The "Janus-like" RNA-editing machinery in innate antiviral immunity

Our innate immune systems are evolved to provide the first line of immune defense against microbial infections. A key effector component is the adenosine deaminase acting on the RNA-1 (ADAR-1)/ interferon (IFN) pathway of the innate cytoplasmic immunity that mounts rapid responses to many viral pathogens. As an RNA-editing enzyme, ADAR-1 targets viral RNA intermediates in the cytoplasmic compartment to interfere with the infection. However, ADAR-1 may also edit characteristic RNA structures of certain host genes, notably, the 5-hydroxytryptamine (serotonin) receptor 2C (5HT2CR). Dysfunction of 5-HT2CR has been linked to the pathology of several human mental conditions, such as Schizophrenia, anxiety, bipolar disorder, major depression, and the mental illnesses of substance use disorders (SUD). Thus, the ADAR-1mediated RNA editing may be either beneficial or harmful;these effects need to be tightly modulated to sustain innate antiviral immunity while restricting undesired off-target self-reactivity. In this communication, we discuss ideas and tools to identify the orphan drug candidates, including small molecules and biologics that may serve as effective modulators of the ADAR-1/IFN innate immunity and are thereby promising for use in treating or preventing SUD-and/or viral infection-associated mental illnesses.Copyright © 2023, Research Trends (P) LTD.. All rights reserved.

Adenosine deaminase augments SARS-CoV-2 specific cellular and humoral responses in aged mouse models of immunization and challenge.

Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of TH2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased TH2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting TH1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a TH1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations.

Pneumopericardium in COVID-19 Infection

Pneumopericardium is a rare medical condition that occurs following trauma, surgery, or other medical interventions. The presence of pneumopericardium after COVID-19 pneumonia has been reported in some cases, and it has been explained that most cases could be self-limited. Here, we describe a 51-year-old man afflicted by pneumopericardium with COVID-19 infection. The patient had pneumopericardium and massive pericardial effusions, necessitating surgical strategies such as pericardial windows. This case highlights the potential severity of COVID-19. We also suggest that cardiologists pay attention to the possibility of pneumopericardium in cases with COVID-19 infection. © 2023, Iranian Heart Association. All rights reserved.

Correlations of Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in the nasopharyngeal specimens with the diagnosis and severity of SARS-CoV-2 infections.

Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell markers and cytokines in fresh nasopharyngeal swab specimens for the diagnosis and for stratifying the severity of COVID-19. This was a retrospective case-control study comparing Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine ligand 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in 490 (327 patients and 163 control) nasopharyngeal specimens from 317 (154 COVID-19 and 163 control) hospitalized patients. Of the 154 COVID-19 cases, 46 died. Both total and normalized MPO, ADA, CCL22, TNFα, and IL-6 mRNA expression levels were significantly higher in the nasopharyngeal specimens of infected patients when compared with controls, with ADA showing better performance (OR 5.703, 95% CI 3.424-9.500, p < 0.001). Receiver operating characteristics (ROC) curve showed that the cut-off value of normalized ADA mRNA level at 2.37 × 10-3 had a sensitivity of 81.8% and specificity of 83.4%. While patients with severe COVID-19 had more respiratory symptoms, and elevated lactate dehydrogenase, multivariate analysis showed that severe COVID-19 patients had lower CCL22 mRNA (OR 0.211, 95% CI 0.060-0.746, p = 0.016) in nasopharyngeal specimens, while lymphocyte count, C-reactive protein, and viral load in nasopharyngeal specimens did not correlate with disease severity. In summary, ADA appears to be a better biomarker to differentiate between infected and uninfected patients, while CCL22 has the potential in stratifying the severity of COVID-19.

The Role of Adenosine Deaminase Levels in The Diagnosis of COVID-19 Infection

Introduction and background: Adenosine deaminase (ADA) is an enzyme produced from body cells after infections due to activations of the immune response toward the microbes. The enzyme was previously used for the diagnosis of tuberculosis, lymphomas, sarcoidosis, lupus, and severe combined immunodeficiency (SCID). COVID-19 is a viral disease caused by Coronaviruses and infected the respiratory tract of patients mainly. The aim of this study is to measure and correlate the level of ADA with COVID-19 during the infection, patient and methods: Two methods;conventional enzymatic (Guisti and Galanti method) and ELISA methods were used to measure the level of ADA in 48 individuals, 12 were suffering from severe COVID-19, 12 has a moderate infection and 24 individuals were used as the control they are negative PCR- COVID-19 infections. Results: Both methods show that the level of ADA in patients suffering from COVID-19 infection is significantly higher in patients with severe infections compared with those in control and moderate infections' P <0.001, conclusion: This study concluded that the use of ADA levels in the serum of COVID-19 patients will be useful during the period of the disease. © 2022, HIV Nursing. All rights reserved.

Community-acquired Methicillin-resistant Staphylococcus aureus Pneumonia and Parapneumonic Effusion in a Male Patient with Diabetes: A Case Report

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a primary health concern. They are commonly differentiated as hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) and community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, based on their epidemiology, susceptibility findings, and molecular typing patterns. Therefore, appropriate contact precautions and isolation measures should be implemented. CA-MRSA mostly causes skin and soft-tissue infections, but the probability and incidence of it causing sepsis and invasive infections have increased dramatically in recent years. In this study, we report a case of CA-MRSA pneumonia with pan-pneumonic effusion in a 59-year-old male diabetic patient with preexisting comorbidities such as diabetic ketoacidosis and non-ST elevated myocardial infarction. The early reporting of the organism's identity and its antimicrobial susceptibility, as well as timely initiation of antibiotic therapy, aided in the successful management and cure of the patient.

TUBERCULOUS TAMPONADE WITH A TWIST: A CASE OF TB AND COVID-19

SESSION TITLE: Critical Care Presentations of TB SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: We present a case of tuberculous pericarditis and cardiac tamponade due to suspected sequela of SARS-Coronavirus 19 (COVID-19) infection. It is important for clinicians to include tuberculosis (TB) in the differential diagnoses for patients presenting with presumptive viral pericarditis and tamponade. CASE PRESENTATION: A 52-year-old Hispanic man with chronic kidney disease not on hemodialysis was admitted with shortness of breath, fluid overload, hypoxemia and concern for uremic pericarditis. The patient tested positive for COVID-19 to which the symptoms were initially attributed, and he was treated with steroids, remdesevir, tocilizumab and hemodialysis. The patient incidentally had a positive QuantiFERON gold test obtained before initiating hemodialysis. On day 60 of hospitalization, the clinical exam abruptly deteriorated with stuporous mentation, hypotension, and cool skin. Bedside point of care echocardiography revealed a new large circumferential pericardial effusion with right ventricular diastolic collapse and increased respiratory variation in peak E-wave mitral inflow velocity consistent with tamponade physiology. Emergent pericardiocentesis was performed, and hemodynamic instability resolved immediately after aspiration of 750 milliliters of frank pus. Empiric antibiotics were initially given for pyogenic pericarditis. When the pericardial fluid later tested positive for acid-fast bacilli and adenosine deaminase, anti-TB therapy was started. The hospitalization was further complicated by septic shock and cardiac arrest. Though found to have a re-accumulated pericardial effusion on bedside ultrasound peri-arrest, there was no tamponade physiology (suggestive of at least a partial response to the TB treatment in the setting of overall poor underlying reserve). DISCUSSION: The coexistence of COVID-19 and tuberculous pericarditis with tamponade has been reported to date in one other case to our knowledge. COVID-19 with massive pericardial tamponade is rare and a careful diagnostic approach involving multi-modality imaging with bedside echocardiogram is invaluable in the evaluation and treatment of obstructive shock. In this case, we hypothesize that the COVID-19 infection may have led to re-activation of latent TB despite treatment of COVID-19 with corticosteroids (which are an adjunct tuberculostatic treatment in patients with tuberculous pericarditis). Tuberculous pericarditis with tamponade is a relatively uncommon manifestation of extrapulmonary TB and is a major cause of cardiovascular death and morbidity. Even with aggressive antituberculosis therapy, 30-60% of patients may need surgical pericardiectomy for constrictive pericarditis. CONCLUSIONS: This case highlights the need to consider possibility of concomitant viral and TB pericarditis in the diagnostic differential for tamponade. More histopathologic or post-mortem examinations of COVID-19 pericarditis cases are needed. Reference #1: Asif T, Kassab K, Iskander F, Alyousef T. Acute pericarditis and cardiac tamponade in a patient with COVID19: a therapeutic challenge. Eur J Case Rep Intern Med. 2020 May 6;7(6):001701. Reference #2: Barrett et al. Increase in disseminated TB during the COVID19 pandemic. Int J Tuberc Lung Dis. 2021 Feb 1;25(2):160-166. Reference #3: Wong SW, Ng J. K.X., Chia YW. Tuberculous pericarditis with tamponade diagnosed concomittantly with COVID19: a case report. Eur Heart J Case Rep. 2020 Dec 28;5(1):ytaa491. eCollection 2021 Jan. DISCLOSURES: No relevant relationships by Jaskiran Khosa No relevant relationships by Walter Klein No relevant relationships by Amy Tran No relevant relationships by Michael Ulrich

TUBERCULOUS PLEURAL EFFUSION MASQUERADING AS DRUG-INDUCED LUPUS

SESSION TITLE: Critical Care Presentations of TB SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: TNFα plays a pivotal role in inflammation and maintenance of immune response against tuberculosis. The use of TNF inhibitors (TNFi) is associated with a significant increase in the incidence of tuberculosis (TB). TNFi may cause drug-induced lupus (ATIL) presenting as constitutional symptoms, rashes, pericardial and pleural effusions with positive autoantibodies. We present a case of pleural TB masquerading as drug-induced lupus. CASE PRESENTATION: A 68y/o woman with a history of ulcerative colitis (on infliximab, mesalamine), hypertension, T2DM, CAD, complained of low-grade fever, rashes, left-sided chest pain, dyspnea, and arthralgias for two weeks. Chest pain- worse with inspiration and cough. She emigrated from India to the USA 40 years ago. Six months before infliximab therapy, Quantiferon gold was negative. Exam: faint hyperpigmentation over shins, minimal swelling of MCPs and ankles, dullness to percussion over the left chest with decreased breath sounds. Labs: CRP 101 mg/dL, Hb 10.8 iron deficient, rheumatoid factor and anti-CCP negative, ANA 1:40, dsDNA 1:640, a reminder of ENA negative, anti-histone negative, C3/C4 normal, UA bland, protein/Cr 0.4 mg/gm, negative blood cultures, SPEP and LDH normal. CXR: opacification of the left lung up to midfield. CT chest: moderate left and small right pleural effusions, enlarged mediastinal lymph nodes. COVID and Quantiferon: negative. Thoracentesis: 850 ml of exudative fluid (2 out of 3 Light's criteria), lymphocytic predominance (76% of 4148 nucleated cells), adenosine deaminase (ADA) 42 U/L, gram stain, culture, acid-fast and MTB PCR negative, cytology negative. Thoracoscopy with biopsy of the parietal pleura: necrotizing granulomatous pleuritis with acid-fast bacilli. Sensitivity: pan-sensitive M. tuberculosis. Sputum: negative for TB. She was discharged on RIPE treatment for reactivation of TB. DISCUSSION: The incidence of infliximab-induced lupus is approximately 0.19% and confirming the diagnosis is challenging. The immunogenicity of infliximab is high, 66% of patients develop positive ANA. Anti-histone antibodies are less commonly associated with ATIL as opposed to classic drug-induced lupus and dsDNA is positive in up to 90% of cases of ATIL. Renal involvement is rare. The diagnostic usefulness of ADA (over 40 U/L) in lymphocytic pleural effusions for the diagnosis of tuberculosis in an immunosuppressed individual is demonstrated here. In countries with low TB burden, such as the USA, the positive predictive value of ADA in pleural fluid declines but the negative predictive value remains high. CONCLUSIONS: Tuberculous pleuritis is not always easily diagnosed since AFB smears and sputum may remain negative. When ADA level in lymphocytic pleural fluid is not low thorough search for TB with thoracoscopy and biopsy is justified. Reference #1: Shovman O, Tamar S, Amital H, Watad A, Shoenfeld Y. Diverse patterns of anti-TNF-α-induced lupus: case series and review of the literature. Clin Rheumatol. 2018 Feb;37(2):563-568. Reference #2: Benucci, M., Gobbi, F. L., Fossi, F., Manfredi, M. & Del Rosso, A. (2005). Drug-Induced Lupus After Treatment With Infliximab in Rheumatoid Arthritis. JCR: Journal of Clinical Rheumatology, 11 (1), 47-49. Reference #3: Valdés L, San José ME, Pose A, Gude F, González-Barcala FJ, Alvarez-Dobaño JM, Sahn SA. Diagnosing tuberculous pleural effusion using clinical data and pleural fluid analysis A study of patients less than 40 years-old in an area with a high incidence of tuberculosis. Respir Med. 2010 Aug;104(8):1211-7. DISCLOSURES: No relevant relationships by Adam Adam No relevant relationships by Moses Bachan No relevant relationships by Chen Chao No relevant relationships by Zinobia Khan No relevant relationships by Milena Vukelic

Massive Pleural Effusion with Adenosine Deaminase (ADA) Test Positive and COVID-19 Confirmed: A Case Report

A 26-year-old man complained of shortness of breath for 3 days before the hospital admission. The patient had a history of coughing up blood and had consumed alcohol and drugs. Decreased vesicular auscultation and dull percussion in the left lateral pulmo. Laboratory result showed increased neutrophil-lymphocyte ratio C-reactive protein, D-dimer, procalcitonin, ferritin, and decreased albumin level. Pleural fluid analysis indicated the presence of exudate, SARS-CoV-2 PCR positive, and increased ADA level to 43 U/L. Based on the examination results, we suspected that the etiology of the massive pleural effusion was tuberculous pleurisy, particularly due to increased ADA levels. The patient was diagnosed with COVID-19 pneumonia with massive pleural effusion and tuberculous pleurisy. Massive pleural effusion in SARS-CoV-2 infection is rare. Thus, laboratory modalities for massive pleural effusion diagnosis are needed to determine the etiology and effective treatment for the patient. ADA analysis could be considered as an initial examination in patients with pleural effusion during the wait for pleural fluid culture results.

Artificial intelligence in clinical care amidst COVID-19 pandemic: A systematic review.

The worldwide health crisis caused by the SARS-Cov-2 virus has resulted in>3 million deaths so far. Improving early screening, diagnosis and prognosis of the disease are critical steps in assisting healthcare professionals to save lives during this pandemic. Since WHO declared the COVID-19 outbreak as a pandemic, several studies have been conducted using Artificial Intelligence techniques to optimize these steps on clinical settings in terms of quality, accuracy and most importantly time. The objective of this study is to conduct a systematic literature review on published and preprint reports of Artificial Intelligence models developed and validated for screening, diagnosis and prognosis of the coronavirus disease 2019. We included 101 studies, published from January 1st, 2020 to December 30th, 2020, that developed AI prediction models which can be applied in the clinical setting. We identified in total 14 models for screening, 38 diagnostic models for detecting COVID-19 and 50 prognostic models for predicting ICU need, ventilator need, mortality risk, severity assessment or hospital length stay. Moreover, 43 studies were based on medical imaging and 58 studies on the use of clinical parameters, laboratory results or demographic features. Several heterogeneous predictors derived from multimodal data were identified. Analysis of these multimodal data, captured from various sources, in terms of prominence for each category of the included studies, was performed. Finally, Risk of Bias (RoB) analysis was also conducted to examine the applicability of the included studies in the clinical setting and assist healthcare providers, guideline developers, and policymakers.

Molecular mechanism of inhibition of COVID-19 main protease by ß-adrenoceptor agonists and adenosine deaminase inhibitors using in silico methods.

Novel coronavirus (COVID-19) responsible for viral pneumonia which emerged in late 2019 has badly affected the world. No clinically proven drugs are available yet as the targeted therapeutic agents for the treatment of this disease. The viral main protease which helps in replication and transcription inside the host can be an effective drug target. In the present study, we aimed to discover the potential of ß-adrenoceptor agonists and adenosine deaminase inhibitors which are used in asthma and cancer/inflammatory disorders, respectively, as repurposing drugs against protease inhibitor by ligand-based and structure-based virtual screening using COVID-19 protease-N3 complex. The AARRR pharmacophore model was used to screen a set of 22,621 molecules to obtain hits, which were subjected to high-throughput virtual screening. Extra precision docking identified four top-scored molecules such as +/--fenoterol, FR236913 and FR230513 with lower binding energy from both categories. Docking identified three major hydrogen bonds with Gly143, Glu166 and Gln189 residues. 100 ns MD simulation was performed for four top-scored molecules to analyze the stability, molecular mechanism and energy requirements. MM/PBSA energy calculation suggested that van der Waals and electrostatic energy components are the main reasons for the stability of complexes. Water-mediated hydrogen bonds between protein-ligand and flexibility of the ligand are found to be responsible for providing extra stability to the complexes. The insights gained from this combinatorial approach can be used to design more potent and bio-available protease inhibitors against novel coronavirus.Communicated by Ramaswamy H. Sarma.

Possible Role of Adenosine in COVID-19 Pathogenesis and Therapeutic Opportunities.

The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) requires urgent clinical interventions. Crucial clinical needs are: 1) prevention of infection and spread of the virus within lung epithelia and between people, 2) attenuation of excessive lung injury in Advanced Respiratory Distress Syndrome, which develops during the end stage of the disease, and 3) prevention of thrombosis associated with SARS-CoV-2 infection. Adenosine and the key adenosine regulators adenosine deaminase (ADA), adenosine kinase (ADK), and equilibrative nucleoside transporter 1 may play a role in COVID-19 pathogenesis. Here, we highlight 1) the non-enzymatic role of ADA by which it might out-compete the virus (SARS-CoV-2) for binding to the CD26 receptor, 2) the enzymatic roles of ADK and ADA to increase adenosine levels and ameliorate Advanced Respiratory Distress Syndrome, and 3) inhibition of adenosine transporters to reduce platelet activation, thrombosis and improve COVID-19 outcomes. Depending on the stage of exposure to and infection by SARS-CoV-2, enhancing adenosine levels by targeting key adenosine regulators such as ADA, ADK and equilibrative nucleoside transporter 1 might find therapeutic use against COVID-19 and warrants further investigation.