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 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.

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 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.

Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins

2019 ◽  
Author(s):  
Steven Banik ◽  
Kayvon Pedram ◽  
Simon Wisnovsky ◽  
Nicholas Riley ◽  
Carolyn Bertozzi
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Membrane Proteins ◽  
Growth Factor Receptor ◽  
Basic Research ◽  
Biochemical Pathway ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
A Cell ◽  
Epidermal Growth ◽  
Powerful Strategy

<p>Targeted protein degradation is a powerful strategy to address the canonically undruggable proteome. However, current technologies are limited to targets with cytosolically-accessible and ligandable domains. Here, we designed and synthesized conjugates capable of binding both a cell surface lysosome targeting receptor and the extracellular domain of a target protein. These lysosome targeting chimeras (LYTACs) consist of an antibody fused to agonist glycopeptide ligands for the cation-independent mannose-6-phosphate receptor (CI-M6PR). LYTACs enabled a CRISPRi knockdown screen revealing the biochemical pathway for CI-M6PR-mediated cargo internalization. We demonstrated that LYTACs mediate efficient degradation of Apolipoprotein-E4, epidermal growth factor receptor (EGFR), CD71, and programmed death-ligand 1 (PD-L1). LYTACs represent a modular strategy for directing secreted and membrane proteins for degradation in the context of both basic research and therapy. <b></b></p>

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