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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. Granulomas are a hallmark and focus of infective and immunological processes during infection with Mycobacterium tuberculosis . Here, Carow and colleagues show distinct spatial and temporal arrangement of immunological transcripts in tuberculosis granulomas.

Mycobacterium tuberculosis and its close relative Mycobacterium marinum infect macrophages and induce the formation of granulomas, organized macrophage-rich immune aggregates. These mycobacterial pathogens can accelerate and co-opt granuloma formation for their benefit, using the specialized secretion system ESX-1, a key virulence determinant. ESX-1–mediated virulence is attributed to the damage it causes to the membranes of macrophage phagosomal compartments, within which the bacteria reside. This phagosomal damage, in turn, has been attributed to the membranolytic activity of ESAT-6, the major secreted substrate of ESX-1. However, mutations that perturb ESAT-6’s membranolytic activity often result in global impairment of ESX-1 secretion. This has precluded an understanding of the causal and mechanistic relationships between ESAT-6 membranolysis and ESX-1–mediated virulence. Here, we identify two conserved residues in the unstructured C-terminal tail of ESAT-6 required for phagosomal damage, granuloma formation, and virulence. Importantly, these ESAT-6 mutants have near-normal levels of secretion, far higher than the minimal threshold we establish is needed for ESX-1–mediated virulence early in infection. Unexpectedly, these loss-of-function ESAT-6 mutants retain the ability to lyse acidified liposomes. Thus, ESAT-6’s virulence functions in vivo can be uncoupled from this in vitro surrogate assay. These uncoupling mutants highlight an enigmatic functional domain of ESAT-6 and provide key tools to investigate the mechanism of phagosomal damage and virulence.

Mycobacterium tuberculosis (MTB) is one of the most successful pathogens in human history and remains a global health challenge. MTB has evolved a plethora of strategies to evade the immune response sufficiently to survive within the macrophage in a bacterial-immunological equilibrium, yet causes sufficient immunopathology to facilitate its transmission. This review highlights MTB as the driver of disease pathogenesis and presents evidence of the mechanisms by which MTB manipulates the protective immune response into a pathological productive infection.

The microbiota of the deep lung regions significantly differs from that of the upper respiratory tract by much lower biomass and dynamic diversity. In our previous studies we found that the biodiversity of the satellite microbiota of tuberculosis foci is sharply reduced in comparison with intact lung tissues. These findings allowed us to classify microbial communities in the caseous necrosis of tuberculomas into two types: (i) mycobacterial caseoma (tuberculoma), where 70% or more of the genomes correspond to Mycobacterium tuberculosis , and (ii) a polymicrobial community, where the concentration of M. tuberculosis varies from 0 to 10%. Using shotgun metagenomic sequencing, 14 tuberculomas from 13 patients were analyzed on a NextSeq 550 platform (Illumina). Taxonomic classification of short reads was performed using Kraken 2. The results show that, on average, 99.95% of the short reads belonged to human DNA or were unclassified. However, the classified reads related to bacterial genomes confirmed the concept that in many cases, tuberculomas contained polymicrobial communities that either replaced or supplemented the original mycobacterial microbiota of the caseous material.

The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1beta, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome.

Granulomas are organized host immune structures composed of tightly interposed macrophages and other cells that form in response to a variety of persistent stimuli, both infectious and noninfectious. The tuberculous granuloma is essential for host containment of mycobacterial infection, although it does not always eradicate it. Therefore, it is considered a host-beneficial, if incompletely efficacious, immune response. The Mycobacterium RD1 locus encodes a specialized secretion system that promotes mycobacterial virulence by an unknown mechanism. Using transparent zebrafish embryos to monitor the infection process in real time, we found that RD1-deficient bacteria fail to elicit efficient granuloma formation despite their ability to grow inside of infected macrophages. We showed that macrophages infected with virulent mycobacteria produce an RD1-dependent signal that directs macrophages to aggregate into granulomas. This Mycobacterium-induced macrophage aggregation in turn is tightly linked to intercellular bacterial dissemination and increased bacterial numbers. Thus, mycobacteria co-opt host granulomas for their virulence.

Tuberculous meningitis is primarily a disease of the meninges of brain and spinal cord along with adjacent brain parenchyma. The characteristic pathological changes are meningeal inflammation, basal exudates, vasculitis and hydrocephalus. Tuberculous meningitis has a strong predilection for basal parts of the brain. Exudates, if dominantly present in the interpeduncular, suprasellar and Sylvian cisterns, result in optochiasmatic arachnoiditis and tuberculoma. Optochiasmatic arachnoiditis and tuberculoma are devastating forms of tuberculous meningitis and often associated with profound vision loss. This clinical entity more frequently affects young adults. In a recent study, on the multivariate logistic regression analysis, female sex, younger age and raised cerebrospinal fluid protein content were identified as predictors for developing optochiasmatic arachnoiditis. Frequently, optochiasmatic tuberculoma and optochiasmatic arachnoiditis develop paradoxically while a patient is being treated with anti-TB drugs. MRI reveals confluent enhancing lesions that are present in the interpeduncular fossa, pontine cistern, and the perimesencephalic and suprasellar cisterns. Management of tuberculous optochiasmatic arachnoiditis and optochiasmatic arachnoiditis tuberculoma has been variable. Treatment of optochiasmatic arachnoiditis continues to be a challenge and the response is generally unsatisfactory. In isolated case reports and in small series, corticosteroids, methyl prednisolone, thalidomide and hyaluronidase have been used with variable success. The benefit from neurosurgery is controversial and deterioration may follow the initial temporary improvement. Management of paradoxical optochiasmatic arachnoiditis is also controversial. Some patients regain vision following treatment with anti-TB drugs and continued usage of corticosteroids. Neurosurgery may be considered in the patients with either treatment failure or when diagnosis is in doubt. In conclusion, presence of optochiasmatic arachnoiditis or tuberculoma has important therapeutic and prognostic implications for patients of tuberculous meningitis.

Mycobacterium tuberculosis infection is associated with thrombocytosis. We sought to determine if this information might be valuable in evaluating granulomas using acid-fast stains (AFS). Fifty-eight patients with culture-confirmed M tuberculosis infection were compared with 75 patients with atypical mycobacterial infection and 48 patients negative for mycobacteria. Thrombocytosis (platelet count >360 × 103/μL [360 × 109/L]) was significantly more common in patients with M tuberculosis (50%) than those with either atypical mycobacterial infection (12%) or negative for mycobacteria (4%, P < .001 for each). In 67 patients, histologic evaluation of tissue samples showed granulomatous inflammation; 37 (55%) had positive AFS results. Of 19 patients with thrombocytosis, 16 (84%) had a positive AFS result compared with 21 (44%) of 48 without thrombocytosis (P = .003). Fifteen of 16 M tuberculosis cases with thrombocytosis had positive AFS findings on histologic evaluation; the single negative case had a platelet count of 362 × 103/μL (362 × 109/L). However, 3 of these cases of positive results on staining were initially diagnosed as negative and only recognized as positive on review. We conclude that patients whose specimens were sent for mycobacterial culture and thrombocytosis had an increased risk for M tuberculosis. Patients with granulomas and thrombocytosis are more likely to have a positive AFS result usually showing M tuberculosis. Finally, patients with initially negative AFS results and thrombocytosis deserve to have additional evaluation of the AFS specimens.

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.

Few studies have compared the clinical and radiographic findings of tuberculomas to those of solitary pulmonary nodules (SPNs) caused by Mycobacterium avium complex (MAC). We retrospectively analyzed clinical and radiographic findings from 26 patients with tuberculomas and 15 patients with SPNs caused by MAC. Median SPN size was 22 mm. In 26 patients (63%), the SPN was detected during a routine health checkup or evaluation of organs other than lungs. Patients with SPNs due to MAC were slightly older (median = 59 years) compared with those with tuberculomas (median = 50 years; P = 0.044). When we compared computed tomography (CT) features between patients with tuberculomas and patients with MAC, no significant differences were found in SPN location or the presence of calcification, cavitation, central low attenuation, and the satellite lesions. Although the maximum standardized uptake values were slightly higher in patients with SPNs due to MAC (median = 8.5) compared with those with tuberculomas (median = 2.2), this difference was not significant (P = 0.053). Of the 15 patients with SPNs due to MAC, 10 were initially diagnosed with “tuberculoma” and administered antituberculosis medication. MAC pulmonary disease should be considered in the differential diagnosis of SPNs, even when encountered in geographic regions with a high prevalence of pulmonary tuberculosis.