L-Tyrosine Limits Mycobacterial Survival in Tuberculous Granuloma.

Caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), tuberculosis (TB) remains a massive global public health issue. A well-known and key TB trait is caseous necrotic granuloma, which allows mycobacteria to reactivate and disseminate, thus confounding TB eradication programs. Amino acid (AA) metabolism is key to regulating immune responses in Mtb infections; however, it is currently unclear if AAs can be used to treat tuberculous granulomas. Here, we screened 20 proteinogenic AAs using a Mycobacterium marinum-infected zebrafish granuloma model. Only L-tyrosine simultaneously reduced Mycobacterium marinum (M. marinum) levels in zebrafish larvae and adults and inhibited intracellular pathogen survival levels. Mechanistically, L-tyrosine significantly upregulated interferon-γ (IFN-γ) expression in M. marinum -infected zebrafish adults but not in larvae. Using N-acetylcysteine (NAC) to inhibit reactive oxygen species (ROS), L-tyrosine appeared to inhibit Mtb intracellular survival by promoting ROS production. Thus, L-tyrosine as a non-essential AA may reduce mycobacterial survival in both macrophages and tuberculous granulomas. Our research provides a platform for the clinical development of AAs for active or latent TB patients infected with drug-sensitive or drug-resistant Mtb.

The use of multiplex imaging techniques to characterize tuberculous granuloma heterogeneity.

Caseous granulomas are pathological hallmarks of tuberculosis (TB), and increasing evidence suggests that TB granuloma composition is highly temporally and spatially heterogenous in both animal models and humans. Traditional pathological techniques are limited in their ability to reveal the heterogeneity present in TB granulomas. Multiplex tissue imaging tools combined with powerful, high resolution spatial analysis have enabled the detection of various cell phenotypes, aiding in the visualization of the granuloma complex and revealing the interactions between immune cells and nonimmune cells. This updated understanding of tuberculous granuloma heterogeneity offers vital insights for researchers aiming to uncover the immunoregulatory mechanisms underlying granuloma formation during TB pathogenesis. More detailed granuloma classification systems will also be of use for precision medicine, and for identifying biological targets for host-directed therapeutics in TB patients. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics Infectious Diseases > Biomedical Engineering Infectious Diseases > Molecular and Cellular Physiology.

[Characterization of a 3-dimensional tuberculosis spheroid model constructed using human monocytic THP-1 cells and Bacillus Calmette-Guerin].

OBJECTIVE: To establish a 3-dimensional tuberculosis spheroid model for studying the formation and characteristics of tuberculous granuloma in vivo. METHODS: Human myeloid leukemia mononuclear THP-1 cells and Bacillus Calmette-Guerin (BCG) were mixed in a 3D cell culture plate and co-cultured in the presence of PMA for 3 days. The growth of the spheroid was examined every 24 h, and the distribution of bacteria, cell survival rate, transformation of the monocytes into macrophages, and penetration of fluorescently labeled nanoparticles into the cell spheroids and tuberculosis spheroids were observed using confocal laser scanning microscopy. The BCG and cell architecture within the 3D tuberculosis spheroid was observed using transmission electron microscopy. Image-iTTM red hypoxia probe, H2O2 test kit, and a waterproof pen PH meter were used to detect the differences in the microenvironment between BCG-infected and non-infected 3D tuberculous spheroids. The utility of this 3D tuberculous spheroids for assessing antibiotic effects of rifampicin and levofloxacin was evaluated by plate colony counting. RESULTS: In the cell-bacterial suspensions, stable 3-D tuberculous spheroids (50-200 µm) occurred slowly, in which the cells adhered tightly with numerous bacteria in the center, and necrotic cells and monocytederived macrophages were seen within the spheroids. Drug penetration was difficult in the 3D tuberculous spheroids as compared with the non-infected cell spheroids. Transmission electron microscopy revealed the presence of cell necrosis and a large number of BCG in the macrophages in the tuberculous spheroids. The tuberculosis spheroid had a more hypoxic microenvironment than the non-infected cell spheroids with higher H2O2 content and nearly a neutral PH. The tuberculous spheroid model was capable of evaluating the efficacy of anti-tuberculosis drugs, and among them rifampicin showed a stronger antibacterial effect. CONCLUSION: The 3-D tuberculous spheroid model established in this study provides a useful platform for studies of tuberculous granuloma.

Extracellular matrix proteins (fibronectin, collagen III, and collagen I) immunoexpression in goat tuberculous granulomas (Mycobacterium caprae).

The lesion resulting from the interaction between Mycobacterium and the host immune response is the tuberculous granuloma. Tuberculous granulomas, except in incipient stages, are partially or totally encapsulated by connective tissue. The aim of this study was to assess the immunoexpression of the extracellular matrix proteins fibronectin, collagen III, and collagen I in granulomas caused by Mycobacterium caprae in goats (Capra aegagrus hircus) to understand capsule development at different granuloma stages. For this purpose, a retrospective study of 56 samples of tuberculous granulomas in lung (n = 30) and mediastinal lymph node (n = 26) from 17 goats naturally infected with M. caprae in stages I (n = 15), II (n = 14) and III (n = 27) was carried out. Fibronectin immunoreaction was extracellular, fibrillar-reticular in the center of stage I, II and III granulomas and peripheral in stages II and III granulomas. Collagen III immunoexpression was extracellular and fibrillar in the center of stages I, II and III tuberculous granulomas in lung and mediastinal lymph node, and progressive expression was observed in the periphery of stages II and III granulomas. Finally, collagen I immunoexpression was extracellular and fibrillar, showing a progressive loss of central expression and an increase in peripheral expression in stage III granulomas compared to stage I granulomas. Immunoexpression of these extracellular matrix proteins could help understand fibrogenesis and dating in tuberculous granuloma in both animal models and humans.

[Granulomatous dermatoses]. / Granulomatöse Dermatosen.

The group of granulomatous dermatoses refers to a multitude of clinically different diseases, which are characterized by a histopathologically similar pattern of inflammation. The cause of granulomatous inflammatory reactions can be infections and also noninfectious stimuli, such as cell disintegration or foreign bodies. The aim of this immunological defence reaction is encapsulation in order to prevent further spread and delimitation from healthy tissue. This is histologically expressed as a granuloma in the sense of a circumscribed aggregation of histiocytes and multinucleated giant cells mostly in dermal connective tissue. The following can be histologically differentiated: sarcoid granuloma characterized by a sparse lymphocytic inflammatory infiltrate and tuberculous granuloma with central necrosis and denser lymphocytic inflammatory infiltrate. Neutrophilic granulocytes together with macrophages occur in suppurative granulomas and palisaded granulomas are characterized by peripherally arrayed macrophages.

Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics.

Mycobacterium tuberculosis infection, which claims hundreds of thousands of lives each year, is typically characterized by the formation of tuberculous granulomas - the histopathological hallmark of tuberculosis (TB). Our knowledge of granulomas, which comprise a biologically diverse body of pro- and anti-inflammatory cells from the host immune responses, is based mainly upon examination of lungs, in both human and animal studies, but little on their counterparts from other organs of the TB patient such as the brain. The biological heterogeneity of TB granulomas has led to their diverse, relatively uncoordinated, categorization, which is summarized here. However, there is a pressing need to elucidate more fully the phenotype of the granulomas from infected patients. Newly emerging studies at the protein (proteomics) and metabolite (metabolomics) levels have the potential to achieve this. In this review we summarize the diverse nature of TB granulomas based upon the literature, and amplify these accounts by reporting on the relatively few, emerging proteomics and metabolomics studies on TB granulomas. Metabolites (for example, trimethylamine-oxide) and proteins (such as the peptide PKAp) associated with TB granulomas, and knowledge of their localizations, help us to understand the resultant phenotype. Nevertheless, more multidisciplinary 'omics studies, especially in human subjects, are required to contribute toward ushering in a new era of understanding of TB granulomas - both at the site of infection, and on a systemic level.

Tuberculous granuloma of maxillary antrum and ethmoid sinus mimicking malignancy and trigeminal neuralgia: A case report and review of the literature.

Tuberculosis is a multi-system disease, but paranasal sinuses involvement is uncommon, and most cases occur secondary to pulmonary tuberculosis. Tuberculous granuloma of the paranasal sinuses is rare and only a few cases are reported. Due to non-specific ways of clinical presentations, diagnosis of paranasal tuberculosis can be missed, delayed or confused with other entities like malignancy. We present an uncommon case of tuberculous granuloma of the left maxillary antrum and ethmoid sinus in a 56-year-old man which mimicked trigeminal neuralgia and malignancy. Medial maxillectomy and anterior ethmoidectomy with clearance of the lesion followed by antituberculous treatment prevented permanent loss of his vision. Depending on the chief complaints, patients may present to various specialties. Early cross-referral is important for early diagnosis, appropriate management and prevention of complications.

An immunomodulatory role for the Mycobacterium tuberculosis Acr protein in the formation of the tuberculous granuloma.

The tuberculous granuloma is a compact aggregate of dormant bacteria encapsulated by host macrophages. It is commonly regarded as a product of the host defense designed to isolate infectious mycobacteria. This work demonstrates that exposure of macrophages to the Mtb heat-shock protein Acr leads to overproduction of the chemokine CXCL16, allowing the mycobacterium to exploit the innate immune response. This induction of chemokine expression is hypothesized to occur through activation of ADAM proteases, providing an immunomodulatory role for Mtb Acr in the formation of the granuloma.

Posterior mediastinal nodule diagnosed as a tuberculous granuloma infiltrating into the aorta.

Although tuberculous infection rarely results in aortic aneurysm formation or rupture, its precursor lesion has never been identified in cases with tuberculosis. We incidentally encountered a case of a posterior mediastinal nodule with concomitant chest computed tomography (CT) findings of multiple pulmonary micronodular shadows. Since an enlargement of the mediastinal nodule was retrospectively apparent, we considered the lesion as malignant. Enhanced CT showed luminal irregularity in the descending aorta, located adjacent to the nodule, in addition to the disappearance of the fat plane between the lesion and the aorta. We successfully resected the nodule with the aorta under partial cardiopulmonary bypass. Based on the pathological and postoperative bacterial findings, the nodule was diagnosed as a tuberculous granuloma infiltrating into the medial layer of the aorta.

Clinical and pathological differences between polymorphonuclear-rich and lymphocyte-rich tuberculous pleural effusion.

OBJECTIVE: Analysis of the occurrence factors and disease characteristics of tuberculous (TB) pleural effusion (TPE) dominated by neutrophils. METHODS: We retrospectively analyzed the clinical data of 304 patients with two types of TB pleurisy. The clinical, laboratory, and pathological features of TB pleurisy separately dominated by lymphocytes and neutrophils were analyzed. RESULTS: Neutrophil-predominant effusion was observed in 33 (10.9%) patients. The patients with TPE with polymorphonuclear leukocytes (PMNLs) had higher fever rates and higher decortication rates than those with lymphocyte-predominant TPE. Otherwise, they had lower chest distress rates and lower positive rates of pulmonary TB and lower biopsy tissue culture-positive rates than patients with lymphocyte-predominant TPE. PMNL TPE patients had higher lactic acid dehydrogenase (LDH) (1297 vs. 410 U/l, P < 0.001) and adenosine deaminase (ADA) levels (54.1 vs. 42.9 U/l, P = 0.043) and lower pleural fluid glucose (1.92 vs. 4.70 mmol/L, P < 0.001) and protein (47.4 vs. 48.4 g/L, P = 0.024) levels than that of lymphocyte-predominant TPE. Otherwise, they had lower blood ALB levels and higher C-reactive protein levels than lymphocyte-predominant TPE. Finally, PMNL TPE patients had lower rates of granuloma formation (27.2% vs. 75.2%, P < 0.001) and pleural nodules than patients with lymphocyte-predominant TPE and more frequent findings of pus, caseous exudate, and necrosis. CONCLUSION: The TB pleurisy patients dominated by neutrophils show strong inflammatory reactions and higher ADA levels in pleural effusion. These findings can significantly improve the positive rate of Mycobacterium tuberculosis in neutrophil-predominant TPE under thoracoscopy.

An unusual case of a tuberculous granuloma of the liver presenting thirteen years after intravesical BCG - therapy for bladder cancer.

The authors present the case of a female patient with a tumor of segment VII of the liver, which was postoperatively identified as a tuberculous granuloma. The patient was admitted for elective surgery for a liver tumor, which had been diagnosed a few months before. Computed tomography and nuclear magnetic resonance were performed, based on which focal nodular hyperplasia was suspected. Thirteen years prior to admission the patient had undergone a transurethral resection of superficial bladder carcinoma, followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG-therapy). Upon surgery, segment VII of the liver was resected; postoperative course was uneventful. After the identification of granuloma, the patient was referred to a phthysiatric clinic for further diagnostics and treatment. The authors have deemed this case worthy of reporting primarily due to the exceptionally long period between the completion of BCG therapy and the onset of hepatic tumor.

Medical thoracoscopy for tuberculous pleurisy: A retrospective analysis of 575 cases.

OBJECTIVE: The objective of this retrospective study was to assess the efficacy of medical thoracoscopy in diagnosing of tuberculous pleurisy and characterize tuberculous pleurisy with medical thoracoscopy. METHODS: A total of 575 patients with tuberculous pleurisy who underwent medical thoracoscopy were included in the study. Demographic data, clinical manifestations, and routine and biochemical tests on pleural fluid, cultures of pleural fluid, sputum, and pleural biopsy for the detection of Mycobacterium tuberculosis and pathological findings were evaluated. RESULTS: Sputum, pleural fluid, and pleural biopsy cultures were positive for M. tuberculosis in 12.5%, 19.2%, and 41.9% of patients, respectively. Furthermore, there were significant differences in total positive tuberculosis (TB) tests in the pleural cavity according to patient's age (<18 years old, 50.0%; 18-34 years old, 50.2%; 35-59 years old, 34.8%; >60 years old, 18.6%; and all groups vs. >60 years old, P < 0.001). Patients with 18-34 years old were more likely to have granuloma in pleural biopsy specimens when compared to patients >60 years old (77.0% vs. 37.9%). The percentage of patients with high adenosine deaminase (ADA) levels in pleural fluid (>40 U/L), who were <18, 18-34, 35-59, and > 60 years old, was 83.3% (15/18), 72.8% (193/265), 51.2% (88/172), and 34.7% (17/49), respectively (all groups vs. >60 years old, P < 0.001). CONCLUSION: Medical thoracoscopy is effective for diagnosing tuberculous pleurisy. Younger patients with tuberculous pleurisy have a higher number of positive TB tests in the pleural cavity, are more likely to have granuloma in pleural biopsy specimens, and have higher ADA levels in the pleural fluid.

Advances in the role of macrophage polarization in tuberculosis / 中华临床感染病杂志

Tuberculosis is a kind of chronic infectious disease caused by Mycobacterium tuberculosis (MTB).Macrophages, as the main host cells against MTB ,play a crucial role in the natural and acquired immune response of the body.Under the stimulation of different inducing factors , macrophages can be polarized to M1-type macrophages and M2-type macrophages,which play different functions in the progression of tuberculosis.Further studies on the polarization signaling pathway of macrophages and dynamic balance between M1 and M2-type macrophages cells have provide a new way to explore the pathogenesis of tuberculosis.In addition, due to the importance of macrophage polarization in the development of MTB infection, the formation of tuberculous granuloma and prognosis of tuberculosis , the in-depth study on macrophages polarization will contribute to the development of new tuberculosis vaccines and immune agents , and lay an important theoretical foundation for the prevention and treatment of tuberculosis .

Tuberculous Granuloma in the Scrotal Skin After Intravesical Bacillus Calmette-Guerin Therapy for Bladder Cancer: A Case Report.

Rare cases of tuberculous urinary tract or genital infection caused by intravesical Intravesical Bacillus Calmette-Guerin (BCG) instillation therapy have been reported. We encountered a patient with tuberculous granuloma in the scrotal skin after intravesical BCG therapy for bladder cancer. There was evidence of infection in the scrotal skin, but not in the epididymis. To the best of our knowledge, this is the first report of tuberculous granuloma in the scrotal skin without epididymitis after intravesical BCG therapy. In our case, lower urinary tract symptoms such as the terminal dribbling of urine appear to support the theory of direct BCG inoculation.

Development of an in vitro model of the early-stage bovine tuberculous granuloma using Mycobacterium bovis-BCG.

Mycobacterium bovis causes 3.1% of human tuberculosis cases, as described by the World Health Organisation. In cattle, this organism causes bovine tuberculosis (BTB) which can have a prevalence of up to 39.5% in some developing countries. In developed countries, although the prevalence of BTB has been reduced through eradication programmes, complete eradication has in some cases proved elusive, with prevalences in cattle of 0.5% in the Republic of Ireland and of 4.3% in the UK. As the tuberculous granuloma is the fundamental lesion that reflects the pathogenesis, immune control and progression of BTB, we aimed to develop an in vitro model of the early-stage bovine tuberculous granuloma, in order to model the early stages of BTB, while also reducing the use of experimentally infected animals. In vitro models of human and ovine mycobacterial granulomas have previously been developed; however, so far, there is no model for the BTB granuloma. As the disease in cattle differs in a number of ways from that in other species, we consider this to be a significant gap in the tools available to study the pathogenesis of BTB. By combining bovine monocyte-derived macrophages infected with M. bovis-BCG and autologous lymphocytes we have developed an early-stage tuberculous bovine granuloma model. In the model, 3D cell aggregations formed a spherical-shape that grew for up to 11 days post-infection. This bovine tuberculous granuloma model can aid in the study of such lesion development, and in comparative studies of pathogenesis, such as, for example, the question of mycobacterial latency in bovine tuberculosis.

Thoracic Spondylodiscitis Caused by Methicillin-resistant Staphylococcus aureus as a Superinfection of Pulmonary Tuberculous Granuloma in an Immunocompetent Patient: A Case Report.

Study Design Case report. Objective To describe a very rare case of an immunocompetent man who underwent surgery for thoracic spondylodiscitis caused by methicillin-resistant Staphylococcus aureus (MRSA) that developed as a superinfection of a pulmonary tuberculous granuloma. Methods Posterior decompression and pedicle screw vertebral fixation were followed by T5-T6 anterior somatotomy with implant of an expandable mesh and lateral plating as symptoms worsened. During the anterior approach, an atypical resection of the left lower lobe was also performed. Results A tuberculous granuloma was detected on histology. Ziehl-Neelsen stain confirmed the diagnosis. Culture also detected MRSA. Conclusions Early medical management is the first choice for spondylodiscitis to eradicate the infection and alleviate pain. Immobilization of the affected spine segments can protect the patient from vertebral collapse and from the appearance of neurologic deficits. Surgery is suggested if there are compressive effects on the spinal cord, spinal epidural abscess, vertebral collapse, and deformity. We decided to remove the abscess and to restore the anterior column using an anterior approach. Moreover, in this case, an anterior approach allowed us to identify the etiology of the lesion and to determine the best chemotherapy regimen.

Pelvic tuberculous granuloma successfully treated with laparoscopy to preserve fertility: a case report and review of the published work.

Tuberculous granuloma must be considered in the differential diagnosis of pelvic masses in women of reproductive age because the major sequela of pelvic tuberculosis is infertility; however, currently there is very little information about its fertility-preserving treatment. We report the case of a woman with a history of tuberculous peritonitis who referred to our hospital for evaluation of an adnexal mass and primary infertility. The patient underwent excision of pelvic tuberculous granuloma with fertility-preserving laparoscopic surgery. We resected as much of the tuberculous granuloma as possible using the laparoscopic technique without causing damage to the uterus or ovaries. In particular, we report for the first time in the published work the laparoscopic removal of tuberculous granuloma without causing damage to the uterus or ovaries. Our experience from this case suggests that laparoscopic diagnosis and treatment of tuberculous granuloma is a feasible procedure in a patient who wants to conceive.

Case report: "spina ventosa" tuberculous dactylitis in a 2 year old boy - a very rare disease.

Tuberculous infection of metacarpals, metatarsals and phalanges is known as tuberculous dactylitis. There is a spindle shaped expansion of the short tubular bones due to tuberculous granuloma. Hence it is also known as spina ventosa. In our case, a two year old boy with a swelling in the metacarpal was provisionally diagnosed as enchondromata while the possibility of spina ventosa was kept in mind. He was posted for excision of the metacarpal followed by bone grafting. Histopathological examination report confirmed it as spina ventosa.

Intracranial Rosai Dorfman Disease: report of three cases and literature review.

BACKGROUND: Rosai-Dorfman Disease (RDD) is a rare idiopathic non-neoplastic histioproliferative disease characterized clinically by massive painless cervical lymphadenopathy, fever and weight loss. Extranodal involvement has also been recognized. Central nervous system (CNS) manifestations are extremely rare and patients with intracranial involvement usually present with clinical and radiological findings suggestive of a meningioma. CASE DESCRIPTION: We report our experience in the management of three patients with RDD. Two patients had dural based lesions, radiologically in favour of a meningioma, and one patient had a parenchymal lesion suggestive of a tuberculous granuloma. Treatment consisted of total excision in one case, and subtotal excision followed by conventional radiotherapy in two cases. The diagnosis was confirmed by histopathology and immunochemistry which is essential for a definite diagnosis of RDD.

A Case of Oculomotor Nerve Palsy and Choroidal Tuberculous Granuloma Associated with Tuberculous Meningoencephalitis

We report a rare case of oculomotor nerve palsy and choroidal tuberculous granuloma associated with tuberculous meningoencephalitis. A 15-year-old male visited our hospital for an acute drop of the left eyelid and diplopia. He has been on anti-tuberculous drugs (isoniazid, rifampin) for 1 year for his tuberculous encephalitis. A neurological examination revealed a conscious clear patient with isolated left oculomotor nerve palsy, which manifested as ptosis, and a fundus examination revealed choroidal tuberculoma. Other anti-tuberculous drugs (pyrazinamide, ethambutol) and a steroid (dexamethasone) were added. After 3 months on this medication, ptosis of the left upper eyelid improved and the choroidal tuberculoma decreasedin size, but a right homonymous visual field defect remained. When a patient with tuberculous meningitis presents with abrupt onset oculomotor nerve palsy, rapid re-diagnosis should be undertaken and proper treatment initiated, because the prognosis is critically dependent on the timing of adequate treatment.