Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12.

COVID-19 patients have shown overexpressed serum levels of several pro-inflammatory cytokines, leading to a high mortality rate due to numerous complications. Also, previous studies demonstrated that the metronidazole (MTZ) administration reduced pro-inflammatory cytokines and improved the treatment outcomes for inflammatory disorders. However, the effect and mechanism of action of MTZ on cytokines have not been studied yet. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm. The interaction of MTZ with key cytokines was investigated using molecular docking studies. MTZ-analogues, and its structurally similar FDA-approved drugs were also virtually screened against interleukin-12 (IL-12). Moreover, their mechanism of inhibition regarding IL-12 binding to IL-12 receptor was investigated by measuring the change in volume and area. IL-12-metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses, indicating that the docking poses were reliable. The current study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.

The rs568408 variant in the IL-12A gene is associated with risk for COVID-19 in Iraqi patients.

Objectives: The objective of the current study was to check the link between potential polymorphism in IL12A rs568408 and the possible risk of COVID-19 in the Iraqi population. Materials and Methods: Allele specific-polymerase chain reaction (PCR) technique was carried out for genotyping and detection of IL12A rs568408 gene polymorphism in a case-control study of 125 severe COVID-19 cases and 60 controls. Patients were admitted to either Marjan medical city or Al-Sadeq hospital's COVID-19 wards between January and June 2022 in Iraq. The diagnosis of COVID-19 in each patient was confirmed by severe acute respiratory coronavirus 2-positive reverse transcription-PCR. Results: The distribution of both genotyping and allele frequencies of IL-12A rs568408 revealed significant differences between patients and control groups (P = 0.006 and P = 0.001, respectively). The IL12A rs568408 AA and AG variant genotypes were associated with a significantly increased risk of COVID-19 (odds ratio [OR] = 5.19, 95% confidence interval [CI]: 1.13-23.82; P = 0.034) and (OR = 2.39, 95% CI = 1.16-4.94, P = 0.018), respectively, compared with the wild-type GG homozygote. Conclusion: These findings indicate that IL12A rs568408 GA/AA variant may contribute to the risk of COVID-19. This study is the first report about the association of IL12A rs568408 with COVID-19.

Alteration of lipid profile, kidney functions, D-dimer and some anti- inflammatory parameters in samples of Iraqi patients with Covid-19

Objective: The Aim of our research was to look into the association between various biochemical indicators and COVID-19 infection in Baghdad, Iraq. Methods: From the 15th of March to the August 2022, a cohort of 45 people with positively COVID-19 and 45 healthy controls visited Al-Yarmouk Teaching Hospital in Baghdad, Iraq. All of the patients have been diagnosed with COVID-19 and are experiencing symptoms and indicators. Each of the patients and healthy controls had their whole blood samples taken to be analyzed for;Lipid profile (triglycerides, Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL) values) Kidney function test (Urea and Creatinine), by using an enzymatic method , Anti-inflammation parameters (INF-, TGF, Interleukin-12, and Interleukin 18), The (Biosours) ELISA kit was used to assess the results., and D-dimer was quantified using mini vidas kits donated by Bio Meriux-France. Results: The results showed that The majority of COVID-19 patients showed elevated lipid profiles and kidney function tests, as well as the anti-inflammatory parameters with increase the levels of D-dimer compared to healthy controls. Conclusion: The present study concludes that Covid-19 cause alteration in lipid profile, kidney functions, D-dimer and some anti-inflammatory parameters.

Effect of Convalescent Plasma Therapy on IL-10 and IL-12 Levels in COVID-19 Patients at Haji Surabaya General Hospital Randomly

Introduction: IL-12 and IL-10 are cytokines with different mechanisms in the pathogenesis of COVID-19. Differences in IL-12 and IL-10 levels in patients receiving convalescent plasma and non-convalescent plasma recipients need to be known because the total levels of IL-12 and IL-10 also determine the clinical condition of the patient. Materials and Methods: This study used 40 randomly selected blood serum samples with details of 20 samples of COVID-19 patients without convalescent plasma therapy and 20 samples of COVID-19 patients. The COVID-19 patients at the Haji General Hospital in Surabaya provided the patient serum that was utilized. Results: Based on the findings, there were differences in IL-10 levels between the control group and convalescent plasma therapy recipients (P<0.05). On IL-12 levels had no difference between the control and treatment groups (P>0.05). Conclusion: According to statistical estimates, convalescent plasma treatment made a difference to IL-10 but not IL-12 levels in COVID-19 patients. © 2023 UPM Press. All rights reserved.

Corrigendum: Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

[This corrects the article DOI: 10.3389/fimmu.2023.1101808.].

Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

Introduction: Despite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. Methods: Here, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. Results: Differential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. Discussion: Aberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.

Early IFNß secretion determines variable downstream IL-12p70 responses upon TLR4 activation.

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon ß (IFNß) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNß as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNß-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNß in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.

Infection of Bone Marrow-Derived Mesenchymal Stem Cells with Virulent Newcastle Disease Virus Maximizes Cytokine Production: A Step Toward vNDV Immunotherapy

Newcastle Disease (ND) vaccines are being used for more than 7 decades, the disease is still a major challenge for poultry industry both locally and internationally. ND frequently emerges in highly vaccinated flocks causing high economic losses without specific treatment. Mesenchymal stem cells (MSCs) are a group of pluripotent cells with multiple biotechnology applications, including but not limited to tissue genesis, tissue repair, hematopoiesis, and immune modulation. Therapeutic strategies based on the usage of stem cells includes the cells either themselves or their secretions (secretome), which has recently shown ability to inhibit SARS-CoV2 replication in-vitro. In this study, MSCs were prepared from the bone marrow of native Egyptian Fayoumi chicken. The MSC with the surface marker CD105 (CD105+) were magnetically separated and infected with virulent Newcastle disease virus (vNDV). The virusinduced multiple changes at the cellular and ultrastructural level in the infected cells, and it was able to maximize the production of interferon-gamma (IFNγ) and interleukin 2 (IL2), interleukin 6 (IL6) and interleukin 12 (IL12). In conclusion, our data represent a preliminary step in vNDV immunotherapy where MSCs media could be used for the treatment of vNDV in infected flocks © 2022 by the authors. Licensee ResearchersLinks Ltd, England, UK

Vaccination Recommendations for Psoriasis and Atopic Dermatitis Patients on Biologic Therapy: A Practical Guide

Novel biologic therapies have revolutionized the treatment of psoriasis and atopic dermatitis. Although they are generally safe, they are immunomodulatory and therefore unique considerations apply in regards to infections and vaccine administration. This review aims to provide a clear and practical guide for dermatologists or other healthcare providers to reference when caring for psoriasis or atopic dermatitis patients being treated with biologic therapies using currently available guidelines and clinical data. Vaccinations for approved biologics including TNF alpha, IL-12/23, IL-23, IL-17, and IL-4/13 inhibitors will be discussed, with a special note on current COVID-19 vaccination recommendations.

Angiotensin-converting enzyme-2 and interleukin-12 serum level as indicator to severity between COVID-19 patients

The Coronavirus, one of the most rapidly spreading respiratory viruses, caused a worldwide epidemic that killed about six million people. This led to the fast development of several vaccines and drugs to reduce disease severity and speed patient recovery. This study aimed to identify the serum levels of each of the angiotensin-converting enzyme-2 and interleukin-12 .The severity of infection in coronavirus COVID-19 patients was compared to immune levels of these cytokines and receptors in the different cases of COVID-19 patients. This case-control study included 90 blood samples from COVID-19 patients with ages between 15-80 years. Results revealed that the serum levels of both angiotensin-converting enzyme-2 ( ACE-2) and interleukin-12 (IL-12) were measured in COVID-19 patients and the results were compared using an independent T-test, it was found that their levels for interleukin-12 revealed a significant difference (P ≤0.05) in the serum levels of severe cases when compared with non-severe cases. There was an increase in the serum level of IL-12 in severe cases was 33.340 ng/L, in the serum level and in non-severe cases was 20.913 ng/L. ( P ≤0.000), and for angiotensin-converting enzyme-2 this study revealed a significant difference in ACE-2 serum levels in severe cases (P ≤0.05) when compared with the non-severe cases of patients with COVID 19. The serum level of ACE-2 in severe cases was 11.023 ng/ml, and in non-severe cases, it was 5.443ng/ml ( P ≤0.000). It was concluded that the emerging coronavirus works to create an immune storm represented by raising the serum levels of both ACE-2 and IL-12 that contribute to the damage to the alveoli in severely COV-19 patients.

Influenza Virus-like Particle-Based Hybrid Vaccine Containing RBD Induces Immunity against Influenza and SARS-CoV-2 Viruses.

Several approaches have produced an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since millions of people are exposed to influenza virus and SARS-CoV-2, it is of great interest to develop a two-in-one vaccine that will be able to protect against infection of both viruses. We have developed a hybrid vaccine for SARS-CoV-2 and influenza viruses using influenza virus-like particles (VLP) incorporated by protein transfer with glycosylphosphatidylinositol (GPI)-anchored SARS-CoV-2 RBD fused to GM-CSF as an adjuvant. GPI-RBD-GM-CSF fusion protein was expressed in CHO-S cells, purified and incorporated onto influenza VLPs to develop the hybrid vaccine. Our results show that the hybrid vaccine induced a strong antibody response and protected mice from both influenza virus and mouse-adapted SARS-CoV-2 challenges, with vaccinated mice having significantly lower lung viral titers compared to naive mice. These results suggest that a hybrid vaccine strategy is a promising approach for developing multivalent vaccines to prevent influenza A and SARS-CoV-2 infections.

Disseminated multidrug-resistant tuberculosis and SARS-CoV-2 co-infection in a child with IL-12Rß1 deficiency.

Mendelian Susceptibility to Mycobacterial Disease describes a spectrum of inherited defects, of which complete deficiency of the interleukin-12 receptor ß subunit 1 (IL-12Rß1) is the most common cause. This condition results in a predisposition to severe disease caused by mycobacteria. We report a case of disseminated multidrug-resistant tuberculosis with extensive central nervous system affection with SARS-CoV-2 co-infection, in a 4-year-old child with IL-12Rß1 complete deficiency.

Research on the mechanism of berberine in the treatment of COVID-19 pneumonia pulmonary fibrosis using network pharmacology and molecular docking.

Purpose Pulmonary fibrosis caused by COVID-19 pneumonia is a serious complication of COVID-19 infection, there is a lack of effective treatment methods clinically. This article explored the mechanism of action of berberine in the treatment of COVID-19 (Corona Virus Disease 2019, COVID-19) pneumonia pulmonary fibrosis with the help of the network pharmacology and molecular docking. Methods We predicted the role of berberine protein targets with the Pharmmapper database and the 3D structure of berberine in the Pubchem database. And GeneCards database was used in order to search disease target genes and screen common target genes. Then we used STRING web to construct PPI interaction network of common target protein. The common target genes were analyzed by GO and KEGG by DAVID database. The disease-core target gene-drug network was established and molecular docking was used for prediction. We also analyzed the binding free energy and simulates molecular dynamics of complexes. Results Berberine had 250 gene targets, COVID-19 pneumonia pulmonary fibrosis had 191 gene targets, the intersection of which was 23 in common gene targets. Molecular docking showed that berberine was associated with CCl2, IL-6, STAT3 and TNF-α. GO and KEGG analysis reveals that berberine mainly plays a vital role by the signaling pathways of influenza, inflammation and immune response. Conclusion Berberine acts on TNF-α, STAT3, IL-6, CCL2 and other targets to inhibit inflammation and the activation of fibrocytes to achieve the purpose of treating COVID-19 pneumonia pulmonary fibrosis.

Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: The serological responses after severe acute respiratory syndrome coronavirus 2 vaccination may be attenuated in immunocompromised individuals. The study aimed to systematically evaluate the seroconversion rates after complete vaccination for coronavirus disease 2019 (COVID-19) in patients with inflammatory bowel disease (IBD). METHODS: Electronic databases were searched to identify studies reporting response to COVID-19 vaccination in IBD. Pooled seroconversion rates after complete vaccination were calculated. Subgroup analysis for vaccine types was also performed. Pooled seroconversion rates for various drugs or classes were also estimated. The pooled rates of breakthrough infections in vaccinated IBD patients were estimated. The pooled neutralization rates after complete vaccination were also estimated. The studies reporting durability of titers were systematically assessed. RESULTS: A total of 46 studies were included. The pooled seroconversion rate for complete vaccination (31 studies, 9447 patients) was 0.96 (95% confidence interval [CI], 0.94-0.97; I2 = 90%). When compared with healthy control subjects, the pooled relative risk of seroconversion was lower (0.98; 95% CI, 0.98-0.99; I2 = 39%). The pooled seroconversion rates were statistically similar among various drug classes. The pooled positivity of neutralization assays (8 studies, 771 participants) was 0.80 (95% CI, 0.70-0.87; I2 = 82%). The pooled relative risk of breakthrough infections in vaccinated IBD patients was similar to vaccinated control subjects (0.60; 95% CI, 0.25-1.42; I2 = 79%). Most studies suggested that titers fall after 4 weeks of COVID-19 vaccination, and the decay was higher in patients on anti-tumor necrosis factor alone or combination with immunomodulators. An additional dose of COVID-19 vaccine elicited serological response in most nonresponders to complete vaccination. CONCLUSIONS: Complete COVID-19 vaccination is associated with seroconversion in most patients with IBD. The decay in titers over time necessitates consideration of additional doses in these patients.

Novel Therapeutic Approaches to Psoriasis and Risk of Infectious Disease.

Psoriasis is a chronic immune-mediated skin and joint disease, with a plethora of comorbidities, characterized by a certain genetic predisposition, and a complex pathogenesis based on the IL-23/IL-17 pathway. There is no doubt that the patients affected by psoriasis are more susceptible to infections as well as that the risk of infection is higher in psoriatic subjects than in the general population. The advent of biotechnological agents on the therapeutic arsenal actually available for the treatment of moderate-to-severe patients, given the fact that the severity of the disease is a predictor of the level of infectious risk, has raised the question of whether these 'new' drugs could be considered a safer option and how they can be used in selected cases. Old and newer strategies in cases of chronic infectious conditions are reviewed under the light of clinical trials and other studies present in literature.

Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposure.

Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. MAIN FINDINGS: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.

Early Differences in Cytokine Production by Severity of Coronavirus Disease 2019.

Most patients with coronavirus disease 2019 (COVID-19) experience asymptomatic disease or mild symptoms, but some have critical symptoms requiring intensive care. It is important to determine how patients with asymptomatic or mild COVID-19 react to severe acute respiratory syndrome coronavirus 2 infection and suppress virus spread. Innate immunity is important for evasion from the first virus attack, and it may play an important role in the pathogenesis in these patients. We measured serum cytokine levels in 95 patients with COVID-19 during the infection's acute phase and report that significantly higher interleukin 12 and 2 levels were induced in patients with asymptomatic or mild disease than in those with moderate or severe disease, indicating the key roles of these cytokines in the pathogenesis of asymptomatic or mild COVID-19.

Immunosuppressive drugs for patients with psoriasis during the COVID-19 pandemic era. A review.

The COVID-19 has been spreading around the world. Concerns about the safety of administration of immunosuppressive drugs have been raised for treatment of psoriasis (PSO), and there is insufficient evidence for the risk of COVID-19 infection for psoriatic patients using these drugs, so we did a review, focusing on the risk of overall infection associated with the most commonly used immunosuppressive drugs, such as methotrexate, biologics, cyclosporin, Janus kinase inhibitors for the treatment of PSO. The data on the effect of immunosuppressive drugs on this virus may be ever-changing and remains to be clear. We recommend the initiation and continuation of low-risk immunomodulating drugs, such as Interleukin (IL)-17, IL-12/23, and IL-23 inhibitors, for treatment of PSO during COVID-19 era. For psoriatic patients with comorbidities switching to safer modalities such as systemic retinoids, apremilast, and home phototherapy is recommended. Immunosuppressive drugs should be withheld in psoriatic patients with the COVID-19 infection.