scholarly journals A zebrafish model of COVID-19-associated cytokine storm syndrome reveals differential proinflammatory activities of Spike proteins of SARS-CoV-2 variants of concern.

2021 ◽  
Author(s):  
Sylwia D Tyrkalska ◽  
Alicia Martinez-Lopez ◽  
Ana B Arroyo ◽  
Francisco J Martinez-Morcillo ◽  
Sergio Candel ◽  
...  
Keyword(s):  
Cytokine Storm ◽  
Zebrafish Model ◽  
Angiotensin Converting Enzyme 2 ◽  
Life Threatening ◽  
Proinflammatory Activity ◽  
Proinflammatory Role ◽  
Emergency Myelopoiesis ◽  
Short Time ◽  
Protein Variants

The sudden and unexpected appearance of the COVID-19 pandemic turned the whole world upside down in a very short time. One of the main challenges faced has been to understand COVID-19 patient heterogeneity, as a minority develop life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). Using the unique advantages of the zebrafish model we report here the proinflammatory role of Spike (S) proteins from different SARS-CoV-2 variants of concern after injection into the hindbrain ventricle, a cavity filled with cerebrospinal fluid to which immune cells can be easily recruited and that mimics the alveolar environment of the human lung. We found that wild type/Wuhan variant S1 (S1WT) protein promoted neutrophil and macrophage recruitment, local and systemic hyperinflammation, emergency myelopoiesis, and hemorrhages. In addition, S1γ protein was more proinflammatory and S1δ was less proinflammatory than S1WT and, strikingly, Sβ promoted delayed and long-lasting inflammation. Pharmacological inhibition of the canonical inflammasome robustly alleviated S1 protein-induced inflammation and emergency myelopoiesis. In contrast, genetic inhibition of angiotensin-converting enzyme 2 strengthened the proinflammatory activity of S1, and the administration of angiopoietin (1-7) fully rescued S1-induced hyperinflammation and hemorrhages. These results shed light into the mechanisms orchestrating the COVID-19-associated CSS and the host immune response to different SARS-CoV-2 S protein variants.

scholarly journals Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence

2021 ◽  
Vol 22 (6) ◽  
pp. 3059
Author(s):  
Corrado Pelaia ◽  
Cecilia Calabrese ◽  
Eugenio Garofalo ◽  
Andrea Bruni ◽  
Alessandro Vatrella ◽  
...  
Keyword(s):  
Review Article ◽  
Lung Damage ◽  
Current Evidence ◽  
Therapeutic Effects ◽  
Cytokine Storm ◽  
Future Perspectives ◽  
Pathogenic Role ◽  
Refractory Rheumatoid Arthritis ◽  
Life Threatening

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab’s therapeutic effects in patients with life-threatening SARS-CoV-2 infection.

Prognostic Factors for Pediatric Acute Encephalopathy Associated with Severe Brain Edema

2021 ◽  
pp. 1-8
Author(s):  
Goichiro Tamura ◽  
Takayuki Inagaki
Keyword(s):  
Brain Edema ◽  
Cytokine Storm ◽  
Acute Encephalopathy ◽  
Brainstem Compression ◽  
Life Threatening ◽  
Group 3 ◽  
Group 2 ◽  
Diffuse Brain ◽  
Group 1

<b><i>Background and Objective:</i></b> Acute encephalopathy is a life-threatening brain dysfunction in children, often associated with a preceding infection and diffuse noninflammatory brain edema. At present, the role of decompressive craniectomy (DC) over the swollen area of the brain is unclear. The risk factors for predicting clinical deterioration also need clarification. <b><i>Methods:</i></b> A retrospective study of pediatric patients admitted between 2015 and 2019 with acute cerebral encephalopathy was carried out. Patients were classified according to: (1) the preceding pathogens, (2) the syndromic classification, and (3) the extent of brain edema. The syndromic classification is a relatively new classification of acute encephalopathy proposed in 2016 and divides patients into 3 groups: those with systemic inflammatory reactions or “cytokine storms” (group 1), those with status epilepticus but no cytokine storm (group 2), and others (group 3). Glasgow Outcome Scale (GOS) scores of 1–3 were defined as unfavorable, while a GOS score of 4 or 5 was defined as a favorable outcome in this study. DC was performed for select patients with life-threatening signs of brainstem compression. <b><i>Results:</i></b> Nineteen patients (mean age: 23.3 months) were included in the study, 8 (42.1%) of whom had an unfavorable outcome. There was no significant correlation between the types of pathogens and outcome. Unfavorable outcomes were observed in significantly more patients in group 1 (87.5%) than group 2 (14.3%) and group 3 (0%). There was a significant association between diffuse brain edema and unfavorable outcomes (72.7%). Neurosurgical DC was performed in 2 patients to alleviate life-threatening brainstem compression: one with a cytokine storm and diffuse bilateral brain edema, and the other with prolonged status epilepticus causing diffuse right-sided brain edema. The GOS score was 3 and 4, respectively. <b><i>Conclusion:</i></b> The risk factors for clinical deterioration in pediatric acute encephalopathy were evaluated based on a variety of classifications, including the new syndromic classification. Laboratory features of cytokine storms and radiological evidence of diffuse brain edema were associated with unfavorable outcomes. The role of surgical decompression is still controversial and should be assessed on a case-by-case basis.

scholarly journals Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

2021 ◽  
Vol 22 (15) ◽  
pp. 8255
Author(s):  
Samantha L. Cooper ◽  
Eleanor Boyle ◽  
Sophie R. Jefferson ◽  
Calum R. A. Heslop ◽  
Pirathini Mohan ◽  
...  
Keyword(s):  
Cardiovascular Complications ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Life Threatening ◽  
Major Route ◽  
Membrane Bound ◽  
The Impact

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin–Angiotensin–Aldosterone System (RAAS) and Kinin–Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.

scholarly journals Interplay of Opposing Effects of the WNT/β-Catenin Pathway and PPARγ and Implications for SARS-CoV2 Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexandre Vallée ◽  
Yves Lecarpentier ◽  
Jean-Noël Vallée
Keyword(s):  
Distress Syndrome ◽  
The Novel ◽  
Cytokine Storm ◽  
Angiotensin Converting Enzyme 2 ◽  
Tnf Α ◽  
Pparγ Agonists ◽  
Novel Coronavirus ◽  
Opposing Effects ◽  
Canonical Wnt

The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has quickly reached pandemic proportions. Cytokine profiles observed in COVID-19 patients have revealed increased levels of IL-1β, IL-2, IL-6, and TNF-α and increased NF-κB pathway activity. Recent evidence has shown that the upregulation of the WNT/β-catenin pathway is associated with inflammation, resulting in a cytokine storm in ARDS (acute respire distress syndrome) and especially in COVID-19 patients. Several studies have shown that the WNT/β-catenin pathway interacts with PPARγ in an opposing interplay in numerous diseases. Furthermore, recent studies have highlighted the interesting role of PPARγ agonists as modulators of inflammatory and immunomodulatory drugs through the targeting of the cytokine storm in COVID-19 patients. SARS-CoV2 infection presents a decrease in the angiotensin-converting enzyme 2 (ACE2) associated with the upregulation of the WNT/β-catenin pathway. SARS-Cov2 may invade human organs besides the lungs through the expression of ACE2. Evidence has highlighted the fact that PPARγ agonists can increase ACE2 expression, suggesting a possible role for PPARγ agonists in the treatment of COVID-19. This review therefore focuses on the opposing interplay between the canonical WNT/β-catenin pathway and PPARγ in SARS-CoV2 infection and the potential beneficial role of PPARγ agonists in this context.

scholarly journals Repurposing of chloroquine and hydroxychloroquine for the management of COVID-19

2021 ◽  
Vol 10 (3) ◽  
pp. 300
Author(s):  
Fidelis A. Gberindyer ◽  
Felix K. Shima ◽  
Joel A. Bosha ◽  
Victor M. Ahur ◽  
Festus T. Swem ◽  
...  
Keyword(s):  
Viral Infections ◽  
Antiviral Effect ◽  
Economic Activities ◽  
Clinical Safety ◽  
Transmembrane Receptors ◽  
Angiotensin Converting Enzyme 2 ◽  
Lysosomal Ph ◽  
Life Threatening ◽  
Near Future

The Coronavirus Disease-19 (COVID-19) pandemic has impacted adversely on the global health and socio-economic activities. There is currently no evidence-based anti-SARS-CoV-2 drug for COVID-19 therapy. This review highlights some pharmacological properties of chloroquine and hydroxychloroquine and prospects of repurposing them for the treatment of COVID-19. Google scholar was employed in searching relevant published journal articles (n=118) in English. The search was later narrowed down to SARS-CoV-2, pathophysiology of COVID-19, available drugs for the management of COVID-19, clinical trials on repurposing drugs for COVID-19 therapy, and the role of chloroquine and hydroxychloroquine in the treatment of COVID-19. Documented evidence revealed that chloroquine and hydroxychloroquine have antiviral and immune-modulatory properties. Their antiviral effect is due to inhibition of the spike proteins of SARS-CoV-2 from binding to the cellular transmembrane receptors, angiotensin converting enzyme-2 thereby preventing viral infections. Also, sequestration of these drugs into the lysosomes elevates lysosomal pH thus inhibiting lysosomal enzymatic functions vital for viral replication in those cells. Whereas, their immune-modulatory activity averts the inflammatory complications of COVID-19, particularly acute respiratory syndrome, by preventing cytokine storm through suppression of the production and putative release of pro-inflammatory cytokines. The adverse effects from these drugs, notably irreversible retinopathy and cardiac arrhythmia are rare but become life-threatening when they occur. These are minimal with hydroxychloroquine compared to chloroquine. Chloroquine and hydroxychloroquine could be repurposed for managing COVID-19 cases because they are already extensively used for treating acute nonresistant malaria and auto-immune diseases. Also, a viable vaccine cannot be available in the near future while there is a pressing need for treatments to lower the daily rise in morbidity and mortality associated with the disease. Nevertheless, we suggest that emphasis should be on hydroxychloroquine because of its superior antiviral effect and clinical safety.

scholarly journals Clinical Efficacy of Eucaloric Ketogenic Nutrion in Covid-19-cytokine Storm: A Retrospective Analysis on Mortality and ICU Access

2020 ◽  
Author(s):  
Samir Giuseppe Sukkar ◽  
Ludovica Cogorno ◽  
Andrea Pasta ◽  
Pisciotta Livia ◽  
Antonio Vena ◽  
...  
Keyword(s):  
Dietary Treatment ◽  
Composite Endpoint ◽  
Clinical Results ◽  
Primary Objective ◽  
Cytokine Storm ◽  
Icu Admission ◽  
Inflammatory Parameters ◽  
Efficacious Treatment ◽  
Life Threatening

Abstract Background: Some patients affected by Covid 19 present a life threatening hyperinflammatory state known as a cytokine storm syndrome (CSS) associated with a high mortality rate. Our hypothesis is that eucaloric ketogenic diet (EKD) may be a safe and efficacious treatment option to reduce CSS and consequently to reduce need of CPAP, ICU admission and mortality COVID-19 related.Aim of the study: Primary objective is to explore the effect of EKD on mortality, access to ICU and the need of NIV in COVID-19 hospitalized patients in comparison to a eucaloric standard dietstandard diet (ESDESD). Secondary objectives are to collect data about safety and feasibility of EKD during hospitalization and to evaluate the effect of the diet on biological and inflammatory parameters and particularly on interleukin -6 (IL-6).Patients and Methods: The study is a retrospective explorative analysis of 34 patients fed with EKD during hospitalization for COVID-19 in comparison to 68 patients in ESDESD selected and matched using propensity score one-to-two to avoid the confounding effect of interfering variables.Results: A trend of reduction of 30-day mortality (HR 0.416, 95% CI 0.122 – 1.413, P = 0.160) and a trend in need for ICU admission (HR 0.357, 95% CI 0.045 – 2.847, P = 0.331) were observed in subjects treated with EKD respect to patients fed with standard one. No significant different risks in need for CPAP (HR 0.968, CI 0.289 – 3.242, P = 0.958 for EKD) and composite endpoint (HR 0.674, CI 0.233 – 1.949, P = 0.446 for EKD) were detectable between the two groups of dietary patterns.Furthermore, IL-6 concentrations, between t 0 and t 7 (seven days after the beginning of the diet), collected in the ketogenic nutrition group, show a median IL-6 difference of -26.0 ȵg/mL or a mean IL-6 difference of -164 ȵg/mL (data from 23 of the 34 pairs) compared to controls, with a trend to (P = 0.062).Discussion and conclusions: These preliminar data, collected in a retrospective way during the most aggressive period of Covid-19 pandemia, on clinical results on mortality, need for ICU and effect on IL-6 concentration during EKD suggest a favorable role of this dietary treatment in COVID-19 clinical management. EKD resulted well accepted by patients during hospitalization and seems to be an interesting tool in controlling Covid-19-CSS. The results of the prospective controlled randomized trial, actually ongoing, in a largest number of subjects are necessary to confirm these preliminary data.

scholarly journals A zebrafish model of granulin deficiency reveals essential roles in myeloid cell differentiation

2021 ◽  
Vol 5 (3) ◽  
pp. 796-811
Author(s):  
Clyde A. Campbell ◽  
Oksana Fursova ◽  
Xiaoyi Cheng ◽  
Elizabeth Snella ◽  
Abbigail McCune ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Differentiation ◽  
Human Health ◽  
Myeloid Cell ◽  
Zebrafish Model ◽  
Functional Conservation ◽  
Emergency Myelopoiesis ◽  
Enhance Wound Healing

Abstract Granulin is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to use granulin to treat rheumatoid arthritis and frontotemporal dementia and to enhance wound healing. But how granulin contributes to each of these diverse biological functions remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. We have taken advantage of the tissue-specific segregation of the zebrafish granulin paralogues to assess the functional role of granulin in hematopoiesis without perturbing other tissues. By using our zebrafish model of granulin deficiency, we revealed that during normal and emergency myelopoiesis, myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), failing to express the myeloid-specific genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Functionally, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8, positively regulates grna expression. In vivo imaging and RNA sequencing experiments show that grna inhibits the expression of gata1, leading to the repression of the erythroid program. Importantly, we demonstrated functional conservation between the mammalian granulin and the zebrafish ortholog grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, which opens a new field of study that can potentially have an impact on different aspects of human health and expand the therapeutic options for treating myeloid disorders such as neutropenia or myeloid leukemia.

scholarly journals Hax1 Is Indispensable for Neutrophil Development in Zebrafish

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 436-436
Author(s):  
Larissa Doll ◽  
Narges Aghaallaei ◽  
Karl Welte ◽  
Julia Skokowa ◽  
Baubak Bajoghli
Keyword(s):  
Cell Death ◽  
Conflicts Of Interest ◽  
Therapeutic Strategies ◽  
In Vivo Model ◽  
Wild Type ◽  
Zebrafish Model ◽  
Compound Screening ◽  
Life Threatening

Inherited deficiency of HCLS1-associated protein X1 (HAX1) in human leads to the development of severe congenital neutropenia (CN), which is characterized by impaired neutrophil development. Patients with HAX1 deficiency are prone to life-threatening infections beginning in their first months of life unless treated by recombinant human granulocyte colony-stimulating factor (rhG-CSF) or bone marrow transplantation. But approximately 10% of these patients do not respond to the rhG-CSF therapy. Therefore, there is an urgent need for new tailored therapeutic strategies for the treatment of this disease. However, there is a lack of an animal model that allows high-throughput compound screening for the HAX1 associated neutropenia. In this study, we sought to determine the role of hax1 in zebrafish hematopoiesis. We used two approaches to interfere with the zebrafish hax1. First, we injected antisense morpholino that efficiently blocked the translation of hax1 mRNA. As a second approach, we used the CRISPR-Cas9 technique to introduce mutations in the zebrafish hax1 gene. Both approaches were used in the in wild-type embryos and transgenic (mpo:gfp) reporter line, where the neutrophils are labeled with GFP. We found that hax1 knockdown reduced the number of neutrophils, without affecting the development of HSPCs and monocytes/macrophages. Compared with their wild-type counterparts, hax1 morphants exhibited reduced expression levels of hcls1 and cebpa. Whereas the expression level of cebpb, a marker of emergency granulopoiesis, was upregulated. Next, we examined whether hax1 knockdown impairs the cellular viability because CN patients who harbor HAX1 mutations exhibit increased apoptosis of myeloid progenitors. Although zebrafish hax1 morphants showed increased cell death throughout the embryo, apoptosis was not triggered in the hematopoietic site. Therefore, our results suggested that reduced neutrophil numbers in zebrafish hax1 morphants is due to decreased production of neutrophils rather than increased cell death. To determine whether our zebrafish model is suitable for discovering human drugs, we treated zebrafish hax1 morphants with human G-CSF and rescued the quantitative reduction of neutrophils. Overall, we have successfully established a novel in vivo model for studying the HAX-1 role in the granulopoiesis, which might open new avenues for developing therapeutic strategies for CN. Disclosures No relevant conflicts of interest to declare.

scholarly journals Myelopoiesis in the Context of Innate Immunity

2018 ◽  
Vol 10 (5-6) ◽  
pp. 365-372 ◽  
Author(s):  
Ioannis Mitroulis ◽  
Lydia Kalafati ◽  
George Hajishengallis ◽  
Triantafyllos Chavakis
Keyword(s):  
Inflammatory Mediators ◽  
Systemic Infection ◽  
Cell Populations ◽  
Receptor Ligands ◽  
Myeloid Lineage ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Life Threatening ◽  
Emergency Myelopoiesis

An intact and fully functional innate immune system is critical in the defense against pathogens. Indeed, during systemic infection, the ability of the organism to cope with the increased demand for phagocytes depends heavily on sufficient replenishment of mature myeloid cells. This process, designated emergency or demand-adapted myelopoiesis, requires the activation of hematopoietic progenitors in the bone marrow (BM), resulting in their proliferation and differentiation toward the myeloid lineage. Failure of BM progenitors to adapt to the enhanced need for mature cells in the periphery can be life-threatening, as indicated by the detrimental effect of chemotherapy-induced myelosuppression on the outcome of systemic infection. Recent advances demonstrate an important role of not only committed myeloid progenitors but also of hematopoietic stem cells (HSCs) in emergency myelopoiesis. In this regard, pathogen-derived products (e.g., Toll-like receptor ligands) activate HSC differentiation towards the myeloid lineage, either directly or indirectly, by inducing the production of inflammatory mediators (e.g., cytokines and growth factors) by hematopoietic and nonhematopoietic cell populations. The inflammatory mediators driving demand-adapted myelopoiesis target not only HSCs but also HSC-supportive cell populations, collectively known as the HSC niche, the microenvironment where HSCs reside. In this review, we discuss recent findings that have further elucidated the mechanisms that drive emergency myelopoiesis, focusing on the interactions of HSCs with their BM microenvironment.

SARS-COV2 virus and Coronavirus disease (COVID-19)

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 977-982
Author(s):  
Mohamed J. Saadh ◽  
Bashar Haj Rashid M ◽  
Roa’a Matar ◽  
Sajeda Riyad Aldibs ◽  
Hala Sbaih ◽  
...  
Keyword(s):  
Close Contact ◽  
Antiviral Agents ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Fatal Disease ◽  
Mild Disease ◽  
Life Threatening ◽  
Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

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