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Key Points The tuberculous granuloma has long been considered a key host-protective immunological structure that restricts mycobacteria even under circumstances in which it fails to eradicate them. It was thought historically to be a relatively static structure and to require interactions between mycobacteria and the host adaptive immune system for its formation. Recent advances, particularly in live imaging technology, reveal that the granuloma is a highly dynamic structure, with cells moving in and out of it and throughout the structure. These cellular dynamics resemble in some ways the movement of lymphocytes in lymph nodes, and indeed granulomas can contain tertiary lymphoid structures. Bona fide granulomas can form in the sole context of innate immunity and, rather than being mycobacterium-restricting structures, early granulomas actually expand the infection by promoting the phagocytosis of apoptotic infected macrophages by multiple newly arriving macrophages. The bacterial secreted protein ESAT6 induces host production of matrix metalloproteinase 9 (MMP9) by epithelial cells surrounding the nascent granuloma to induce the chemotaxis of these new macrophages. The granuloma also disseminates infection through the egress of infected macrophages to new sites. Granuloma expansion and dissemination can occur during effective antibiotic treatment through the participation of macrophages containing drug-tolerant bacteria. The onset of adaptive immunity a few weeks after infection can thwart bacterial proliferation in the granuloma but often fails to eradicate infection. Its failure to sterilize infection is attributed to multiple complex mechanisms that result in the delayed arrival and activation of effector T cells. An understanding of the host pathways that are exploited by mycobacteria to first expand and disseminate infection in the granuloma and to then prevent adaptive immune mechanisms from eradicating infection could provide new host-targeting therapies for tuberculosis. These might be useful not only to shorten the long treatment required for drug-sensitive tuberculosis but also to provide much-needed therapies against drug-resistant tuberculosis. Finally, this understanding might suggest entirely new ways to think about tuberculosis vaccines. This Review argues against the historical view of the granuloma as a host-protective structure and provides evidence that the innate immune mechanisms of tuberculous granulomas are involved in the expansion and dissemination of infection. The granuloma, which is a compact aggregate of immune cells, is the hallmark structure of tuberculosis. It is historically regarded as a host-protective structure that 'walls off' the infecting mycobacteria. This Review discusses surprising new discoveries — from imaging studies coupled with genetic manipulations — that implicate the innate immune mechanisms of the tuberculous granuloma in the expansion and dissemination of infection. It also covers why the granuloma can fail to eradicate infection even after adaptive immunity develops. An understanding of the mechanisms and impact of tuberculous granuloma formation can guide the development of therapies to modulate granuloma formation. Such therapies might be effective for tuberculosis as well as for other granulomatous diseases.

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

IntroductionSarcoidosis is a multi-system granulomatous disease. Thoracic involvement can sometimes present asymptomatically, only being detected incidentally during imaging studies for other conditions or non-specific symptoms. Appropriate follow up of these patients has not been well defined.ObjectiveTo define the clinical course of incidentally identified Scadding stage 1 sarcoidosis.MethodologyRetrospective case note analysis of endobronchial-ultrasound guided lymph node biopsy confirmed cases of sarcoidosis was undertaken. These were patients who presented incidentally to Bristol and Liverpool ILD services, with Scadding stage 1 disease. Clinical features, lung function parameters and radiological staging were examined at baseline, 12 and 24 months. We hypothesized that there would be no progression of disease in these patients. T-test was used with statistical significance of p< 0.05. ResultsFifty-two cases were identified; 52% were male. The cohort had a median (IQR) age of 54 (43–63) years, and baseline FEV1 of 99 (86–112)%, FVC of 106 (99–119)%, FEV1/FVC ratio of 76 (72–81)% and TLCO of 90 (76–102)%.All patients were asymptomatic in terms of fatigue, arthralgia, eye and respiratory symptoms at baseline. Baseline calcium was normal in all patients.At 12 months there was no significant change in FEV1 3.21 ± 9.44% (n=24; p= 0.75) and FVC 0.47 ±7.44% (n=23; p= 0.68) compared to baseline. At 24 months there was also no significant change in FEV1 1.17 ±12.2% (n=11; p= 0.90) and FVC -0.66% ±10.96% (n=10; p= 0.49) compared to baseline.Chest X-rays showed stability or regression in 90.3% of cases (n=31) at 12.7 ±4.9 months and 100% of cases (n=17) at 23.9 ±4.2 months.No patients required therapeutic intervention over 24 months of follow up, for organ threatening disease or symptoms deemed by patient and/or physician to be significantly impacting on quality of life.Furthermore, no patients went on to develop any symptomatic features attributable to sarcoidosis during the study period.ConclusionOur results show that patients with incidental findings of non-caseating granulomas and Stage 1 disease at baseline remain asymptomatic over a 24 month period. Our results suggest that prolonged follow up is unnecessary.ReferenceScadding JG, Mitchell DN. Sarcoidosis. London: Chapman & Hall, 1985.

The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free control subjects were incubated for 7 days with purified protein derivative-coated polystyrene beads. Molecular responses, as reflected by differential expression of genes, extracellular cytokine patterns, and cell surface receptor expression, were analyzed. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared with human lung and mediastinal lymph node gene expression profiles. Compared with identically treated PBMCs of control subjects (n = 5), purified protein derivative-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Ingenuity Pathway Analysis of differential expression gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).

Background Invasive Cerebral Aspergillosis (ICA) is a rare fungal infection affecting the brain, primarily seen in individuals with compromised immune systems. Despite various treatment options, substantial cerebral granulomas caused by ICA still result in high mortality and recurrence rates. Case presentation We report a rare instance of ICA in a 30-year-old pregnant woman. The infection initiated in the nasal cavity and progressed to form a large intracranial granuloma, leading to brain herniation. Diagnosis was confirmed through histopathology, Polymerase Chain Reaction (PCR), and metagenomic next-generation sequencing (mNGS) following decompressive craniotomy and sinus window drainage surgery. Prompt administration of antifungal medication resulted in a favorable prognosis. Conclusion This case highlights the critical roles of mNGS and PCR in the early diagnosis of ICA, as well as the pivotal importance of surgical interventions and prompt initiation of antifungal therapy in enhancing patient outcomes.