Utility of Esophageal Ultrasound-guided Biopsy of Mediastinal Lymph Nodes in Diagnosis of Childhood Tuberculosis.

A 6-year-old boy with autistic spectrum disorder was diagnosed with tuberculosis infection following contact tracing of his mother who had isoniazid-resistant pulmonary tuberculosis. He progressed to develop mediastinal lymphadenopathy causing a persistent cough. He was too small to undergo endobronchial ultrasound-guided biopsy. As an alternative, he underwent esophageal endoscopic ultrasound-guided biopsy, leading to confirmation of the diagnosis. We believe this approach to diagnostic biopsy is underrecognized in pediatric practice, and highlight its utility with this case and a brief literature review.

miR-495 Regulates Cellular Reactive Oxygen Species Levels by Targeting sod2 To Inhibit Intracellular Survival of Mycobacterium tuberculosis in Macrophages.

Mycobacterium tuberculosis is a chronic infectious disease pathogen. To date, tuberculosis is a major infectious disease that endangers human health. To better prevent and treat tuberculosis, it is important to study the pathogenesis of M. tuberculosis. Based on early-stage laboratory research results, in this study, we verified the upregulation of sod2 in Bacillus Calmette-Guérin (BCG) and H37Rv infection. By detecting BCG/H37Rv intracellular survival in sod2-silenced and sod2-overexpressing macrophages, sod2 was found to promote the intracellular survival of BCG/H37Rv. miR-495 then was determined to be downregulated by BCG/H37Rv. BCG/H37Rv can upregulate sod2 expression by miR-495 to promote the intracellular survival of BCG/H37Rv through a decline in ROS levels. This study provides a theoretical basis for developing new drug targets and treating tuberculosis.

Characterization of Phosphopantetheinyl Hydrolase from Mycobacterium tuberculosis.

Phosphopantetheinyl hydrolase, PptH (Rv2795c), is a recently discovered enzyme from Mycobacterium tuberculosis that removes 4'-phosphopantetheine (Ppt) from holo-carrier proteins (CPs) and thereby opposes the action of phosphopantetheinyl transferases (PPTases). PptH is the first structurally characterized enzyme of the phosphopantetheinyl hydrolase family. However, conditions for optimal activity of PptH have not been defined, and only one substrate has been identified. Here, we provide biochemical characterization of PptH and demonstrate that the enzyme hydrolyzes Ppt in vitro from more than one M. tuberculosis holo-CP as well as holo-CPs from other organisms. PptH provided the only detectable activity in mycobacterial lysates that dephosphopantetheinylated acyl carrier protein M (AcpM), suggesting that PptH is the main Ppt hydrolase in M. tuberculosis. We could not detect a role for PptH in coenzyme A (CoA) salvage, and PptH was not required for virulence of M. tuberculosis during infection of mice. It remains to be determined why mycobacteria conserve a broadly acting phosphohydrolase that removes the Ppt prosthetic group from essential CPs. We speculate that the enzyme is critical for aspects of the life cycle of M. tuberculosis that are not routinely modeled. IMPORTANCE Tuberculosis (TB), caused by Mycobacterium tuberculosis, was the leading cause of death from an infectious disease before COVID, yet the in vivo essentiality and function of many of the protein-encoding genes expressed by M. tuberculosis are not known. We biochemically characterize M. tuberculosis's phosphopantetheinyl hydrolase, PptH, a protein unique to mycobacteria that removes an essential posttranslational modification on proteins involved in synthesis of lipids important for the bacterium's cell wall and virulence. We demonstrate that the enzyme has broad substrate specificity, but it does not appear to have a role in coenzyme A (CoA) salvage or virulence in a mouse model of TB.

Relationship of SARS-CoV-2-specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection.

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2-specific (SARS-CoV-2-specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non-COVID-19 patients. We showed that SARS-CoV-2-specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1-mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis-specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.

Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.

Rapid Detection of COVID-19 Using MALDI-TOF-Based Serum Peptidome Profiling.

The outbreak of coronavirus disease 2019 (COVID-19) caused by SARS CoV-2 is ongoing and a serious threat to global public health. It is essential to detect the disease quickly and immediately to isolate the infected individuals. Nevertheless, the current widely used PCR and immunoassay-based methods suffer from false negative results and delays in diagnosis. Herein, a high-throughput serum peptidome profiling method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is developed for efficient detection of COVID-19. We analyzed the serum samples from 146 COVID-19 patients and 152 control cases (including 73 non-COVID-19 patients with similar clinical symptoms, 33 tuberculosis patients, and 46 healthy individuals). After MS data processing and feature selection, eight machine learning methods were used to build classification models. A logistic regression machine learning model with 25 feature peaks achieved the highest accuracy (99%), with sensitivity of 98% and specificity of 100%, for the detection of COVID-19. This result demonstrated a great potential of the method for screening, routine surveillance, and diagnosis of COVID-19 in large populations, which is an important part of the pandemic control.

Tuberculosis and COVID-19 interaction: A review of biological, clinical and public health effects.

Evidence is accumulating on the interaction between tuberculosis (TB) and COVID-19. The aim of the present review is to report the available evidence on the interaction between these two infections. Differences and similarities of TB and COVID-19, their immunological features, diagnostics, epidemiological and clinical characteristics and public health implications are discussed. The key published documents and guidelines on the topic have been reviewed. Based on the immunological mechanism involved, a shared dysregulation of immune responses in COVID-19 and TB has been found, suggesting a dual risk posed by co-infection worsening COVID-19 severity and favouring TB disease progression. The available evidence on clinical aspects suggests that COVID-19 happens regardless of TB occurrence either before, during or after an active TB diagnosis. More evidence is required to determine if COVID-19 may reactivate or worsen active TB disease. The role of sequeale and the need for further rehabilitation must be further studied Similarly, the potential role of drugs prescribed during the initial phase to treat COVID-19 and their interaction with anti-TB drugs require caution. Regarding risk of morbidity and mortality, several risk scores for COVID-19 and independent risk factors for TB have been identified: including, among others, age, poverty, malnutrition and co-morbidities (HIV co-infection, diabetes, etc.). Additional evidence is expected to be provided by the ongoing global TB/COVID-19 study.