Metabolic Biological Markers for Diagnosing and Monitoring the Course of Tuberculosis

The international biomedical community has been currently facing a need to find a simple and most accessible type of analysis that helps to diagnose tuberculosis ( TB) with the maximum reliability even before the onset of clinical manifestations. Tuberculosis results in more deaths than any other pathogen, second only to pneumonia caused by the SARS-CoV-2 virus, but the majority of infected people remain asymptomatic. In addition, it is important to develop methods to distinguish various forms of tuberculosis infection course at early stages and to reliably stratify patients into appropriate groups (persons with a rapidly progressing infection, chronic course, latent infection carriers). Immunometabolism investigates a relationship between bioenergetic pathways and specific functions of immune cells that has recently become increasingly important in scientific research. The host anti-mycobacteria immune response in tuberculosis is regu lated by a number of metabolic networks that can interact both cooperatively and antagonistically, influencing an outcome of the disease. The balance between inflammatory and immune reactions limits the spread of mycobacteria in vivo and protects from developing tuberculosis. Cytokines are essential for host defense, but if uncontrolled, some mediators may contribute to developing disease and pathology. Differences in plasma levels of metabolites between individuals with advanced infection, LTBI and healthy individuals can be detected long before the onset of the major related clinical signs. Changes in amino acid and cortisol level may be detected as early as 12 months before the onset of the disease and become more prominent at verifying clinical diagnosis. Assessing serum level of certain amino acids and their ratios may be used as additional diagnostic markers of active pulmonary TB. Metabolites, including serum fatty acids, amino acids and lipids may contribute to detecting active TB. Metabolic profiles indicate about increased indolamine 2.3-dioxygenase 1 (IDO1) activity, decreased phospholipase activity, increased adenosine metabolite level, and fibrous lesions in active vs. latent infection. TB treatment can be adjusted based on individual patient metabolism and biomarker profiles. Thus, exploring immunometabolism in tuberculosis is necessary for development of new therapeutic strategies.

COVID-19 and Pain

SARS-CoV-2 causes COVID-19, which includes acute respiratory tract infections with a variety of manifestations such as pneumonia and bronchiolitis which are accompanied by other symptoms such as wheezing, cough, respiratory distress, and pain. The novel Coronavirus has caused millions of deaths and increasing challenges for healthcare professionals globally. When the virus enters our organism through nasal mucosa it is identified by the innate immune system such as macrophages and mast cells, therefore producing pro-inflammatory cytokines including IL-1beta, IL-6, and TNF. The production of cytokines mediates fever, malaise, depression, anxiety, loss of appetite, hyperalgesia, and pain. Here in this paper, we report the interrelationship between COVID-19 and pain.Copyright © by BIOLIFE.

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19.

Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3-4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions.

Importance of IL-1 beta in SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provokes the host immune responses and induces severe respiratory syndrome by overreaction of immune cells. IL-1 beta is a pro-inflammatory cytokine highly associated with the related inflammation and cytokine storm, and several IL-1 beta antagonists are being used to treat cytokine release syndrome (CRS). Accordingly, some studies and clinical trials are investigating the effects of IL-1 beta antagonists for controlling Coronavirus disease 2019 (COVID-19) associated CRS. Here, we will review any interaction and association between IL-1 beta and SARS-CoV-2 infection.

Importance of IL-1 beta in SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provokes the host immune responses and induces severe respiratory syndrome by overreaction of immune cells. IL-1 beta is a proinflammatory cytokine highly associated with the related inflammation and cytokine storm, and several IL-1 beta antagonists are being used to treat cytokine release syndrome (CRS). Accordingly, some studies and clinical trials are investigating the effects of IL-1 beta antagonists for controlling Coronavirus disease 2019 (COVID-19) associated CRS. Here, we will review any interaction and association between IL-1 beta and SARS-CoV-2 infection.

Canakinumab in patients with COVID-19 and type 2 diabetes - A multicentre, randomised, double-blind, placebo-controlled trial.

Background: Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1ß (IL-1ß) blockade using canakinumab improves clinical outcome. Methods: CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI > 25 kg/m2 hospitalised with SARS-CoV2 infection in seven tertiary-hospitals in Switzerland. Patients were randomly assigned 1:1 to a single intravenous dose of canakinumab (body weight adapted dose of 450-750 mg) or placebo. Canakinumab and placebo were compared based on an unmatched win-ratio approach based on length of survival, ventilation, ICU stay and hospitalization at day 29. This study is registered with ClinicalTrials.gov, NCT04510493. Findings: Between October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group. Interpretation: In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation. Funding: Swiss National Science Foundation grant #198415 and University of Basel. Novartis supplied study medication.

The Inflammasome in Times of COVID-19.

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1ß and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1ß in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients.