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1.
Front Immunol ; 12: 741218, 2021.
Article in English | MEDLINE | ID: covidwho-1518486

ABSTRACT

The global outbreak of the SARS-Cov-2 virus in 2020 has killed millions of people worldwide and forced large parts of the world into lockdowns. While multiple vaccine programs are starting to immunize the global population, there is no direct cure for COVID-19, the disease caused by the SARS-Cov-2 infection. A common symptom in patients is a decrease in T cells, called lymphopenia. It is as of yet unclear what the exact role of T cells are in the immune response to COVID-19. The research so far has mainly focused on the involvement of classical αß T cells. However, another subset of T cells called γδ T cells could have an important role to play. As part of the innate immune system, γδ T cells respond to inflammation and stressed or infected cells. The γδ T cell subset appears to be particularly affected by lymphopenia in COVID-19 patients and commonly express activation and exhaustion markers. Particularly in children, this subset of T cells seems to be most affected. This is interesting and relevant because γδ T cells are more prominent and active in early life. Their specific involvement in this group of patients could indicate a significant role for γδ T cells in this disease. Furthermore, they seem to be involved in other viral infections and were able to kill SARS infected cells in vitro. γδ T cells can take up, process and present antigens from microbes and human cells. As e.g. tumour-associated antigens are presented by MHC on γδ T cells to classical T-cells, we argue here that it stands to reason that also viral antigens, such as SARS-Cov-2-derived peptides, can be presented in the same way. γδ T cells are already used for medical purposes in oncology and have potential in cancer therapy. As γδ T cells are not necessarily able to distinguish between a transformed and a virally infected cell it could therefore be of great interest to investigate further the relationship between COVID-19 and γδ T cells.


Subject(s)
COVID-19/immunology , Intraepithelial Lymphocytes/immunology , SARS-CoV-2 , Animals , Cytokine Release Syndrome/immunology , Humans , Neoplasms/immunology , Pulmonary Fibrosis/immunology
2.
Front Immunol ; 12: 740260, 2021.
Article in English | MEDLINE | ID: covidwho-1506482

ABSTRACT

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor ß1 (TGF-ß1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-ß1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-ß1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-ß1 mRNA performed at the time of first medical contact.


Subject(s)
COVID-19/physiopathology , Heart Ventricles/pathology , Myocardium/pathology , Pulmonary Fibrosis/physiopathology , SARS-CoV-2/physiology , Adult , Aged , COVID-19/immunology , Female , Fibrosis , Heart Ventricles/metabolism , Humans , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/metabolism , Male , Middle Aged , Myocardium/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Pulmonary Fibrosis/immunology , Risk , Severity of Illness Index , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Viral Load
3.
Biochem Pharmacol ; 193: 114812, 2021 11.
Article in English | MEDLINE | ID: covidwho-1474355

ABSTRACT

Pulmonary fibrosis (PF) is characterised by several grades of chronic inflammation and collagen deposition in the interalveolar space and is a hallmark of interstitial lung diseases (ILDs). Recently, infectious agents have emerged as driving causes for PF development; however, the role of viral/bacterial infections in the initiation and propagation of PF is still debated. In this context, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current coronavirus disease 2019 (COVID-19) pandemic, has been associated with acute respiratory distress syndrome (ARDS) and PF development. Although the infection by SARS-CoV-2 can be eradicated in most cases, the development of fibrotic lesions cannot be precluded; furthermore, whether these lesions are stable or progressive fibrotic events is still unknown. Herein, an overview of the main molecular mechanisms driving the fibrotic process together with the currently approved and newly proposed therapeutic solutions was given. Then, the most recent data that emerged from post-COVID-19 patients was discussed, in order to compare PF and COVID-19-dependent PF, highlighting shared and specific mechanisms. A better understanding of PF aetiology is certainly needed, also to develop effective therapeutic strategies and COVID-19 pathology is offering one more chance to do it. Overall, the work reported here could help to define new approaches for therapeutic intervention in the diversity of the ILD spectrum.


Subject(s)
COVID-19/complications , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/metabolism , Animals , COVID-19/etiology , COVID-19/immunology , COVID-19/metabolism , Humans , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Pulmonary Fibrosis/etiology
4.
Stem Cells ; 39(6): 707-722, 2021 06.
Article in English | MEDLINE | ID: covidwho-1121521

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus pathogen that causes COVID-19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS-CoV-2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID-19 related pulmonary disease.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , COVID-19/therapy , COVID-19/virology , Cytokine Release Syndrome/therapy , Cytokine Release Syndrome/virology , Humans , Immunomodulation , Lung/immunology , Lung/pathology , Lung/virology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/virology , Pandemics , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/therapy , Pulmonary Fibrosis/virology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/virology , SARS-CoV-2/genetics
5.
Med Sci Monit ; 26: e928996, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-921300

ABSTRACT

Since the initial reports of coronavirus disease 2019 (COVID-19) in China in late 2019, infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have spread rapidly, resulting in a global pandemic that has caused millions of deaths. Initially, the large number of infected people required the direction of global healthcare resources to provide supportive care for the acutely ill population in an attempt to reduce mortality. While clinical trials for safe and effective antiviral agents are ongoing, and vaccine development programs are being accelerated, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized and concerning. Although the upper and lower respiratory tracts are the main sites of entry of SARS-CoV-2 into the body, resulting in COVID-19 pneumonia as the most common presentation, acute lung damage may be followed by pulmonary fibrosis and chronic impairment of lung function, with impaired quality of life. Also, increasing reports have shown that SARS-CoV-2 infection involves the central nervous system (CNS) and the peripheral nervous system (PNS) and directly or indirectly damages neurons, leading to long-term neurological sequelae. This review aims to provide an update on the mechanisms involved in the development of the long-term sequelae of SARS-CoV-2 infection in the 3 main areas of lung injury, neuronal injury, and neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and multiple sclerosis, and highlights the need for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide a rationale for the prevention, diagnosis, and management of these potential long-term sequelae.


Subject(s)
COVID-19/complications , Lung Injury/epidemiology , Neurodegenerative Diseases/epidemiology , Pulmonary Fibrosis/epidemiology , SARS-CoV-2/pathogenicity , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Disease Progression , Humans , Lung Injury/diagnosis , Lung Injury/immunology , Lung Injury/prevention & control , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/prevention & control , Pandemics , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/prevention & control , Quality of Life , SARS-CoV-2/immunology , Time Factors
6.
Drug Discov Ther ; 14(5): 259-261, 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-895584

ABSTRACT

Regardless of the severity of coronavirus disease 2019 (COVID-19), a high proportion of patients struggle with persistent respiratory or systemic symptoms after recovery. This is called "postCOVID syndrome", for which pulmonary fibrosis is one of the pathogenesis. Besides T-lymphocytes and macrophages, mast cells also contribute to the development of cytokine storm and thus stimulate the activity of fibroblasts. Additionally, by the exocytotic release of fibroblast-activating factors, mast cells directly facilitate the progression of pulmonary fibrosis. In our previous basic studies, anti-allergic drugs (olopatadine, ketotifen), antibiotics (clarithromycin) and corticosteroids (hydrocortisone, dexamethasone) inhibited the process of exocytosis and showed their potency as highly effective mast cell stabilizers. Given such pharmacological properties of these commonly used drugs, they may be useful in the treatment of post-COVID-19 pulmonary fibrosis and in relieving the symptoms of post-COVID syndrome.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Anti-Allergic Agents/therapeutic use , Anti-Bacterial Agents/therapeutic use , Betacoronavirus/pathogenicity , Cell Degranulation/drug effects , Coronavirus Infections/virology , Mast Cells/drug effects , Pneumonia, Viral/virology , Pulmonary Fibrosis/drug therapy , Animals , COVID-19 , Coronavirus Infections/immunology , Host-Pathogen Interactions , Humans , Mast Cells/immunology , Mast Cells/virology , Pandemics , Pneumonia, Viral/immunology , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/virology , SARS-CoV-2
7.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Article in English | MEDLINE | ID: covidwho-841900

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Subject(s)
Apoptosis/immunology , Betacoronavirus/pathogenicity , Caspase 8/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Necroptosis/immunology , Pneumonia, Viral/immunology , Pulmonary Fibrosis/immunology , Animals , COVID-19 , Caspase 8/genetics , Cell Line, Tumor , Chemokine CCL5/genetics , Chemokine CCL5/immunology , Chemokine CXCL10/genetics , Chemokine CXCL10/immunology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Disease Models, Animal , Epithelial Cells/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression Regulation , Humans , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-7/genetics , Interleukin-7/immunology , Interleukin-8/genetics , Interleukin-8/immunology , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/virology , SARS-CoV-2 , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
8.
Front Immunol ; 11: 2069, 2020.
Article in English | MEDLINE | ID: covidwho-769216

ABSTRACT

COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Galectin 3/antagonists & inhibitors , Galectin 3/blood , Molecular Targeted Therapy/methods , Pneumonia, Viral/drug therapy , Pulmonary Fibrosis/drug therapy , Severity of Illness Index , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/chemistry , Biomarkers/blood , Blood Proteins , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Disease Progression , Galectins , Host-Pathogen Interactions/immunology , Humans , Inflammation/drug therapy , Inflammation/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Prognosis , Pulmonary Fibrosis/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
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