The C terminus of the mycobacterium ESX-1 secretion system substrate ESAT-6 is required for phagosomal membrane damage and virulence.

SignificanceTuberculosis (TB), an ancient disease of humanity, continues to be a major cause of worldwide death. The causative agent of TB, Mycobacterium tuberculosis, and its close pathogenic relative Mycobacterium marinum, initially infect, evade, and exploit macrophages, a major host defense against invading pathogens. Within macrophages, mycobacteria reside within host membrane-bound compartments called phagosomes. Mycobacterium-induced damage of the phagosomal membranes is integral to pathogenesis, and this activity has been attributed to the specialized mycobacterial secretion system ESX-1, and particularly to ESAT-6, its major secreted protein. Here, we show that the integrity of the unstructured ESAT-6 C terminus is required for macrophage phagosomal damage, granuloma formation, and virulence.

Resolution of Large Choroidal Tuberculoma following Monotherapy with Intravitreal Ranibizumab.

Background: Ocular tuberculosis can have protean manifestations. Anti-tubercular therapy (ATT) and oral steroids are employed in the management of this condition. There is evidence in the literature which has highlighted the use of intravitreal anti-vascular endothelial growth factor drugs as an adjunct to systemic therapy.Report of the Case: A 44-year-old male presented with a decrease of vision in the right eye was diagnosed choroidal tuberculoma with massive exudation and subretinal fluid. The patient was treated with intravitreal ranibizumab injection. The lesion regressed completely within 6 weeks without any additional systemic corticosteroids and ATT without any recurrence over 6 months during follow-up.Conclusions: Ranibizumab monotherapy may lead in complete regression of vascularized tubercular choroidal granulomas without the need of adjunctive ATT and corticosteroids. After intravitreal injection of ranibizumab, the lesion may be observed for regression over several weeks.

Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma.

Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 µm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.

Lesiones cutáneas de muy larga evolución / Very long evolution skin injuries

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Paradigm changing evidence that alter tuberculosis perception and detection: Focus on latency.

Tuberculosis remains a devastating disease to Mankind, ranking as the ninth cause of death worldwide. Eliminating tuberculosis as proven much more difficult than once anticipated. In addition to the delay in diagnosis and drug resistance problems that compromise the efficacy of treatment, the enormous reservoir of latently infected individuals continuously feeds the epidemics. However, targeting latency with prophylactic antibiotic administration is not possible at the populational level. Together, these issues call for a better understanding of latency, as well as for a more precise identification of individuals at high risk of reactivation. For this, recent paradigm changing evidence need to be taken into account, most notably, the existence of a tuberculosis spectrum; the genetic diversity of both humans and tuberculosis-causing bacteria; and the changes in the human population that interfere with tuberculosis. Here we discuss latency in the light of these variables and how that understanding can move forward tuberculosis research and elimination.

Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling.

Mycobacterial infection leads to the formation of characteristic immune aggregates called granulomas, a process accompanied by dramatic remodeling of the host vasculature. As granuloma angiogenesis favors the infecting mycobacteria, it may be actively promoted by bacterial determinants during infection. Using Mycobacterium marinum-infected zebrafish as a model, we identify the enzyme proximal cyclopropane synthase of alpha-mycolates (PcaA) as an important bacterial determinant of granuloma-associated angiogenesis. cis-Cyclopropanation of mycobacterial mycolic acids by pcaA drives the activation of host Vegf signaling within granuloma macrophages. Cyclopropanation of the mycobacterial cell wall glycolipid trehalose dimycolate is both required and sufficient to induce robust host angiogenesis. Inducible genetic inhibition of angiogenesis and Vegf signaling during granuloma formation results in bacterial growth deficits. Together, these data reveal a mechanism by which PcaA-mediated cis-cyclopropanation of mycolic acids promotes bacterial growth and dissemination in vivo by eliciting granuloma vascularization and suggest potential approaches for host-directed therapies.

Tuberculoma Cavitation: A Rare Aspect of a Common Disease Clinical Image / Tuberculoma cavitado: un patrón inusual en la imagen clínica de una enfermedad común

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A case of hepatic tuberculosis: A tuberculoma.

Tuberculosis (TB) is a common cause of morbidity and mortality worldwide and its eradication in the United States has stalled for the first time in decades. Isolated hepatic TB is an extremely uncommon form of extrapulmonary TB. Here we present a case of a tuberculous liver abscess and suggest that TB should be considered in patients who fail to respond to antibiotics and prompt diagnostic intervention.

Use of TBAg/PHA ratio in distinguishing tuberculoma from cancer in solitary pulmonary nodule or mass.

INTRODUCTION: Differentiation of tuberculoma from cancer in solitary pulmonary nodule or mass still remains a major challenge in diagnostic laboratories. OBJECTIVES: The objective of this study is to determine the performance of T-SPOT.TB assay in discriminating these 2 diseases. METHODS: We prospectively enrolled 331 patients with a solitary pulmonary nodule or mass on computed tomography scans. Conventional tests and T-SPOT.TB assay were simultaneously performed in all participants. RESULTS: Our results showed that the performance of directly using T-SPOT.TB results in distinguishing tuberculoma from cancer in solitary pulmonary nodule or mass was not satisfactory because of moderate sensitivity and specificity. However, a further calculation of the ratio of TB-specific antigen (TBAg) to phytohemagglutinin (PHA) (TBAg/PHA ratio) of T-SPOT.TB assay may lead to improvement in distinguishing these 2 diseases. If using the threshold value of 0.236, the sensitivity and specificity of the TBAg/PHA ratio in distinguishing tuberculoma from cancer in solitary pulmonary nodule or mass were, respectively, 80.6% and 93.3%. The area under the curve (AUC) of the receiver operating characteristic curve was 0.921 (95% confidence interval, 0.875-0.967). Furthermore, the TBAg/PHA ratio may also be used to distinguish tuberculoma from other benign diseases (AUC: 0.909, sensitivity: 85.07%, specificity: 90%). CONCLUSIONS: Calculation of the TBAg/PHA ratio might provide a useful non-invasive tool for distinguishing tuberculoma from cancer in patients with a solitary pulmonary nodule or mass in TB-endemic countries.

Spinal intramedullary tuberculoma following pulmonary tuberculosis: A case report and literature review.

RATIONALE: Spinal intramedullary tuberculoma (IMTB) is a rare disease that accounts for 1 to 2/100,000 patients with tuberculosis. We presented a case with pulmonary tuberculosis and concurrent IMTB at C3 to C5 level and reviewed the recent case series and discussed the diagnosis, treatment, and outcome. PATIENT CONCERNS: A 33-year-old male had concurrent pulmonary TB and IMTB at the C3 to C5 level. He had quadriplegia (muscle power 0 at 4 limbs) and sensory loss below C5 level. He also had incontinence, anal tone loss, and paradoxical respiratory pattern. DIAGNOSIS: Spinal magnetic resonance imaging (MRI) showed a 25 11mm intramedullary lesion at C3/C4 level. Under the impression of IMTB, he underwent surgery. INTERVENTION: We performed C3 to C5 laminectomy and en bloc removal of the tumor. The patient kept receiving anti-TB medications after the surgery. OUTCOME: His 4 limbs muscle power had improved but could not be liberated from the endotracheal tube, so tracheostomy was performed. Muscle power gradually increased to 3 points in his upper limbs and to 2 points in his lower limbs. Sensation in his 4 limbs gradually improved as well. LESSONS: IMTB is a rare disease that should be treated with a combination of medication and surgery. For patients with prominent spinal cord compression and neurological symptoms, early operation to remove the tumor is necessary.

Clinical and cytological features in diagnosis of peripheral tubercular lymphadenitis - A hospital-based study from central India.

BACKGROUND: Tuberculosis lymphadenitis is difficult to diagnose clinically, and often the laboratory confirmation is not available in resource-poor countries. We describe here the symptoms, clinical characteristics, and results of cytological analysis in peripheral tuberculous lymphadenitis patients. METHODS: One hundred and fifty-six patients with peripheral lymph node for cytological evaluation presenting to Department of Pathology, Acharya Vinoba Bhave Rural Hospital, Wardha, India were included in this study. RESULTS: Sixty-nine cases were tuberculous lymphadenitis, with female to male ratio of 1.3:1. One or more constitutional symptoms were present in 59.4% of patients, with 89.9% of lymph nodes ≥2×2cm and the most common site of involvement was cervical lymph node (70.3%). The lymph nodes were multiple (85.5%), either discrete or matted. Cytomorphologically, hemorrhagic aspirate was observed in 29 cases, well-formed epithelioid cell granuloma with caseous necrosis was seen in 34 cases, and Zeihl Neelsen staining was positive in 45 cases. Correlation between character of aspirate and cytomorphological pattern was found highly significant. CONCLUSION: These data suggest that constitutional symptoms and clinical and cytological features help in diagnosing cases of peripheral tubercular lymphadenitis and also open new frontiers to further research that affects the cytological features of these cases.

Diagnosis and treatment of paediatric tuberculosis: An insight review.

Tuberculosis (TB) is a major public health problem, invading all age groups world-wide. It is an opportunistic infection affecting the individuals alone or with co-infections. Childhood TB is a neglected aspect and a significant health problem in epidemic areas. It constitutes more than 20% of TB incidence. Pediatric TB exists in the shadow of adult TB. The clinicians concentrate on pulmonary manifestation of TB, whereas it is a major problem in both pulmonary and extra-pulmonary infections. The rate of infection with this disease is mostly associated with poverty, social disruption and human immunodeficiency virus (HIV) infection. The diagnosis of extra-pulmonary TB (EPTB) is more difficult than pulmonary TB (PTB). Delayed diagnosis and executive treatment contribute to increase in the mortality rate in endemic areas. This article provides the evidence-based simple and safe screening method, indicating rapid, highly sensitive and specific diagnostic tests for pulmonary and EPTB in children. The most important aspect of treatment is the correct course of anti-tubercular drugs. This review serves the purpose of quick reference for microbiologists, epidemiologists, academicians, students and researchers. It provides guidance regarding early diagnosis and treatment accuracy of pediatric TB.

Bioengineered 3D Models for Studying Human Cell-Tuberculosis Interactions.

In vivo animal models have intrinsic limitations for studying relationships between tuberculosis and its host and there is a need for alternative, in vitro cellular models. A microsphere-based 3D in vitro culture system of Mycobacterium tuberculosis-infected human blood mononuclear cells was reported to address specific aspects of host-pathogen interactions.

Intracardiac tuberculomas caused by Mycobacterium tuberculosis in a dog.

BACKGROUND: This paper presents an unusual form of disseminated Mycobacterium tuberculosis infection in a dog. The infection lasted at least one year and its main gross lesions were massive cardiac tuberculomas. To the best of our knowledge, this is the first report of heart tuberculomas in a dog. CASE PRESENTATION: A 9-year-old mixed-breed male dog weighing 10 kg was referred to the clinic for cardiological evaluation before general anesthesia. The echocardiography revealed a lump of about 20 mm in diameter in the area of the left atrium. Almost one year later the same dog was presented again in severe clinical state (fever, anorexia, weight loss, depression, cough, dyspnea, lymphadenomegaly, vomiting, recent episodes of fainting). Due to progression of the disease and poor effects of treatment the owner decided to euthanize the dog. Most prominent lesions observed during autopsy were diffuse pneumonia, fibrinous pericarditis and epicarditis as well as large, yellow, semisolid masses of caseous necrosis in the left and right atrium (30 mm and 15 mm in diameter, respectively). From both pulmonary and cardiac lesions M. tuberculosis was isolated on Lowenstein-Jensen slants and in Bactec Mycobacteria Growth Indicator Tube 960 liquid media, and confirmed by BD ProbeTec ET Direct Detection Assay and spoligotyping. CONCLUSION: Companion animals may occasionally suffer from tuberculosis but majority of cases probably remain misdiagnosed or undetected. Typically tuberculosis in dogs affects lungs and their regional lymph nodes. Even in humans tuberculomas are rare manifestation of mycobacterial infection, mostly seen in the central nervous system. Atypical location of main tuberculous lesions may account for lack of correct ante mortem diagnosis in this case.

[Interlaboratory test: Isolation of Mycobacterium bovis from granulomatous lesions in bovine]. / Ensayo interlaboratorio: aislamiento de Mycobacterium bovis a partir de lesiones granulomatosas en bovinos.

Mycobacterium bovis is the causative agent of bovine tuberculosis. The diagnostic laboratory confirmation is made through bacterial isolation. The aim of interlaboratory tests is to assess the performance of each participant in comparison with other of similar capacities. The test objective was to determine the efficiency of isolation of M. bovis. Four laboratories were part of the test and processed 25 blind tissue samples from granulomatous lesions and with previous M. bovis isolation. The laboratory that had the highest proportion of isolates was A (68%), followed by C (60%) and then B and D (both with 52%). The greatest concordance was observed between B-D and B-C laboratories (68%). The differences could be due to specific factors in each laboratory procedures. This type of interlaboratory tests highlights errors in the bacteriology and identifies critical points in the process to detect M. bovis accurately.