Glutamine is required for M1-like polarization in response to Mycobacterium tuberculosis infection

In response to Mycobacterium tuberculosis infection, macrophages mount early proinflammatory and antimicrobial responses similar to those observed in M1 macrophages classically activated by LPS and IFN-γ. A metabolic reprogramming to HIF-1-mediated uptake of glucose and its metabolism by glycolysis is required for M1-like polarization, but little is known about other metabolic programs driving M1-like polarization during M. tuberculosis infection. Identification and quantification of labeling patterns of U 13 C glutamine and U 13 C glucose-derived metabolites demonstrated that glutamine, rather than glucose, is catabolized in both the oxidative and reductive TCA cycle of M1-like macrophages, thereby generating signaling molecules that include succinate, biosynthetic precursors such as aspartate, and the antimicrobial metabolite itaconate. This conclusion is corroborated by diminished M1 polarization via chemical inhibition of glutaminase (GLS), the key enzyme of the glutaminolysis pathway, and by genetic deletion of GLS in infected macrophages. Furthermore, characterization of the labeling distribution pattern of U 15 N glutamine in M1-like macrophages indicates that glutamine serves as a nitrogen source for the synthesis of intermediates of purine and pyrimidine metabolism plus amino acids including aspartate. Thus, the catabolism of glutamine, as an integral component of metabolic reprogramming in activating macrophages, fulfills the cellular demand for bioenergetic and biosynthetic precursors of M1-like macrophages. Knowledge of these new immunometabolic features of M1-like macrophages is expected to advance the development of host-directed therapies that will enhance bacterial clearance and prevent immunopathology during tuberculosis.

Variant Type X91+ Chronic Granulomatous Disease: Clinical and Molecular Characterization in a Chinese Cohort

Purpose: We aimed to report the clinical and immunological characteristics of variant type X91+ CGD in a Chinese cohort.Methods: The clinical manifestations and immunological phenotypes of X91+ CGD patients were collected. Dihydrorhodamine (DHR) analysis was performed to evaluate neutrophil function. Gp91phox protein expression was determined by flow cytometry-based extracellular staining with the monoclonal antibody (mAb) 7D5. Results: X91+CGD patients accounted for 8% (7/85) of all patients with GCD. The median onset age in the 7 X91+ CGD patients was 4 months. Six patients received the same BCG vaccine strain, and three had probable BCG infections. Moreover, 4 patients were highly suspected of having Mycobacterium tuberculosis infection. Recurrent infections of the lungs and soft tissues (3/7) were the most common symptoms. Two patients had noninfectious recurrent oral ulcers and received interferon gamma (IFN-γ) treatment afterward. In our cohort, the stimulation index (SI) of the 7 X91+ CGD patients ranged widely from 1.9 to 67.5, while the SI ranged from 1.2 to 35.7 in patents with X910 CGD. The level of SI between these two groups was statistically significant (P<0.05). CYBB mutations associated with X91+CGD were usually located in or near the FAD and NADPH binding domains. Three new X91+ CGD related mutations (c.1462-2 A>T, c.1243C>T and c.925G>A) were identified. Conclusions: Variant type X91+ CGD may have varied severities of clinical manifestations. Moreover, the laboratory findings of X91+ CGD could present with a moderate neutrophil stimulation index. We should deepen our understanding of the X91+ variant CGD to prevent missed diagnosis.

A Case of Hemophagocytic Lymphohistiocytosis Triggered by Disseminated Tuberculosis and Hairy Cell Leukaemia after SARS-CoV2 Infection

Hemophagocytic Lymphohistiocytosis (HLH) is a rare but life-threatening disease that can occur either as a primary condition or as a consequence of a variety of triggers, including infectious diseases. Here we present a case of secondary HLH triggered by systemic Mycobacterium tuberculosis infection in a 59-year-old immunocompromised Hairy Cell Leukemia and previous SARS-CoV2 infected patient. This case report underlines the role of Etoposide-based chemotherapy in treating the severe inflammation that is the defining factor of HLH, suggesting how, even when such therapy is not effective, it may still give the clinicians time to identify the underlying condition and start the appropriate targeted therapy. Moreover, it gives insight on our decision to treat the underlying haematological condition with a BRAF-targeted therapy rather than purine analog-based chemotherapy to reduce the risk of future severe infections.

Investigation of Contacts for Latent Mycobacterium Tuberculosis Infection: Application Software Development

Introduction: Tuberculosis is a pathology that continues to be worthy of special attention from health professionals and society due to its high prevalence, proving to be a crucial public health problem. Objectives: To describe the development of an application for family health strategy professionals’ investigation of tuberculosis contacts for Latent Mycobacterium tuberculosis Infection. Methods: This study is applied research on an application software developed according to three of the five phases described by Falkembach for developing digital educational materials, which include analysis and planning, modeling, and implementation. Results: The application is dynamic; that is, it guides health professionals through sequenced screens according to professionals’ self-informed answers. This functionality helps them deciding whether to proceed to the treatment of the patient with Latent Mycobacterium tuberculosis Infection or returning to the initial stage of a tuberculosis contact. The screens of the application follow the flowchart presented in the Ministry of Health’s Manual of recommendations for tuberculosis control in Brazil of 2018. Conclusion: The application developed to guide Family Health Strategy professionals regarding Latent Infection by Mycobacterium Tuberculosis can prevent human errors and increase the care quality when assessing tuberculosis contacts.

Lipid Droplets, the Central Hub Integrating Cell Metabolism and the Immune System

Lipid droplets (LDs) are commonly found in various biological cells and are organelles related to cell metabolism. LDs, the number and size of which are heterogeneous across cell type, are primarily composed of polar lipids and proteins on the surface with neutral lipids in the core. Neutral lipids stored in LDs can be degraded by lipolysis and lipophagocytosis, which are regulated by various proteins. The process of LD formation can be summarized in four steps. In addition to energy production, LDs play an extremely pivotal role in a variety of physiological and pathological processes, such as endoplasmic reticulum stress, lipid toxicity, storage of fat-soluble vitamins, regulation of oxidative stress, and reprogramming of cell metabolism. Interestingly, LDs, the hub of integration between metabolism and the immune system, are involved in antitumor immunity, anti-infective immunity (viruses, bacteria, parasites, etc.) and some metabolic immune diseases. Herein, we summarize the role of LDs in several major immune cells as elucidated in recent years, including T cells, dendritic cells, macrophages, mast cells, and neutrophils. Additionally, we analyze the role of the interaction between LDs and immune cells in two typical metabolic immune diseases: atherosclerosis and Mycobacterium tuberculosis infection.

The effect of new Mycobacterium tuberculosis infection on the sensitivity of prognostic TB signatures

BACKGROUND: Tests that identify individuals at greatest risk of TB will allow more efficient targeting of preventive therapy. The WHO target product profile for such tests defines optimal sensitivity of 90% and minimum sensitivity of 75% for predicting incident TB. The CORTIS (Correlate of Risk Targeted Intervention Study) evaluated a blood transcriptomic signature (RISK11) for predicting incident TB in a high transmission setting. RISK11 is able to predict TB disease progression but optimal prognostic performance was limited to a 6-month horizon.METHODS: Using a mathematical model, we estimated how subsequent Mycobacterium tuberculosis (MTB) infection may have contributed to the decline in sensitivity of RISK11. We calculated the effect at different RISK11 thresholds (60% and 26%) and for different assumptions about the risk of MTB infection.RESULTS: Modelled sensitivity over 15 months, excluding new infection, was 28.7% (95% CI 12.3–74.1) compared to 25.0% (95% CI 12.7–45.9) observed in the trial. Modelled sensitivity exceeded the minimum criteria (>75%) over a 9-month horizon at the 60% threshold and over 12 months at the 26% threshold.CONCLUSIONS: The effect of new infection on prognostic signature performance is likely to be small. Signatures such as RISK11 may be most useful in individuals, such as household contacts, where probable time of infection is known.

T-Cell Exhaustion in Mycobacterium tuberculosis and Nontuberculous Mycobacteria Infection: Pathophysiology and Therapeutic Perspectives

Immune exhaustion is a condition associated with chronic infections and cancers, characterized by the inability of antigen-specific T cells to eliminate the cognate antigen. Exhausted T cells display a peculiar phenotypic profile and exclusive functional characteristics. Immune exhaustion has been described in patients with Mycobacterium tuberculosis infection, and cases of tuberculosis reactivation have been reported in those treated with immune checkpoint inhibitors, drugs able to re-establish T-cells’ function. Exhausted T CD8+ cells’ profile has also been described in patients with infection due to nontuberculous mycobacteria. In this review, we initially provide an overview of the mechanisms leading to immune exhaustion in patients infected by Mycobacterium tuberculosis and nontuberculous mycobacteria. We then dissect the therapeutic perspectives related to immune checkpoint blockade in patients with these infections.