sensitized T cells before onset of clinical disease. Here we demonstrate antigen of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests a new synthesis of the pathogenesis of post-primary tuberculosis in which M. tuberculosis use its secreted antigens and cord factor to direct prolonged subclinical development of the early lesions in preparation for a sudden necrotizing reaction sufficient to produce a cavity and/or granulomas. Available evidence indicates that most successful human and animal vaccines and host directed therapies of post-primary tuberculosis target the early lesion, not granulomas. Recognition of this will facilitate design and evaluation of improved vaccines and therapies for tuberculosis.

scholarly journals T-Cell and Antibody Responses to Mycobacterial Antigens in Tuberculin Skin-Test-PositiveBos indicusandBos taurusCattle in Ethiopia

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Gobena Ameni ◽  
Paul Cockle ◽  
Konstantin Lyashchenko ◽  
Martin Vordermeier
Keyword(s):  
T Cell ◽  
Skin Test ◽  
Bos Taurus ◽  
Bos Indicus ◽  
Antigen Recognition ◽  
Antibody Responses ◽  
Zebu Cattle ◽  
Mycobacterial Antigen ◽  
Multiple Antigen ◽  
Mycobacterial Antigens

Higher IFN-γresponses to mycobacterial antigens were observed inBos taurus(Holsteins) than inBos indicus(Zebu) cattle which could due to differences in antigen recognition profiles between the two breeds. The present study was conducted to evaluate mycobacterial antigen recognition profiles of the two breeds. Twenty-three mycobacterial antigens were tested on 46 skin test positive (24 Zebu and 22 Holstein) using enzyme-linked immunospot assay (ELISPOT) and multiple antigen print immunoassay (MAPIA). Herds from which the study cattle obtained were tested for Fasciola antibody. The T cells from both breeds recognized most of the mycobacterial antigens at lower and comparable frequencies. However, antigens such as CFP-10, ESAT-6, Rv0287, Rv0288, MPB87, Acr-2, Rv3616c, and Rv3879c were recognized at higher frequencies in zebu while higher frequencies of T cell responses were observed to Hsp65 in both breeds. Furthermore, comparable antibody responses were observed in both breeds; MPB83 being the sero-dominant antigen in both breeds. The prevalence of Fasciola antibody was 81% and similar in both breeds. This piece of work could not lead to a definitive conclusion if there are differences in mycobacterial recognition profiles between the two breeds warranting for further similar studies using sound sample size from the two breeds.

scholarly journals Mycobacterial Antigens Exacerbate Disease Manifestations in Mycobacterium tuberculosis-Infected Mice

2002 ◽  
Vol 70 (4) ◽  
pp. 2100-2107 ◽  
Author(s):  
Andre L. Moreira ◽  
Liana Tsenova ◽  
Melles Haile Aman ◽  
Linda-Gail Bekker ◽  
Sherry Freeman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pulmonary Disease ◽  
Bacterial Load ◽  
Subcutaneous Administration ◽  
Mycobacterial Antigen ◽  
Lung Pathology ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Aerosol Infection ◽  
Mycobacterial Antigens

ABSTRACT To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-α, and to a lesser extent, IL-2 and gamma interferon (IFN-γ), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-α resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-α-induced inflammation without reducing the bacillary load.

scholarly journals Immunocytochemical Method for Early Laboratory Diagnosis of Tuberculous Meningitis

2002 ◽  
Vol 9 (2) ◽  
pp. 344-347 ◽  
Author(s):  
M. G. Sumi ◽  
A. Mathai ◽  
S. Reuben ◽  
C. Sarada ◽  
V. V. Radhakrishnan
Keyword(s):  
Disease Control ◽  
Tuberculous Meningitis ◽  
Neurological Diseases ◽  
Laboratory Diagnosis ◽  
Mycobacterial Antigen ◽  
Direct Demonstration ◽  
Number Of Patients ◽  
Positive Immunostaining ◽  
Immunocytochemical Method ◽  
Mycobacterial Antigens

ABSTRACT A simple immunocytochemical method was standardized for the direct demonstration of mycobacterial antigen in cerebrospinal fluid (CSF) specimens of patients with tuberculous meningitis (TBM). CSF-cytospin smears were prepared from 22 patients with a clinical diagnosis of TBM and also from an equal number of patients with nontuberculous neurological diseases (disease control). Immunocytological demonstration of mycobacterial antigens in the cytoplasm of monocytoid cells was attempted, by using rabbit immunoglobulin G to Mycobacterium tuberculosis as the primary antibody. Of the 22 CSF-cytospin smears from TBM patients, 16 showed positive immunostaining, while all of the CSF-cytospin smears from the disease control showed negative immunostaining for mycobacterial antigen. The technical aspects of this immunocytological method for the demonstration of mycobacterial antigens are simple, rapid, and reproducible, as well as specific, and therefore can be applied for the early diagnosis of TBM, particularly in patients in whom bacteriological methods did not demonstrate the presence of M. tuberculosis in the CSF.

scholarly journals The Pathogenesis of Tuberculosis–The Koch Phenomenon Reinstated

Pathogens ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 813
Author(s):  
Robert L. Hunter
Keyword(s):  
T Cells ◽  
Animal Models ◽  
Hypersensitivity Reaction ◽  
Alveolar Macrophages ◽  
Adult Type ◽  
New Approaches ◽  
Early Lesion ◽  
Mycobacterial Antigens ◽  
Active Disease

Research on the pathogenesis of tuberculosis (TB) has been hamstrung for half a century by the paradigm that granulomas are the hallmark of active disease. Human TB, in fact, produces two types of granulomas, neither of which is involved in the development of adult type or post-primary TB. This disease begins as the early lesion; a prolonged subclinical stockpiling of secreted mycobacterial antigens in foamy alveolar macrophages and nearby highly sensitized T cells in preparation for a massive necrotizing hypersensitivity reaction, the Koch Phenomenon, that produces caseous pneumonia that is either coughed out to form cavities or retained to become the focus of post-primary granulomas and fibrocaseous disease. Post-primary TB progresses if the antigens are continuously released and regresses when they are depleted. This revised paradigm is supported by nearly 200 years of research and suggests new approaches and animal models to investigate long standing mysteries of human TB and vaccines that inhibit the early lesion to finally end its transmission.

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