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1.
Int J Mol Sci ; 23(3)2022 Feb 02.
Article in English | MEDLINE | ID: covidwho-1674667

ABSTRACT

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein-kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE+ MCs, tryptase+ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Capillary Permeability , Kallikrein-Kinin System/physiology , Lung/pathology , Mast Cells/immunology , SARS-CoV-2/immunology , Adult , Aged , Autopsy , COVID-19/immunology , COVID-19/virology , Caspase 1/metabolism , Female , Humans , Interleukin-33/metabolism , Lung/immunology , Lung/metabolism , Lung/virology , Male , Mast Cells/metabolism , Mast Cells/virology , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
3.
Immunology ; 164(3): 541-554, 2021 11.
Article in English | MEDLINE | ID: covidwho-1488214

ABSTRACT

IL-33 and ATP are alarmins, which are released upon damage of cellular barriers or are actively secreted upon cell stress. Due to high-density expression of the IL-33 receptor T1/ST2 (IL-33R), and the ATP receptor P2X7, mast cells (MCs) are one of the first highly sensitive sentinels recognizing released IL-33 or ATP in damaged peripheral tissues. Whereas IL-33 induces the MyD88-dependent activation of the TAK1-IKK2-NF-κB signalling, ATP induces the Ca2+ -dependent activation of NFAT. Thereby, each signal alone only induces a moderate production of pro-inflammatory cytokines and lipid mediators (LMs). However, MCs, which simultaneously sense (co-sensing) IL-33 and ATP, display an enhanced and prolonged activation of the TAK1-IKK2-NF-κB signalling pathway. This resulted in a massive production of pro-inflammatory cytokines such as IL-2, IL-4, IL-6 and GM-CSF as well as of arachidonic acid-derived cyclooxygenase (COX)-mediated pro-inflammatory prostaglandins (PGs) and thromboxanes (TXs), hallmarks of strong MC activation. Collectively, these data show that co-sensing of ATP and IL-33 results in hyperactivation of MCs, which resembles to MC activation induced by IgE-mediated crosslinking of the FcεRI. Therefore, the IL-33/IL-33R and/or the ATP/P2X7 signalling axis are attractive targets for therapeutical intervention of diseases associated with the loss of integrity of cellular barriers such as allergic and infectious respiratory reactions.


Subject(s)
Adenosine Triphosphate/metabolism , Hypersensitivity/immunology , Interleukin-33/metabolism , Mast Cells/immunology , Animals , Anti-Allergic Agents/pharmacology , Anti-Allergic Agents/therapeutic use , Cell Degranulation/drug effects , Cytokines/metabolism , Disease Models, Animal , Eicosanoids/metabolism , Humans , Hypersensitivity/drug therapy , Interleukin-1 Receptor-Like 1 Protein/antagonists & inhibitors , Interleukin-1 Receptor-Like 1 Protein/metabolism , Interleukin-33/antagonists & inhibitors , Lipidomics , Mast Cells/drug effects , Mast Cells/metabolism , Mice , Mice, Knockout , NFATC Transcription Factors/genetics , Primary Cell Culture , Receptors, Purinergic P2X7/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology
4.
Nutrients ; 13(10)2021 Sep 29.
Article in English | MEDLINE | ID: covidwho-1444284

ABSTRACT

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.


Subject(s)
COVID-19/immunology , Histamine/immunology , Immune System/immunology , Mast Cells/immunology , Nutritional Physiological Phenomena/immunology , Signal Transduction/immunology , Humans , SARS-CoV-2
5.
Clin Exp Allergy ; 52(2): 324-333, 2022 02.
Article in English | MEDLINE | ID: covidwho-1437986

ABSTRACT

BACKGROUND: Deaths attributed to Coronavirus Disease 2019 (COVID-19) are mainly due to severe hypoxemic respiratory failure. Although the inflammatory storm has been considered the main pathogenesis of severe COVID-19, hypersensitivity may be another important mechanism involved in severe cases, which have a perfect response to corticosteroids (CS). METHOD: We detected the serum level of anti-SARS-CoV-2-spike S1 protein-specific IgE (SP-IgE) and anti-SARS-CoV-2 nucleocapsid protein-specific IgE (NP-IgE) in COVID-19. Correlation of levels of specific IgE and clinical severity were analysed. Pulmonary function test and bronchial provocation test were conducted in early convalescence of COVID-19. We also obtained histological samples via endoscopy to detect the evidence of mast cell activation. RESULT: The levels of serum SP-IgE and NP-IgE were significantly higher in severe cases, and were correlated with the total lung severity scores (TLSS) and the PaO2 /FiO2 ratio. Nucleocapsid protein could be detected in both airway and intestinal tissues, which was stained positive together with activated mast cells, binded with IgE. Airway hyperresponsiveness (AHR) exists in the early convalescence of COVID-19. After the application of CS in severe COVID-19, SP-IgE and NP-IgE decreased, but maintained at a high level. CONCLUSION: Hypersensitivity may be involved in severe COVID-19.


Subject(s)
Bronchi/immunology , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Duodenum/immunology , Hypersensitivity/immunology , Immunoglobulin E/immunology , Mast Cells/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Bronchi/metabolism , Bronchi/pathology , COVID-19/metabolism , COVID-19/pathology , COVID-19/physiopathology , Case-Control Studies , Coronavirus Nucleocapsid Proteins/metabolism , Duodenum/metabolism , Duodenum/pathology , Female , Humans , Hypersensitivity/metabolism , Hypersensitivity/pathology , Hypersensitivity/physiopathology , Lung/physiopathology , Male , Mast Cells/metabolism , Mast Cells/pathology , Middle Aged , Mucous Membrane/immunology , Mucous Membrane/metabolism , Mucous Membrane/pathology , Phosphoproteins/immunology , Phosphoproteins/metabolism , Recovery of Function , Respiratory Hypersensitivity/physiopathology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Spike Glycoprotein, Coronavirus/metabolism , Young Adult
6.
IUBMB Life ; 73(11): 1278-1292, 2021 11.
Article in English | MEDLINE | ID: covidwho-1380387

ABSTRACT

Mast cells (MCs) are innate immune cells that widely distribute throughout all tissues and express a variety of cell surface receptors. Upon activation, MCs can rapidly release a diverse array of preformed mediators residing within their secretory granules and newly synthesize a broad spectrum of inflammatory and immunomodulatory mediators. These unique features of MCs enable them to act as sentinels in response to rapid changes within their microenvironment. There is increasing evidence now that MCs play prominent roles in other pathophysiological processes besides allergic inflammation. In this review, we highlight the recent findings on the emerging roles of MCs in the pathogenesis of coronavirus disease-2019 (COVID-19) and discuss the potential of MCs as novel therapeutic targets for COVID-19 and other non-allergic inflammatory diseases.


Subject(s)
COVID-19/prevention & control , Immunity, Innate/immunology , Mast Cells/immunology , SARS-CoV-2/isolation & purification , Animals , COVID-19/immunology , COVID-19/pathology , Humans
7.
J Leukoc Biol ; 110(3): 425-431, 2021 09.
Article in English | MEDLINE | ID: covidwho-1375609

ABSTRACT

The immune response plays a critical role in the pathophysiology of SARS-CoV-2 infection ranging from protection to tissue damage and all occur in the development of acute respiratory distress syndrome (ARDS). ARDS patients display elevated levels of inflammatory cytokines and innate immune cells, and T and B cell lymphocytes have been implicated in this dysregulated immune response. Mast cells are abundant resident cells of the respiratory tract and are able to release different inflammatory mediators rapidly following stimulation. Recently, mast cells have been associated with tissue damage during viral infections, but their role in SARS-CoV-2 infection remains unclear. In this study, we examined the profile of mast cell activation markers in the serum of COVID-19 patients. We noticed that SARS-CoV-2-infected patients showed increased carboxypeptidase A3 (CPA3) and decreased serotonin levels in their serum when compared with symptomatic SARS-CoV-2-negative patients. CPA3 levels correlated with C-reactive protein, the number of circulating neutrophils, and quick SOFA. CPA3 in serum was a good biomarker for identifying severe COVID-19 patients, whereas serotonin was a good predictor of SARS-CoV-2 infection. In summary, our results show that serum CPA3 and serotonin levels are relevant biomarkers during SARS-CoV-2 infection. This suggests that mast cells and basophils are relevant players in the inflammatory response in COVID-19 and may represent targets for therapeutic intervention.


Subject(s)
COVID-19/diagnosis , Carboxypeptidases A/metabolism , Inflammation Mediators/metabolism , Inflammation/diagnosis , Mast Cells/immunology , SARS-CoV-2/isolation & purification , Serotonin/metabolism , Biomarkers/analysis , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Mast Cells/pathology , Severity of Illness Index
8.
Cells ; 10(8)2021 07 26.
Article in English | MEDLINE | ID: covidwho-1335011

ABSTRACT

The first formal description of the microbicidal activity of extracellular traps (ETs) containing DNA occurred in neutrophils in 2004. Since then, ETs have been identified in different populations of cells involved in both innate and adaptive immune responses. Much of the knowledge has been obtained from in vitro or ex vivo studies; however, in vivo evaluations in experimental models and human biological materials have corroborated some of the results obtained. Two types of ETs have been described-suicidal and vital ETs, with or without the death of the producer cell. The studies showed that the same cell type may have more than one ETs formation mechanism and that different cells may have similar ETs formation mechanisms. ETs can act by controlling or promoting the mechanisms involved in the development and evolution of various infectious and non-infectious diseases, such as autoimmune, cardiovascular, thrombotic, and neoplastic diseases, among others. This review discusses the presence of ETs in neutrophils, macrophages, mast cells, eosinophils, basophils, plasmacytoid dendritic cells, and recent evidence of the presence of ETs in B lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes. Moreover, due to recently collected information, the effect of ETs on COVID-19 is also discussed.


Subject(s)
Extracellular Traps/immunology , Animals , Basophils/immunology , COVID-19 , Eosinophils/immunology , Humans , Lymphocytes/immunology , Macrophages/immunology , Mast Cells/immunology , Neutrophils/immunology
9.
Cells ; 10(7)2021 07 12.
Article in English | MEDLINE | ID: covidwho-1308301

ABSTRACT

Cytokine storm syndrome is a cascade of escalated immune responses disposing the immune system to exhaustion, which might ultimately result in organ failure and fatal respiratory distress. Infection with severe acute respiratory syndrome-coronavirus-2 can result in uncontrolled production of cytokines and eventually the development of cytokine storm syndrome. Mast cells may react to viruses in collaboration with other cells and lung autopsy findings from patients that died from the coronavirus disease that emerged in 2019 (COVID-19) showed accumulation of mast cells in the lungs that was thought to be the cause of pulmonary edema, inflammation, and thrombosis. In this review, we present evidence that a cytokine response by mast cells may initiate inappropriate antiviral immune responses and cause the development of cytokine storm syndrome. We also explore the potential of mast cell activators as adjuvants for COVID-19 vaccines and discuss the medications that target the functions of mast cells and could be of value in the treatment of COVID-19. Recognition of the cytokine storm is crucial for proper treatment of patients and preventing the release of mast cell mediators, as impeding the impacts imposed by these mediators could reduce the severity of COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Mast Cells/immunology , SARS-CoV-2/immunology , Animals , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/immunology , Humans , Mast Cells/drug effects , SARS-CoV-2/drug effects
10.
J Allergy Clin Immunol ; 147(6): 2075-2082.e2, 2021 06.
Article in English | MEDLINE | ID: covidwho-1185028

ABSTRACT

Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti-polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.


Subject(s)
Anaphylaxis/immunology , COVID-19 Vaccines/adverse effects , COVID-19/immunology , Drug Hypersensitivity/immunology , Lipids/adverse effects , Nanoparticles/adverse effects , RNA, Messenger/adverse effects , SARS-CoV-2/immunology , Anaphylaxis/chemically induced , Animals , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Drug Hypersensitivity/pathology , Humans , Lipids/immunology , Lipids/therapeutic use , Mast Cells/immunology , Mast Cells/pathology , Nanoparticles/therapeutic use , RNA, Messenger/immunology , RNA, Messenger/therapeutic use , Risk Factors
11.
Front Immunol ; 12: 650331, 2021.
Article in English | MEDLINE | ID: covidwho-1156125

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.


Subject(s)
Antigens, CD/immunology , Antigens, Differentiation, B-Lymphocyte/immunology , COVID-19/immunology , Eosinophils/immunology , Lectins/immunology , Mast Cells/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/genetics , Antigens, Differentiation, B-Lymphocyte/metabolism , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , Case-Control Studies , Cytokines/metabolism , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/metabolism , Eosinophils/virology , Host-Pathogen Interactions , Humans , Lectins/antagonists & inhibitors , Lectins/genetics , Lectins/metabolism , Mast Cells/drug effects , Mast Cells/metabolism , Mast Cells/virology , Mice, Transgenic , Peptide Hydrolases/metabolism , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Toll-Like Receptors/metabolism
12.
Dermatol Ther ; 33(6): e14068, 2020 11.
Article in English | MEDLINE | ID: covidwho-1153451

ABSTRACT

Coronavirus disease (COVID-19) pandemic presents several dermatological manifestations described in the present indexed literature, with around 700 cases reported until May 2020, some described as urticaria or urticarial rashes. Urticaria is constituted by evanescent erythematous-edematous lesions (wheals and flare), which does not persist in the same site for more than 24 to 48 hours and appears in other topographic localization, resolving without residual hyper pigmentation. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, some cytokines are synthesized, including Interferon (IFN) type I, TNF-α, and chemokines which may induce mast cells (MCs) and basophils degranulation by mechanisms similar to the autoinflammatory monogenic or polygenic diseases. In this article, we discuss the spectrum of the urticaria and urticarial-like lesions in the COVID-19's era, besides other aspects related to innate and adaptative immune response to viral infections, interactions between dermal dendritic cells and MCs, and degranulation of MCs by different stimuli. Plasmacytoid dendritic cells share, in allergic patients, expression of the high-affinity IgE receptors on cell membranes and demonstrated a low pattern of type I IFN secretion in viral infections. We discuss the previous descriptions of the effects of omalizumab, a monoclonal antibody directed to IgE and high-affinity IgE receptors, to improve the IFN responses and enhance their antiviral effects.


Subject(s)
COVID-19/complications , Omalizumab/pharmacology , Urticaria/virology , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Cytokines/immunology , Dendritic Cells/immunology , Humans , Immunoglobulin E/immunology , Mast Cells/immunology , SARS-CoV-2/isolation & purification , Urticaria/drug therapy , Urticaria/immunology
13.
Front Immunol ; 12: 640093, 2021.
Article in English | MEDLINE | ID: covidwho-1133915

ABSTRACT

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.


Subject(s)
Antibody-Dependent Enhancement , COVID-19/immunology , Mast Cells/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , Phagocytes/immunology , SARS-CoV-2/physiology , Systemic Inflammatory Response Syndrome/immunology , Animals , Antibodies, Viral/metabolism , COVID-19/transmission , Child , Cross Reactions , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Models, Immunological , Pregnancy , Receptors, Fc/metabolism , Risk , T-Lymphocytes/immunology
16.
Int J Infect Dis ; 100: 327-332, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-959834

ABSTRACT

OBJECTIVES: One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses. METHODS: Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS. RESULTS: The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19's hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors' treated MCAS patients with Covid-19 suffered severe infection, let alone mortality. CONCLUSIONS: Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.


Subject(s)
COVID-19/complications , Mastocytosis/etiology , COVID-19/immunology , Humans , Inflammation/immunology , Mast Cells/immunology , Mastocytosis/drug therapy , Mastocytosis/epidemiology , Pandemics , SARS-CoV-2
17.
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
18.
Front Immunol ; 11: 574862, 2020.
Article in English | MEDLINE | ID: covidwho-845301

ABSTRACT

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Mast Cells/immunology , Pneumonia, Viral/immunology , Pulmonary Alveoli/immunology , Pulmonary Edema/immunology , Thrombosis/immunology , Adult , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/immunology , Influenza, Human/pathology , Influenza, Human/virology , Interleukin-4/immunology , Male , Mast Cells/pathology , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proto-Oncogene Proteins c-kit/immunology , Pulmonary Alveoli/pathology , Pulmonary Alveoli/virology , Pulmonary Edema/pathology , Pulmonary Edema/virology , SARS-CoV-2 , Thrombosis/pathology , Thrombosis/virology
19.
Clin Ther ; 42(10): 1850-1852, 2020 10.
Article in English | MEDLINE | ID: covidwho-743922

ABSTRACT

Recent articles have reported elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased patients with coronavirus 2019 (COVID-19). Platelets are critical in the formation of thrombi, and their most potent trigger is platelet activating factor (PAF). PAF is produced by cells involved in host defense, and its biological actions bear similarities with COVID-19 disease manifestations, including pulmonary microthromboses and inflammation, possibly via activation of mast cells. The histamine1 receptor antagonist rupatadine was developed to have anti-PAF activity and inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for COVID-19 prophylaxis.


Subject(s)
Coronavirus Infections , Pandemics , Platelet Activating Factor , Pneumonia, Viral , Thrombosis , Betacoronavirus , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Humans , Inflammation/immunology , Inflammation/physiopathology , Mast Cells/immunology , Platelet Aggregation/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , SARS-CoV-2
20.
Neuroscientist ; 26(5-6): 402-414, 2020.
Article in English | MEDLINE | ID: covidwho-655850

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pandemic infectious disease that originated in China. COVID-19 is a global public health emergency of international concern. COVID-19 causes mild to severe illness with high morbidity and mortality, especially in preexisting risk groups. Therapeutic options are now limited to COVID-19. The hallmark of COVID-19 pathogenesis is the cytokine storm with elevated levels of interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-alpha (TNF-α), chemokine (C-C-motif) ligand 2 (CCL2), and granulocyte-macrophage colony-stimulating factor (GM-CSF). COVID-19 can cause severe pneumonia, and neurological disorders, including stroke, the damage to the neurovascular unit, blood-brain barrier disruption, high intracranial proinflammatory cytokines, and endothelial cell damage in the brain. Mast cells are innate immune cells and also implicated in adaptive immune response, systemic inflammatory diseases, neuroinflammatory diseases, traumatic brain injury and stroke, and stress disorders. SARS-CoV-2 can activate monocytes/macrophages, dendritic cells, T cells, mast cells, neutrophils, and induce cytokine storm in the lung. COVID-19 can activate mast cells, neurons, glial cells, and endothelial cells. SARS-CoV-2 infection can cause psychological stress and neuroinflammation. In conclusion, COVID-19 can induce mast cell activation, psychological stress, cytokine storm, and neuroinflammation.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Cytokines/immunology , Mast Cells/immunology , Nervous System Diseases/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Stress, Psychological/physiopathology , COVID-19 , Coronavirus Infections/complications , Humans , Mast Cells/virology , Nervous System Diseases/complications , Pandemics , Pneumonia, Viral/complications , SARS-CoV-2
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