Morphoproteomic-Guided Host-Directed Therapy for Tuberculosis

Brown, Robert E.; Hunter, Robert L.; Hwang, Shen-An

doi:10.3389/fimmu.2017.00078

Cited by 16 publications

(16 citation statements)

References 69 publications

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“…As has been demonstrated (for our contribution, see [ 30 ]), in vitro infection of mouse cells and in vivo infection of animals lead to different, even opposing, responses of mycobacteria and macrophages. Also, the hypothesis that foamy alveolar macrophages are directly responsible for the development of cavities in the lungs of TB patients was solely based on the results of histological analysis of some human autopsy specimens and did not consider levels of infection with Mtb in the cells of these lung tissues [ 50 , 51 ]. Therefore, it is necessary to collect more data about relationships between foamy alveolar macrophages and Mtb in the lungs of TB patients, because adjunctive host-directed therapy proposed for treatment of TB includes the use of statins, which inhibit the biosynthesis of cholesterol in host cells [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Ex vivo expansion of alveolar macrophages with Mycobacterium tuberculosis from the resected lungs of patients with pulmonary tuberculosis

et al. 2018

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Tuberculosis (TB), with the Mycobacterium tuberculosis (Mtb) as the causative agent, remains to be a serious world health problem. Traditional methods used for the study of Mtb in the lungs of TB patients do not provide information about the number and functional status of Mtb, especially if Mtb are located in alveolar macrophages. We have developed a technique to produce ex vivo cultures of cells from different parts of lung tissues surgically removed from patients with pulmonary TB and compared data on the number of cells with Mtb inferred by the proposed technique to the results of bacteriological and histological analyses used for examination of the resected lungs. The ex vivo cultures of cells obtained from the resected lungs of all patients were largely composed of CD14-positive alveolar macrophages, foamy or not, with or without Mtb. Lymphocytes, fibroblasts, neutrophils, and multinucleate Langhans giant cells were also observed. We found alveolar macrophages with Mtb in the ex vivo cultures of cells from the resected lungs of even those TB patients, whose sputum smears and lung tissues did not contain acid-fast Mtb or reveal growing Mtb colonies on dense medium. The detection of alveolar macrophages with Mtb in ex vivo culture as soon as 16–18 h after isolation of cells from the resected lungs of all TB patients suggests that the technique proposed for assessing the level of infection in alveolar macrophages of TB patients has higher sensitivity than do prolonged bacteriological or pathomorphological methods. The proposed technique allowed us to rapidly (in two days after surgery) determine the level of infection with Mtb in the cells of the resected lungs of TB patients and, by the presence or absence of Mtb colonies, including those with cording morphology, the functional status of the TB agent at the time of surgery.

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Section: Discussionmentioning

confidence: 99%

Ex vivo expansion of alveolar macrophages with Mycobacterium tuberculosis from the resected lungs of patients with pulmonary tuberculosis

et al. 2018

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“…Nevertheless, a third new beginning is now necessary to merge the clinical, pathologic and radiologic insights of the first era with the immunology, cell biology and genetics of the second so that the tools of modern science can finally be used to study the actual human disease. Recognition of primary and post-primary as separate pathologic entities immediately suggests resolution of long standing questions and multiple testable hypotheses as follows ( 28 – 30 , 62 , 68 – 70 ).…”

Section: Implications For Future Researchmentioning

confidence: 99%

“…More foxp3 + (Treg) cells were found in cavity walls than in other types of lesions. In other studies, we investigated the presence of regulatory markers associated within early infiltrates of post-primary TB ( 70 ). We chose three markers of mTOR signaling (pmTOR, insulin-like growth factor-1 receptor and activated Akt) and a second pathway of macrophage activation, COX-2.…”

Section: Potential Of Advanced Technologymentioning

confidence: 99%

“…It is now possible to assess gene expression of both host cells and bacteria on routinely prepared slides ( 75 ). With recent advances in the immunotherapy of cancer, the methods for studying mutations, cell maturation and differentiation, immune parameters, inflammation, and healing on slides have advanced dramatically and will continue to increase ( 70 ). Thousands of studies can be done on single paraffin embedded samples over a period of years.…”

Section: Potential Of Advanced Technologymentioning

confidence: 99%

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The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

Hunter

2018

Front. Immunol.

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It has long been recognized that tuberculosis (TB) induces both protective and tissue damaging immune responses. This paper reviews nearly two centuries of evidence that protection and tissue damage are mediated by separate disease entities in humans. Primary TB mediates protective immunity to disseminated infection while post-primary TB causes tissue damage that results in formation of cavities. Both are necessary for continued survival of Mycobacterium tuberculosis (MTB). Primary TB has been extensively studied in humans and animals. Post-primary TB, in contrast, is seldom recognized or studied. It begins as an asymptomatic early infiltrate that may resolve or progress by bronchogenic spread to caseous pneumonia that either fragments to produce cavities or is retained to produce post-primary granulomas and fibrocaseous disease. Primary and post-primary TB differ in typical age of onset, histopathology, organ distribution, x-ray appearance, genetic predisposition, immune status of the host, clinical course and susceptibility to protection by BCG. MTB is a highly successful human parasite because it produces both primary and post-primary TB as distinct disease entities in humans. No animal reproduces this sequence of lesions. Recognition of these facts immediately suggests plausible solutions, animal models and testable hypotheses to otherwise inaccessible questions of the immunity and pathogenesis of TB.

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“…This situation has led to the emergence of a new paradigm in TB drug discovery that involves therapeutic modulation of host cell functions in order to improve pathogen eradication, namely, host-directed therapy (HDT) (6). Since the mechanisms underlying HDT are completely different from those for antibiotics, which directly kill the mycobacteria, HDT has become an attractive strategy to shorten treatment regimens and to treat TB patients infected with drug-resistant M. tuberculosis strains (6,7).…”

Section: Importancementioning

confidence: 99%

Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy

Ouyang

Zhang

Lin

et al. 2020

mSphere

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Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection. There is a clear need for new treatment strategy against TB. It has been reported that tamoxifen, known as a selective estrogen receptor modulator (SERM), exhibits antimycobacterial activity and inhibits M. tuberculosis growth in macrophages. However, it remains unknown whether such antimicrobial activity is a general property of all SERMs and how it works. In this study, we identified that bazedoxifene (BZA), a newer SERM, inhibits intracellular M. tuberculosis growth in macrophages. BZA treatment increases autophagosome formation and LC3B-II protein expression in M. tuberculosis-infected macrophages. We further demonstrated that the enhancement of autophagy by BZA is dependent on increased reactive oxygen species (ROS) production and associated with phosphorylation of Akt/mTOR signaling. In summary, our data reveal a previously unappreciated antimicrobial function of BZA and suggest that future investigation focusing on the mechanism of action of SERMs in macrophages may lead to new host-directed therapies against TB. IMPORTANCE Since current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-directed therapy (HDT) has become a promising idea to modulate host cell responses to enhance protective immunity against pathogens. Bazedoxifene (BZA), which belongs to a new generation of SERMs, shows the ability to inhibit the growth of M. tuberculosis in macrophages and is associated with autophagy. Our findings reveal a previously unrecognized antibacterial function of BZA. We propose that the mechanism of SERMs action in macrophages may provide a new potential measure for host-directed therapies against TB.

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Morphoproteomic-Guided Host-Directed Therapy for Tuberculosis

Cited by 16 publications

References 69 publications

Ex vivo expansion of alveolar macrophages with Mycobacterium tuberculosis from the resected lungs of patients with pulmonary tuberculosis

Ex vivo expansion of alveolar macrophages with Mycobacterium tuberculosis from the resected lungs of patients with pulmonary tuberculosis

The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy

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