Myocarditis due to COVID-19 in a pediatric patient

Current knowledge about the COVID-19 pandemic is still limited, especially in the pediatric age group. So far, children are considered to be a minimally affected population;however, physicians from different parts of the world have recognized a new pediatric multi-systemic inflammatory syndrome, that provokes a multiple organ dysfunction, from which the heart is not exempted. The direct action of the virus on myocardial cells, as well as the cytokines storm -triggered by the infection- are responsible for the myocarditis developed in these patients. In this article a case with criteria of myocarditis associated with COVID-19 is described. Achieving an early diagnosis ofmyocarditis secondary to SARS-CoV-2 infection in the current epidemiological context allows a correct and timely therapeutic approach, avoiding the torpid evolution and fatal outcome of this disease, as well as other long-term complications.

Overview of interleukin-6 levels in COVID-19 (coronavirus disease 2019) patients at Dr. M. Djamil General Hospital, Padang, Indonesia

Background: COVID-19 infection can cause an exaggerated immune response. This immune response is associated with an increase in proinflammatory cytokines, especially interleukin-6 (IL-6). High IL-6 levels are found in the acute stage of COVID-19, and IL-6 can induce an excessive humoral inflammatory response. This study aimed to provide an overview of IL-6 levels in coronavirus disease 2019 (COVID-19) patients at Dr. M. Djamil General Hospital, Padang, Indonesia. Methods: Descriptive observational study of 102 research subjects. Observations on sociodemographic, clinical, and laboratory data were carried out in this study. Univariate analysis was carried out using SPSS version 25. Results: Patients with symptom onset <7 days had higher IL-6 levels than those with an onset of more than 7 days. Patients with critical degrees have the highest IL-6 levels compared to moderate and severe degrees. Patients with more than 1 comorbid had higher IL-6 levels than patients who had no comorbid or only had 1 comorbid. Patients with <21 days of treatment had higher IL-6 levels than patients with more than 21 days of treatment. Conclusion: COVID-19 patients at Dr. M. Djamil General Hospital, Padang, Indonesia, with an onset of less than 7 days, a critical degree, and more than 1 comorbidity have higher IL-6 levels.

INFLAMMATORY RESPONSE AND ITS CORRECTION IN FORMING A HOST RESPONSE TO EXPOSURE TO ADVERSE ENVIRONMENTAL FACTORS

This study systematically review knowledge about the mechanisms of formation of an inflammatory reaction under the influence of biological, physical, and chemical factors, their similarities and differences, and possible methods of pharmacological correction of pathological conditions associated with excessive activation. The effect of adverse environmental factors, such as biological, physical, and chemical factors, causes a systemic response, which is aimed at maintaining homeostasis and is caused, among other things, by a coordinated reaction of the immune system. Phlogogenic agents result in the activation and regulation of the inflammatory response, which is formed by cellular and humoral components of innate immunity. The activation of innate immunity is characterized by a rapid host response, which diminishes following the elimination of "foreign” invaders, endogenous killer cells, and neogenesis. Depending on the nature of the active factors (biopathogens, allergens, toxins, ionizing radiation, etc.), the mechanisms of immune response arousal have unique features mainly originating from the differences in the recognition of specific molecular patterns and "danger signals” by different receptors. However, inflammatory mediators and inflammatory response patterns at the systemic level are largely similar even under widely different triggers. Inflammation, having evolved as an adaptive reaction directed at the immune response, can lead to the development of chronic inflammation and autoimmune diseases due to a mismatch in mechanisms of its control. A "failure” in the regulation of the inflammatory process is the excessive activation of the immune system, which leads to the cytokine release syndrome (hypercytokinemia, or "cytokine storm”) and can cause self-damage (destruction) of tissues, multiple-organ failure, sepsis, and even death. Modern advances in the study of the pathogenetic bases of the inflammatory response are suggested, such as pharmacological correction using pattern recognition receptor antagonists, pro-inflammatory cytokine inhibitors, or blocking of key control genes or signaling pathways. All rights reserved © Eco-Vector, 2022.

Controversial role of neutrophilic granulocytes in the immunopathogenesis of COVID-19: correlation with imbalance of pro-inflammatory neutrophil-associated cytokines and interferon alpha deficiency.

Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

PROTEIN SIGNALING MOLECULES AFFECTING THE DEVELOPMENT OF INNATE IMMUNITY MECHANISMS

The principle protein molecules (interferon gene stimulator, adapter proteins, B-cell lymphoma 2 proteins, zinc-finger antiviral protein, and others), mechanisms of apoptosis, necroptosis, perforation of plasma membranes with kinase-like proteins of a mixed line, and ribonucleic acid neutralization, which ensure the development of innate immunity, are described. The main defense mechanisms that viruses have developed at the various stages of evolution are considered. The features of the development of the mechanisms of apoptosis and autophagy in a new coronavirus infection, which are associated with increased secretion of pro-inflammatory cytokines and chemokines, leading to severe damage to host cells, are given. It has been found that serum levels of several proteins formed during autophagy caused by SARS-CoV-2 can be used to predict disease severity. These include a protein associated with microtubules 1A/1B, a protein of sequestoma 1, and a protein of the cellular system of autophagy ― beclin-1. The multifaceted role of interferons in the inhibition of viral infection and the features of the violation of the activating functions of interferons in coronavirus infection are described. The article can be used under the CC BY-NC-ND 4.0 license © Authors, 2022.

Psychosomatic state and laboratory parameters of COVID-19 convalescent patients.

Objective. To evaluate some parameters of the psychosomatic state, cytokine levels (IL-6, IL-8, IL-17A), and free radical status (levels of nitrates and nitrites, antioxidant plasma activity) in convalescent patients after severe COVID-19. Patients and methods. We examined 64 patients who had severe COVID-19 and underwent either a 30-35-day course of inpatient rehabilitation after their discharge from a hospital for infectious diseases or a 60-65-day course of outpatient rehabilitation at the Ambulatory Center of Nalchik, Clinical Hospital No 1. Results. We surveyed patients after severe COVID-19 and found that they required a long rehabilitation. Many of them reported asthenic syndrome, psycho-emotional disorders, and other complaints upon discharge from the hospital. Serum levels of proinflammatory cytokines remained high in patients after severe COVID-19 even 30-35 days following their discharge (p < 0.05). Serum levels of IL-6, IL-8, nitrites, and nitrates remained elevated on days 60-65 following discharge (p < 0.05), despite comprehensive therapy in a rehabilitation department. Plasma antioxidant activity was reduced, whereas IL-17A level normalized by this time. Conclusion. Our findings suggest that currently used rehabilitation measures for COVID-19 are insufficient. Adequate rehabilitation of convalescent COVID-19 patients requires proper monitoring of their immune system condition, as well as new effective methods for immune correction and restoration of their psychoemotional status after the acute phase of the disease.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Immunogenetic landscape of COVID-19 infections related neurological complications

The human leukocyte antigen (HLA) is a critical component of antigen presentation and plays crucial role in conferring differential susceptibility and severity of diseases caused by viruses such as COVID-19. The immunogenetic profile of populations, BCG vaccination status, and a host of lifestyle factors might contribute to the observed variations in mortality rates due to COVID-19. These genetic, epigenetic, and environmental factors could widely influence infection dynamics and immune responses against COVID-19. The aim of this review is to provide an update on HLA association with SARS-CoV-2 infection in global populations and to highlight the possible neurological involvements. We also set out to explore the HLA immunogenetic markers related to COVID‐19 infections that can be used in screening high‐risk individuals for personalized therapies and in community-based vaccine development. © 2023 Elsevier Inc. All rights reserved.

LABORATORY PARAMETERS ASSOCIATED WITH CODIV-19 CYTOKINE STORM DEVELOPMENT

BackgroundSince the end of 2019, physicians became more and more familiar with SARS-CoV-2 infection and the variety of forms in which it may present and evolve. There have been a lot of studies trying to understand and predict why some patients develop a dysregulation of the immune response, with an exaggerated release of pro-inflammatory cytokines, called cytokine storm (1–4). There is scarce evidence in Romania regarding this aspect.ObjectivesThis study aims to verify the correlation between some laboratory parameters and the development of cytokine storm in SARS-CoV-2 infection in a cohort of over 200 patients admitted in a tertiary hospital from Romania, hoping that early identification of these risk factors of progression to a severe form of the disease can bring considerable benefit to patient care.MethodsThis is an analytical, observational, case-control study which includes 219 patients (all COVID-19 hospitalized patients on the Internal Medicine 3 department of Colentina Clinical Hospital, Bucharest, from 01 March 2020 to 1 April 2021). A series of data were collected, the laboratory parameters being the most important, including: albumin, lymphocyte (percentage), neutrophil (absolute value), aspartate aminotransferase, alanine aminotransferase, D-dimers, lactate dehydrogenase (LDH), anionic gap, chloremia, potassium and the BUN:creatinine ratio (BUN - blood urea nitrogen). The laboratory parameters used for the statistical analysis represent the average values of the first 7 days of hospitalization for those who did not develop cytokine storm, respectively until the day of its development, for the others. Patients were classified into these groups, those who developed cytokine storm, respectively those who did not have this complication taking into account the clinical and paraclinical criteria (impairment of respiratory function, elevations of certain markers 2-3 times above the upper limit of normal, those who died as a result of SARS-CoV-2 infection). Then Binary Univariate Logistic Regression was applied in order to verify the individual impact of every laboratory parameter on cytokine storm development. Furthermore, all laboratory parameters were subsequently included in the multivariate analysis, using the backward selection technique to achieve a model as predictive as possible.ResultsWe mention that the analysis of demographic data was previously performed, showing no statistically significant relationship between patient gender, age or comorbidities (history of neoplasm, lung diseases, cardiac pathology, obesity, type II diabetes and hypertension) and their evolution to cytokine storm. After performing binary univariate logistic regression we concluded that 8 of the 13 laboratory analyzes have had a significant change between groups (ferritin, PCR, albumin, Lymphocyte, Neutrophils, TGO, LDH, BUN:creatinine ratio). Only 150 patients were then included in the multivariate analysis. After the analysis, some of the variables lost their statistical significance, the final model including C-reactive protein, neutrophilia, LDH, ferritin and the BUN:creatinine ratio. This model correctly predicts the development of cytokine storm in 88% of cases.ConclusionHigh C-reactive protein, neutrophilia, LDH, ferritin and the BUN:creatinine ratio are risk factors for cytokine storm development and should be monitored in all COVID-19 patients in order to predict their evolution.References[1]Pedersen SF et all. SARS-CoV-2: A storm is raging[2]Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression[3]Hu B et al. The cytokine storm and COVID-19.[4]Caricchio R et al. Preliminary predictive criteria for COVID-19 cytokine stormAcknowledgements:NIL.Disclosure of InterestsNone Declared.

Pharmacological Properties and Safe Use of 12 Medicinal Plant Species and Their Bioactive Compounds Affecting the Immune System

This paper presents raw plant materials and their characteristic compounds which may affect the immune system. Plant-derived agents in specific doses affect the body's non-specific, antigen-independent defense system. They have immunostimulatory effects on the entire immune regulatory system. They can enhance the immune response through various factors such as macrophages, leukocytes, and granulocytes, as well as through mediators released by the cellular immune system. This paper was inspired by the threats caused by the COVID-19 pandemic. The proper functioning of the immune system is important in limiting the effects of viral infection and restoring the normal functioning of the body. This paper also emphasizes the importance of the skillful use of plant immunostimulants by potential patients, but also by those who prescribe drugs. It is important not only to choose the right plant drug but above all to choose the correct dose and duration of treatment.

The pathogenesis of COVID-19: Hypercoagulation and D-dimer in thrombotic complications

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a new coronavirus disease (COVID-19), which is highly contagious and its pathogenesis has not been fully elucidated. In COVID-19, the inflammation and blood coagulation systems are excessively activated. SARS-CoV-2 damages endothelial cells and pneumocytes, which leads to disruption of hemostasis in SARS. Thromboembolism is the main cause of mortality in patients with COVID-19. Clots, including pulmonary embolism (PE) and deep vein thrombosis (DVT), ranging from minor to fatal complications of the SARS-CoV-2 infection are known. Individuals with pre-existing diseases are more susceptible to the development of blood clots and poor outcomes. High levels of circulating cytokines and D-dimer (DD) are influential biomarkers of poor outcomes in COVID-19. The latter occurs as a result of hyperfibrinolysis and hypercoagulation. Plasmin is a key player in fibrinolysis and is involved in the cleavage of many viral envelope proteins, including SARS-CoV. Due to this function penetration of viruses into the host cell occurs. In addition, plasmin is involved in the pathophysiology of acute respiratory distress syndrome (ARDS) in SARS and promotes the secretion of cytokines, such as IL-6 and TNF, from activated macrophages. The focus of existing treatment to alleviate fibrinolysis in patients with COVID-19 is the use of systemic fibrinolytic therapy given thrombotic pathology in severe forms of COVID-19 which may lead to death. However, fibrinolytic therapy may be harmful in the advanced stages of COVID-19, when the status of disseminated intravascular coagulation (DIC) changes from suppressed fibrinolysis to its enhancement during the progression of the disease. This narrative review aims to elucidate the pathogenesis of COVID-19, which will further help in precise diagnosis and treatment. Take-home message: The COVID-19 virus disrupts haemostasis and thromboembolism by over activating the inflammation and blood coagulation systems. High levels of cytokines and D-dimer are indicators of pre-existing diseases and blood clots. Systemic fibrinolytic treatment can reduce severe fibrinolysis in COVID-19, which is caused by plasmin. In the late stages of DIC, when fibrinolysis increases, it may be dangerous. To improve therapy and results, understanding COVID-19 pathogenicity is critical. © 2023 by the authors.

Technological Mapping of Plant-Derived Immunomodulator Drugs: A Patent-Guided Overview about Species and its Main Compounds

Research on natural products has investigated and employed many (bio)technologies to find out plant active fractions and optimize extraction and isolation of molecules looking for innovative clinical therapies for several clinical conditions, as well as immune-related diseases. Indeed, the world incidence and prevalence of autoimmune diseases have increased over the last years, while immune therapy has arisen as a new promising tool for cancer treatment. Also, in the emergence of COVID-19 pandemic, immunomodulation has been proved effective to reduce the "cytokine storm” and avoid worsening the clinical condition of patients in the acute stage of respiratory syndrome. These health issues have also driven the search for new immunomodulatory compounds. In this context, prospective analysis is an important tool to identify the most relevant opportunities and demands in research and development (R&D) of pharmaceutical medicines, including substances able to modulate immune and inflammatory responses. In addition, prospection allows understanding the landscape of immunomodulatory plant-derived drugs and the associated technologies described in patents. This chapter employed the descriptors "Immunomodulator*” and "drug” and "plant” in search strategy to map the technological potential of immunomodulatory herbal drugs, using the software VantagePoint, Cortellis Competitive Intelligence, and Orbit Intelligence, respectively. The results provided quantitative data and technological indicators to drive future strategies for the development of these drugs. In conclusion, the most cited plant species in patents expressing molecules with immunomodulatory properties were Curcuma longa, Moringa oleifera, Remirea maritima, Maytenus ssp., Angelica sp., Fagopyrum esculentum, as well as plants from the families Leguminosae, Rosaceae, Iridaceae, Moraceae, and Amaranthaceae, among others. The main chemical classes implicated in immunomodulation were xanthones, coumarins, flavonoids, and (tri)terpenes. The technological mapping also showed that in the year 2002, there was an increased deposit of patents, reaching the highest peak in 2009 with 56 patents. Nowadays, the United States is the country with the biggest number of patents, followed by Canada, Australia, and Korea. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.

Inhalation Vaccine Development

Numerous advantages to inhalation vaccines Vaccines delivered via inhalation enable targeting of the respiratory tract mucosa and generation of both humoral and cell-mediated immunity, according to Pierre A. Morgon, executive vice president. [...]inhaled vaccines delivered as liquids using nebulizers can potentially be administered with lower requirement for extensive healthcare infrastructure or as many trained healthcare personnel within an immunization centre (2). Researchers at McMaster University, for instance, have shown inhalation of a tuberculosis vaccine to be more effective than delivery via nasal sprays, because the vaccine penetrates much deeper into the airway (8). Because inhaled vaccines provide local immunity to the respiratory tract, they are seen to be ideal solutions for interrupting the spread of viruses with high transmission rates and the potential to lead to global pandemics (9). Beyond these two approaches, there are inhalation vaccines under development based on attenuated influenza virus, parainfluenza virus (PIV) 5, lentiviruses, Newcastle disease virus (NDV), and vesicular stomatitis virus (VSV);bacterium vectors, nucleic acids (messenger RNA, DNA), and protein subunits (3).

Pathogenetic therapy of COVID-19: focus on glucocorticoids

The problem of preventing excessive production of pro-inflammatory cytokines in the case of COVID-19 remains unre-solved. The use of steroids in the treatment of coronavirus pneumonia remains controversial. To date, there is insufficient literature data for the routine use of steroids in COVID-19 intensive care programs, and this issue remains the subject of continuous research and endless debate. The review of the scientific literature focuses on one of the areas of pathogenetic therapy for COVID-19 — the pre- vention and elimination of hyperproduction of pro-inflammatory cytokines using glucocorticoid drugs. The review presents modern international recommendations on the use of glucocorticoid drugs in severe COVID-19, examines the pathogenetic mechanisms of their action and side effects. © 2022. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.

Repurposing Anti-inflammatory Agents in the Potential Treatment of SARS-COV-2 Infection

SARS-Cov-2 is the novel coronavirus with predominantly inflammatory pathogenesis. The inflammation can be initiated and finally aggravated through a number of interconnected inflammatory pathways such as NF-κB, JAK-STAT, MAPK TLRs, iNOS, COX, etc. In the current chapter, these signaling pathways which instigate inflammation in SARS-Cov-2 are discussed. Moreover, drugs inhibiting these pathways in other inflammatory conditions or diseases are either in clinical use as COVID-19 therapy, or have been proposed as potential future therapeutic interventions in this chapter. These repurposing strategies can halt the COVID-19 symptoms as well as disease progression. This was demonstrated by establishing a link between the regulatory actions of these molecules or drugs in the inflammatory pathway like cytokine release against the COVID-19-related inflammatory havoc. Hence, the chapter will provide profound insights in the inflammatory control pertaining to COVID-19 severity and complications. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.

Evaluation of Immune Nanoparticles for Rapid and Non-Specific Activation of Antiviral and Antibacterial Immune Responses in Cattle, Swine, and Poultry.

Given the rapid potential spread of agricultural pathogens, and the lack of vaccines for many, there is an important unmet need for strategies to induce rapid and non-specific immunity against these viral and bacterial threats. One approach to the problem is to generate non-specific immune responses at mucosal surfaces to rapidly protect from entry and replication of both viral and bacterial pathogens. Using complexes of charged nanoparticle liposomes with both antiviral and antibacterial toll-like receptor (TLR) nucleic acid ligands (termed liposome-TLR complexes or LTC), we have previously demonstrated considerable induction of innate immune responses in nasal and oropharyngeal tissues and protection from viral and bacterial pathogens in mixed challenge studies in rodents, cattle, and companion animals. Therefore, in the present study, we used in vitro assays to evaluate the ability of the LTC immune stimulant to activate key innate immune pathways, particularly interferon pathways, in cattle, swine, and poultry. We found that LTC complexes induced strong production of type I interferons (IFNα and IFNß) in both macrophages and leukocyte cultures from all three species. In addition, the LTC complexes induced the production of additional key protective cytokines (IL-6, IFNγ, and TNFα) in macrophages and leukocytes in cattle and poultry. These findings indicate that the LTC mucosal immunotherapeutic has the capability to activate key innate immune defenses in three major agricultural species and potentially induce broad protective immunity against both viral and bacterial pathogens. Additional animal challenge studies are warranted to evaluate the protective potential of LTC immunotherapy in cattle, swine, and poultry.

Pro- and Anti-Inflammatory Prostaglandins and Cytokines in Humans: A Mini Review.

Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFß families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some cases of COVID-19 infection. Cytokines such as interferon and hematopoietic growth factor have been used as therapy. Alternatively, the inhibition of cytokine functions has been largely developed using anti-interleukin or anti-TNF monoclonal antibodies in the treatment of sepsis or chronic inflammation.

Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.

Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of Chymase, Tryptase, and IL-1ß from Human Mast Cells, Augmented by IL-33.

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin-converting enzyme 2 (ACE2) and results in the production of multiple proinflammatory cytokines, especially in the lungs, leading to what is known as COVID-19. However, the cell source and the mechanism of secretion of such cytokines have not been adequately characterized. In this study, we used human cultured mast cells that are plentiful in the lungs and showed that recombinant SARS-CoV-2 full-length S protein (1-10 ng/mL), but not its receptor-binding domain (RBD), stimulates the secretion of the proinflammatory cytokine interleukin-1ß (IL-1ß) as well as the proteolytic enzymes chymase and tryptase. The secretion of IL-1ß, chymase, and tryptase is augmented by the co-administration of interleukin-33 (IL-33) (30 ng/mL). This effect is mediated via toll-like receptor 4 (TLR4) for IL-1ß and via ACE2 for chymase and tryptase. These results provide evidence that the SARS-CoV-2 S protein contributes to inflammation by stimulating mast cells through different receptors and could lead to new targeted treatment approaches.

Clinical characteristics and host immunity responses of SARS-CoV-2 Omicron variant BA.2 with deletion of ORF7a, ORF7b and ORF8.

BACKGROUND: The pathogenicity and virulence of the Omicron strain have weakened significantly pathogenesis of Omicron variants. Accumulating data indicated accessory proteins play crucial roles in host immune evasion and virus pathogenesis of SARS-CoV-2. Therefore, the impact of simultaneous deletion of accessory protein ORF7a, ORF7b and ORF8 on the clinical characteristics and specific immunity in Omicron breakthrough infected patients (BIPs) need to be verified. METHODS: Herein, plasma cytokines were identified using a commercial Multi-cytokine detection kit. Enzyme-linked immunosorbent assay and pseudovirus neutralization assays were utilized to determine the titers of SARS-CoV-2 specific binding antibodies and neutralizing antibodies, respectively. In addition, an enzyme-linked immunospot assay was used to quantify SARS-CoV-2 specific T cells and memory B cells. RESULTS: A local COVID-19 outbreak was caused by the Omicron BA.2 variant, which featured a deletion of 871 base pairs (∆871 BA.2), resulting in the removal of ORF7a, ORF7b, and ORF8. We found that hospitalized patients with ∆871 BA.2 had significantly shorter hospital stays than those with wild-type (WT) BA.2. Plasma cytokine levels in both ∆871 BA.2 and WT BA.2 patients were within the normal range of reference, and there was no notable difference in the titers of SARS-CoV-2 ancestor or Omicron-specific binding IgG antibodies, neutralizing antibody titers, effector T cells, and memory B cells frequencies between ∆871 BA.2 and WT BA.2 infected adult patients. However, antibody titers in ∆871 BA.2 infected adolescents were higher than in adults. CONCLUSIONS: The simultaneous deletion of ORF7a, ORF7b, and ORF8 facilitates the rapid clearance of the BA.2 variant, without impacting cytokine levels or affecting SARS-CoV-2 specific humoral and cellular immunity in Omicron-infected individuals.

Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation.

Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that upon phagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turn mediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF. Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrin-mediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present study describes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells. These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which may contribute to tissue damage and severe disease.