Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection.

Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF(Δ) ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth.

Inflammation and the coagulation system in tuberculosis: Tissue Factor leads the dance.

Mycobacterium tuberculosis, the causative agent of tuberculosis, drives the formation of granulomas, structures in which both immune cells and the bacterial pathogen cohabit. The most abundant cells in granulomas are macrophages, which contribute as both cells with bactericidal activity and as targets for M. tuberculosis infection and proliferation during the entire course of infection. The mechanisms and factors involved in the regulation and control of macrophage microenvironment-specific polarization and plasticity are not well understood, as some granulomas are able to control bacteria growth and others fail to do so, permitting bacterial spread. In this issue of the European Journal of Immunology, Venkatasubramanian et al. [Eur. J. Immunol. 2016. 46: 464-479] show that mice lacking the tissue factor gene in myeloid cells have augmented M. tuberculosis growth and increased inflammation in the lungs. This suggests that tissue factor, an initiator of coagulation, is important for the generation of fibrin, which supports granuloma formation. This article demonstrates for the first time the involvement of tissue factor in inducing effective immunity against M. tuberculosis, and sheds new lights on the complex interplay between host inflammatory response, the coagulation system, and the control of M. tuberculosis infection.

Primary musculoskeletal mycobacterium infection with large cystic masses after total hip arthroplasty.

Primary mycobacterial infections in the musculoskeletal system are rare with a limited number of published case reports. This report describes a case involving a primary musculoskeletal tuberculous abscess. A 62-year-old male patient who had a right total hip arthroplasty performed 8 years earlier, using metal-on-metal articulation presented with a 1-year history of non-tender masses on his right thigh. Initially, it was assumed he had metallosis. Intraoperatively, an incision into the mass was conducted which resulted in draining of a whitish-grey pus like fluid. A diagnosis of tuberculosis was confirmed with both microscopic and histological examination. The patient was treated over a course of six months with an anti-tuberculosis medication regimen following the confirmation of a solitary soft tissue tuberculosis infection. At the 24 month follow-up, the patient was asymptomatic with no relapse of the mass.

Anhelation due to formation of tuberculomas at the medulla oblongata during chemotherapy of tuberculous meningitis.

Formation of tuberculoma is a rare response of neurotuberculosis in patients regularly and adequately treated with anti-tuberculous drugs. We report a 13-year-old girl with two tuberculomas which formed in the dorsal part of the medulla oblongata during chemotherapy for tuberculous meningitis. The tuberculomas were both removed via a suboccipital midline approach and were demonstrated by pathological findings but the girl died of cardiac arrest that was thought to be caused by postoperative medulla oblongata oedema. In combination with a literature review, we discuss the clinical features and treatment options of brainstem tuberculomas.

[Molecular mechanisms of formation of blood eosinophilia under pulmonary tuberculosis].

Molecular factors of pathogenesis of the eosinophilic blood reaction under pulmonary tuberculosis are analyzed in the article. It has been established that the key cytokine providing the development of hemic eosinophilia in patients with pulmonary tuberculosis is IL-5. IL-5 plasma concentration turned out to be increased only in patients with eosinophilia. Increase of eotaxin was determined in patients with tuberculosis despite of the presense of eosinophilia. One-directional nature of the defined changes in eotaxin concentration might be explained by dual properties of this chemokine: on the one hand, eotaxin mediates long-term presence of eosinophils in blood; on the other hand, it initiates the process of adhesion of eosinophilic leucocytes to vascular endothelium with their further migration to the focus of granulomatous inflammation. The established increase in number of IL-5R-positive eosinophils presents one more mechanism which explains the basis of long-term presence of eosinophils in peripheral blood in patients with pulmonary tuberculosis.

Worsening CSF parameters after the start of anti-tuberculosis treatment predicts intracerebral tuberculoma development.

OBJECTIVES: We investigated whether early worsening of cerebrospinal fluid (CSF) predicts the later paradoxical tuberculomas and is a potential predictive biomarker. METHODS: Patients of HIV-negative tuberculous meningitis fulfilling the inclusion criteria(n = 98) underwent clinical and CSF evaluation, together with repeated neuroimaging. We compared the baseline clinical data and continuous CSF of patients who did (n = 36) and did not (n = 62) develop paradoxical tuberculomas, and reported the changes associated with symptomatic tuberculomas. A logistic regression analysis was developed to reveal predictors for paradoxical tuberculomas. RESULTS: The proportion of worsening CSF parameters (WBC count and percent neutrophils) in the paradoxical tuberculomas group (27/36, 75.0%) was significantly higher than the non-paradoxical tuberculomas group (15/62, 24.2%). The logistic regression analysis revealed that worsening CSF parameters was the highest risk predictor for paradoxical tuberculomas. Most worsening CSF parameters (81.0%) occurred within two weeks after treatment (2-24 days, median 7 days), and paradoxical tuberculomas commonly happened two weeks later (12 days to 13 months, median 22 days). The period between worsening CSF parameters and paradoxical tuberculomas ranged from 6 to 383 days (median 21days). There were no significant differences in mortality and prognosis between the two groups. CONCLUSIONS: Early worsening of CSF parameters predicts subsequent development or progression of tuberculomas.

A Novel In Vitro Mouse Model to Study Mycobacterium tuberculosis Dissemination Across Brain Vessels: A Combination Granuloma and Blood-Brain Barrier Mouse Model.

In vitro culture models of the blood-brain barrier (BBB) provide a useful platform to test the mechanisms of cellular infiltration and pathogen dissemination into the central nervous system (CNS). We present an in vitro mouse model of the BBB to test Mycobacterium tuberculosis (Mtb) dissemination across brain endothelial cells. One-third of the global population is infected with Mtb, and in 1%-2% of cases bacteria invade the CNS through a largely unknown process. The "Trojan horse" theory supports the role of a cellular carrier that engulfs bacteria and carries them to the brain without being recognized. We present for the first time a protocol for an in vitro BBB-granuloma model that supports the Trojan horse mechanism of Mtb dissemination into the CNS. Handling of bacterial cultures, in vivo and in vitro infections, isolation of primary astroglial and endothelial cells, and assembly of the in vitro BBB model is presented. These techniques can be used to analyze the interaction of adaptive and innate immune system cells with brain endothelial cells, cellular transmigration, BBB morphological and functional changes, and methods of bacterial dissemination. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Isolation of primary mouse brain astrocytes and endothelial cells Basic Protocol 2: Isolation of primary mouse bone marrow-derived dendritic cells Support Protocol 1: Validation of dendritic cell purity by flow cytometry Basic Protocol 3: Isolation of primary mouse peripheral blood mononuclear cells Support Protocol 2: Isolation of primary mouse spleen cells Support Protocol 3: Purification and validation of CD4+ T cells from PBMCs and spleen cells Basic Protocol 4: Isolation of liver granuloma supernatant and determination of organ load Support Protocol 4: In vivo and in vitro infection with mycobacteria Basic Protocol 5: Assembly of the BBB co-culture model Basic Protocol 6: Assembly of the combined in vitro granuloma and BBB model.

Papillitis and neuroretinitis of tuberculous etiology. / Papilitis y neurorretinitis de etiología tuberculosa.

A 57-year-old man with miliary tuberculosis reported visual loss in his right eye, a month after starting a four-drug antituberculous treatment regimen. On exploration, an inferior segmental optic disc edema was objectived and it was attributed to ischemic aetiology. Ethambutol was withdrawn and 60mg of oral prednisone daily were given with a tapering dosage. One and a half months later, he presented a sudden loss of vision in his left eye. In fundoscopy, a papillary edema accompanied by a foveal neurosensory detachment was observed but with no more accompanying uveitic signs. Treatment was intensified with moxifloxacin and corticosteroids were reduced, showing a resolution of the macular detachment but with optic atrophy. Isolated tuberculous involvement of the optic nerve may possible in the context of miliary tuberculosis. In this case, the adopted therapeutic approach to the initial papillitis, which was interpreted as ischemic, could favour the appearance of a neuroretinitis in the fellow eye.

Central Nervous System Tuberculosis : Etiology, Clinical Manifestations and Neuroradiological Features.

PURPOSE: As a result of multilateral migration and globalization in times of humanitarian crises, western countries face a possible increase in the incidence of central nervous system tuberculosis (CNS TB). The diagnosis of CNS TB is challenging and often delayed due to the manifold and often non-specific presentation of the disease. The aim of this review is to analyze and summarize imaging features and correlated clinical findings of CNS TB. METHODS: The different manifestations of CNS TB are explained and illustrated by characteristic neuroradiological as well as neuropathological findings. An overview on diagnostic and therapeutic approaches is provided. For clarity, tables summarizing the lesion patterns, differential diagnoses and diagnostic hints are added. RESULTS: The CNS TB can be manifested (1) diffuse as tuberculous meningitis (TBM), (2) localized as tuberculoma or (3) tuberculous abscess or (4) in extradural and intradural spinal infections. Information on clinical presentation, underlying pathology and the distinguishing features is demonstrated. The TBM is further described, which may lead to cranial nerve palsy, hydrocephalus and infarction due to associated arteritis of the basal perforators. The differential diagnoses are vast and include other infections, such as bacterial, viral or fungal meningoencephalitis, malignant causes or systemic inflammation with CNS. Complicating factors of diagnosis and treatment are HIV coinfection, multi-drug resistance and TB-associated immune reconstitution inflammatory syndrome (IRIS). CONCLUSIONS: Neurologists and (neuro-)radiologists should be familiar with the neuroradiological presentation and the clinical course of CNS TB to ensure timely diagnosis and treatment.

Subretinal Hypopyon in Presumed Tubercular Uveitis: A Report of Two Cases.

Subretinal hypopyon is an uncommon entity which has been described in ocular infections and inflammations including endophthalmitis, acute retinal necrosis, and sympathetic ophthalmia. The authors report subretinal hypopyon in two cases of presumed tubercular uveitis which responded well to antitubercular therapy (ATT). The first case was a 47-year-old male with bilateral peripapillary chorioretinitis with a subretinal hypopyon. Tuberculosis was confirmed on biopsy of a cervical lymph node which revealed acid-fast bacilli. Case 2 was a 17-year-old male with unilateral involvement in the form of a choroidal granuloma with disc edema and retinitis. In addition, a subretinal hypopyon was evident. Both these cases showed dramatic anatomical improvement with ATT. A novel finding of subretinal hypopyon is described in these cases of presumed ocular tuberculosis. It may be prudent to start empirical ATT early on detection of a subretinal hypopyon along with other manifestations compatible with tubercular etiology.

Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study.

BACKGROUND: Adjunctive dexamethasone increases survival from tuberculous meningitis, but the underlying mechanism is unclear. We aimed to determine the effect of dexamethasone on cerebral MRI changes and their association with intracerebral inflammatory responses and clinical outcome in adults treated for tuberculous meningitis. METHODS: Cerebral MRI was undertaken, when possible, at diagnosis and after 60 days and 270 days of treatment in adults with tuberculous meningitis admitted to two hospitals in Vietnam. Patients were randomly assigned either dexamethasone (n=24) or placebo (n=19) and received 9 months of treatment with standard first-line antituberculosis drugs. We assessed associations between MRI findings, treatment allocation, and resolution of fever, coma, cerebrospinal fluid inflammation, and neurological outcome. FINDINGS: 83 scans were done for 43 patients: 19 given placebo, 24 given dexamethasone. Basal meningeal enhancement (82%) and hydrocephalus (77%) were the most common presenting findings. Fewer patients had hydrocephalus after 60 days of treatment with dexamethasone than after placebo treatment (p=0.217). Tuberculomas developed in 74% of patients during treatment and in equal proportions in the treatment groups; they were associated with long-term fever, but not relapse or poor clinical outcome. The basal ganglia were the most common site of infarction; the proportion with infarction after 60 days was halved in the dexamethasone group (27%vs 58%, p=0.130). INTERPRETATION: Dexamethasone may affect outcome from tuberculous meningitis by reducing hydrocephalus and preventing infarction. The effect may have been under-estimated because the most severe patients could not be scanned.

Intradural extramedullary tuberculoma of the spinal cord: a review of reported cases.

Intradural extramedullary tuberculoma of the spinal cord (IETSC) is a rare modality of tuberculosis, with only a few cases described so far. Here we review 22 reports of the disease found in the literature of the last 25 years. IETSC is closely associated with tuberculous meningitis (TM). Both conditions may occur simultaneously, but more frequently IETSC is preceded by TM. IETSC has been described in a predominantly young population of both genders. The pathogenesis is unknown, although a paradoxical reaction to antituberculous medication is a reasonable possibility. The disease presents insidiously with paraparesis, hypoesthesia with a sensory level, and bladder dysfunction, due to cord involvement or compression by the inflammatory process. Permanent paraparesis is a common sequela. MRI is the diagnostic technique of choice in IETSC. Prompt surgical excision of the tuberculoma is the cornerstone of therapy. Antituberculous treatment is also indicated; unless resistance is present, conventional chemotherapy is probably enough. Corticosteroids are also generally recommended. In conclusion, IETSC is a rare complication of TM, which presents insidiously, despite adequate antituberculous treatment. To avoid the permanent disability that this condition may provoke, an early diagnosis and prompt treatment is critical.

A Case of Probable MHC Class II Deficiency with Disseminated BCGitis.

Major histocompatibility complex (MHC) class II deficiency is a primary immunodeficiency disease characterized by abnormality of MHC class II molecules surface expression on peripheral blood lymphocytes and monocytes. Clinical manifestations include extreme susceptibility to viral, bacterial, and fungal infections but the immunodeficiency is not as severe as SCID (severe combined immunodeficiency), as evidenced by failure to develop disseminated infection after BCG vaccination. Therefore, MHC II deficiency with BCGosis, that is disseminated BCGitis, is not reported commonly. We report an interesting case of BCGosis after vaccination that was diagnosed to have probable MHC II deficiency.

Mycobacterial infections in marrow transplant patients.

Bone marrow transplant recipients undergo ablation of host immune defenses with total-body irradiation or high dose chemotherapy, or both. Over a 5.6-year period, mycobacterial infections were observed in 7 of 682 patients with leukemia who received marrow grafts. Four patients had pulmonary and three extrapulmonary infection. Granulomas were observed in the lungs of three patients, in the liver of one patient, and in the skin of one patient. Cultures revealed Mycobacterium tuberculosis in two patients, Mycobacterium fortuitum in two patients, and Mycobacterium kansasii in one patient. In the six patients treated with antimycobacterial therapy in either the pretransplant or posttransplant period, complete resolution of the infection was achieved. Pretransplant chest radiograph abnormalities suggesting mycobacterial infections should be aggressively evaluated in these immunocompromised hosts. Prophylaxis should be considered in marrow graft recipients with a well-established history of inadequately treated tuberculosis, previous Bacille Calmette-Guerin immunotherapy, known family contacts, recent skin test conversion, or past skin test positivity.

Endobronchial tuberculosis presenting as asthma.

Clinical deterioration with features suggestive of asthma was seen in three patients following two to six months of drug therapy of primary tuberculosis. There was a poor clinical response to administered bronchodilators. Bronchoscopy in all three revealed culture-negative mycobacterial caseating granulomas. Corticosteroid therapy resulted in good clinical response, with resolution of the asthmatic symptoms and improvement in the expiratory flow rates. In our opinion these patients are clinically compatible with a hypersensitivity response to mycobacteria following antituberculosis therapy and release of tuberculosis antigens. Corticosteroid therapy is appropriate in this form of tuberculous disease.