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1.
Front Immunol ; 13: 807454, 2022.
Article in English | MEDLINE | ID: covidwho-1686483

ABSTRACT

Background: Innate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce. Methods: Fifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination. Results: The older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses. Conclusions: The innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , B-Lymphocytes/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Adult , Aged , COVID-19/prevention & control , Female , Humans , Imiquimod/pharmacology , Immunity, Innate/immunology , Immunosenescence/immunology , Interferon-gamma/blood , Male , Middle Aged , Poly I-C/administration & dosage , Poly I-C/immunology , Toll-Like Receptors/immunology , Vaccination
2.
Nat Immunol ; 23(2): 165-176, 2022 02.
Article in English | MEDLINE | ID: covidwho-1671597

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.


Subject(s)
COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Animals , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Immune Evasion , Inflammasomes/immunology , Inflammasomes/metabolism , NLR Proteins/immunology , NLR Proteins/metabolism , Receptors, Pattern Recognition/immunology , Receptors, Pattern Recognition/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism , Virus Internalization
3.
Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124

ABSTRACT

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
4.
Viruses ; 13(11)2021 11 18.
Article in English | MEDLINE | ID: covidwho-1524175

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to coronavirus disease (COVID-19), a global health pandemic causing millions of deaths worldwide. However, the immunopathogenesis of COVID-19, particularly the interaction between SARS-CoV-2 and host innate immunity, remains unclear. The innate immune system acts as the first line of host defense, which is critical for the initial detection of invading pathogens and the activation and shaping of adaptive immunity. Toll-like receptors (TLRs) are key sensors of innate immunity that recognize pathogen-associated molecular patterns and activate downstream signaling for pro-inflammatory cytokine and chemokine production. However, TLRs may also act as a double-edged sword, and dysregulated TLR responses may enhance immune-mediated pathology, instead of providing protection. Therefore, a proper understanding of the interaction between TLRs and SARS-CoV-2 is of great importance for devising therapeutic and preventive strategies. The use of TLR agonists as vaccine adjuvants for human disease is a promising approach that could be applied in the investigation of COVID-19 vaccines. In this review, we discuss the recent progress in our understanding of host innate immune responses in SARS-CoV-2 infection, with particular focus on TLR response. In addition, we discuss the use of TLR agonists as vaccine adjuvants in enhancing the efficacy of COVID-19 vaccine.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Toll-Like Receptors/agonists , Toll-Like Receptors/immunology , Animals , Humans , SARS-CoV-2/immunology , Toll-Like Receptors/metabolism
5.
Sci Rep ; 11(1): 21849, 2021 11 08.
Article in English | MEDLINE | ID: covidwho-1505527

ABSTRACT

The huge worldwide demand for vaccines targeting SARS-CoV-2 has necessitated the continued development of novel improved formulations capable of reducing the burden of the COVID-19 pandemic. Herein, we evaluated novel protein subunit vaccine formulations containing a resistin-trimerized spike antigen, SmT1. When combined with sulfated lactosyl archaeol (SLA) archaeosome adjuvant, formulations induced robust antigen-specific humoral and cellular immune responses in mice. Antibodies had strong neutralizing activity, preventing viral spike binding and viral infection. In addition, the formulations were highly efficacious in a hamster challenge model reducing viral load and body weight loss even after a single vaccination. The antigen-specific antibodies generated by our vaccine formulations had stronger neutralizing activity than human convalescent plasma, neutralizing the spike proteins of the B.1.1.7 and B.1.351 variants of concern. As such, our SmT1 antigen along with SLA archaeosome adjuvant comprise a promising platform for the development of efficacious protein subunit vaccine formulations for SARS-CoV-2.


Subject(s)
Adjuvants, Immunologic/chemistry , Antigens, Archaeal/chemistry , COVID-19 Vaccines/therapeutic use , Lipids/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Body Weight , COVID-19/therapy , Chlorocebus aethiops , Cricetinae , Cytokines/metabolism , Female , Humans , Immunity, Cellular , Immunity, Humoral , Immunization, Passive , Mesocricetus , Mice , Mice, Inbred C57BL , Neutralization Tests , Peptides/chemistry , Protein Domains , SARS-CoV-2 , Toll-Like Receptors/immunology , Vero Cells , Viral Load
6.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Article in English | MEDLINE | ID: covidwho-1493337

ABSTRACT

The COVID-19 pandemic highlights the importance of efficient and safe vaccine development. Vaccine adjuvants are essential to boost and tailor the immune response to the corresponding pathogen. To allow for an educated selection, we assessed the effect of different adjuvants on human monocyte-derived dendritic cells (DCs) and their ability to polarize innate and adaptive immune responses. In contrast to commonly used adjuvants, such as aluminum hydroxide, Toll-like receptor (TLR) agonists induced robust phenotypic and functional DC maturation. In a DC-lymphocyte coculture system, we investigated the ensuing immune reactions. While monophosphoryl lipid A synthetic, a TLR4 ligand, induced checkpoint inhibitors indicative for immune exhaustion, the TLR7/8 agonist Resiquimod (R848) induced prominent type-1 interferon and interleukin 6 responses and robust CTL, B-cell, and NK-cell proliferation, which is particularly suited for antiviral immune responses. The recently licensed COVID-19 vaccines, BNT162b and mRNA-1273, are both based on single-stranded RNA. Indeed, we could confirm that the cytokine profile induced by lipid-complexed RNA was almost identical to the pattern induced by R848. Although this awaits further investigation, our results suggest that their efficacy involves the highly efficient antiviral response pattern stimulated by the RNAs' TLR7/8 activation.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19/immunology , Dendritic Cells/immunology , Immunity, Cellular/drug effects , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Female , Humans , Imidazoles/pharmacology , Lipid A/analogs & derivatives , Lipid A/pharmacology , Male , Middle Aged , Toll-Like Receptors/immunology
7.
Viruses ; 13(11)2021 10 22.
Article in English | MEDLINE | ID: covidwho-1481020

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory immune responses are responsible for the severity of COVID-19, which suggests that anti-inflammatory drugs may be promising therapeutic treatments. However, there are currently a limited number of approved therapeutics for COVID-19. Toll-like receptors (TLRs), which recognize microbial components derived from invading pathogens, are involved in both the initiation of innate responses against SARS-CoV-2 infection and the hyperinflammatory phenotype of COVID-19. In this review, we provide current knowledge on the pivotal role of TLRs in immune responses against SARS-CoV-2 infection and demonstrate the potential effectiveness of TLR-targeting drugs on the control of hyperinflammation in patients with COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Animals , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cytokine Release Syndrome , Humans , SARS-CoV-2/physiology , Severity of Illness Index , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/drug therapy , Toll-Like Receptors/antagonists & inhibitors , Toll-Like Receptors/metabolism
9.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
10.
Front Immunol ; 12: 720192, 2021.
Article in English | MEDLINE | ID: covidwho-1378190

ABSTRACT

COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.


Subject(s)
Alarmins/immunology , COVID-19/physiopathology , Inflammation Mediators/immunology , Adenosine/metabolism , Alarmins/antagonists & inhibitors , Animals , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Humans , Inflammation/prevention & control , Inflammation Mediators/antagonists & inhibitors , Multiple Organ Failure/etiology , Multiple Organ Failure/prevention & control , Patient Acuity , Signal Transduction , Toll-Like Receptors/antagonists & inhibitors , Toll-Like Receptors/immunology
11.
Nat Commun ; 12(1): 4869, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1354100

ABSTRACT

In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.


Subject(s)
COVID-19/immunology , Disease Models, Animal , Alveolar Epithelial Cells/immunology , Animals , Cricetinae , Cytokines/genetics , Cytokines/immunology , Endothelial Cells/immunology , Humans , Immunoglobulin M/immunology , Inflammation , Lung/immunology , Macrophages/immunology , Mesocricetus , Monocytes/immunology , SARS-CoV-2/immunology , Signal Transduction , T-Lymphocytes, Cytotoxic/immunology , Toll-Like Receptors/immunology
12.
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
13.
Platelets ; 32(3): 325-330, 2021 Apr 03.
Article in English | MEDLINE | ID: covidwho-1092288

ABSTRACT

Platelets play an essential role in maintaining vascular integrity after injury. In addition, platelets contribute to the immune response to pathogens. For instance, they express receptors that mediate binding of viruses, and toll-like receptors that activate the cell in response to pathogen-associated molecular patterns. Platelets can be beneficial and/or detrimental during viral infections. They reduce blood-borne viruses by engulfing the free virus and presenting the virus to neutrophils. However, platelets can also enhance inflammation and tissue injury during viral infections. Here, we discuss the roles of platelets in viral infection.


Subject(s)
Blood Platelets/immunology , COVID-19/immunology , Host-Pathogen Interactions/immunology , Neutrophils/immunology , Receptors, Virus/immunology , Viral Proteins/immunology , Viruses/immunology , Animals , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Communication/genetics , Cell Communication/immunology , Dendritic Cells/immunology , Dendritic Cells/pathology , Dendritic Cells/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate , Lymphocytes/immunology , Lymphocytes/pathology , Lymphocytes/virology , Neutrophils/pathology , Neutrophils/virology , Platelet Activation/immunology , Protein Binding , Receptors, Virus/genetics , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Viral Proteins/genetics , Viruses/pathogenicity
14.
Int J Mol Sci ; 22(4)2021 Feb 20.
Article in English | MEDLINE | ID: covidwho-1090323

ABSTRACT

Severe COVID-19 is characterized by a "cytokine storm", the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.


Subject(s)
Acute Lung Injury/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , NLR Proteins/immunology , Respiratory Distress Syndrome/immunology , Sepsis/immunology , Toll-Like Receptors/immunology , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Animals , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Humans , Inflammation/drug therapy , Inflammation/immunology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/immunology , Sepsis/drug therapy , Sepsis/metabolism , Toll-Like Receptors/metabolism
15.
Int J Mol Sci ; 22(3)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1067752

ABSTRACT

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , SARS-CoV-2/physiology , Virus Internalization , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , Disease Progression , Heat-Shock Proteins/immunology , Heat-Shock Proteins/metabolism , Host-Pathogen Interactions , Humans , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Neuropilin-1/immunology , Neuropilin-1/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism
16.
Comp Immunol Microbiol Infect Dis ; 74: 101581, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-926806

ABSTRACT

In this study, primary and immortalized bovine intestinal epithelial cells (BIECs) were characterized for the expression of surface carbohydrate moieties. Primary BIEC-c4 cells showed staining greater than 90 % for 16 lectins but less than 50 % staining for four lectins. Immortalized BIECs showed significantly different lectin binding profile for few lectins compared to BIEC-c4 cells. BIEC-c4 cells were studied for infectivity to E. coli, Salmonella enterica, bovine rotavirus, bovine coronavirus, and bovine viral diarrhea virus. Bovine strain E. coli B41 adhered to BIEC-c4 cells and Salmonella strains S. Dublin and S. Mbandaka showed strong cell invasion. BIEC-c4 cells were susceptible to bovine rotavirus. LPS stimulation upregulated IL-10, IL-8, and IL-6 expression and Poly I:C upregulated TLR 8 and TLR 9 expression. This study provides important knowledge on the glycoconjugate expression profile of primary and immortalized BIECs and infectivity and immune responses of primary BIECs to bacterial and viral pathogens or ligands.


Subject(s)
Cell Line , Epithelial Cells/immunology , Epithelial Cells/microbiology , Lectins/metabolism , Toll-Like Receptors/immunology , Animals , Cattle , Coronavirus, Bovine , Diarrhea Viruses, Bovine Viral , Escherichia coli , Immunity , Interleukins/immunology , Rotavirus , Salmonella enterica
17.
Int J Biochem Cell Biol ; 122: 105738, 2020 05.
Article in English | MEDLINE | ID: covidwho-824867

ABSTRACT

Viroporins are virus encoded proteins that alter membrane permeability and can trigger subsequent cellular signals. Oligomerization of viroporin subunits results in formation of a hydrophilic pore which facilitates ion transport across host cell membranes. These viral channel proteins may be involved in different stages of the virus infection cycle. Inflammasomes are large multimolecular complexes best recognized for their ability to control activation of caspase-1, which in turn regulates the maturation of interleukin-1 ß (IL-1ß) and interleukin 18 (IL-18). IL-1ß was originally identified as a pro-inflammatory cytokine able to induce both local and systemic inflammation and a febrile reaction in response to infection or injury. Excessive production of IL-1ß is associated with autoimmune and inflammatory diseases. Microbial derivatives, bacterial pore-forming toxins, extracellular ATP and other pathogen-associated molecular patterns trigger activation of NLRP3 inflammasomes. Recent studies have reported that viroporin activity is capable of inducing inflammasome activity and production of IL-1ß, where NLRP3 is shown to be regulated by fluxes of K+, H+ and Ca2+ in addition to reactive oxygen species, autophagy and endoplasmic reticulum stress. The aim of this review is to present an overview of the key findings on viroporin activity with special emphasis on their role in virus immunity and as possible activators of inflammasomes.


Subject(s)
Inflammasomes/immunology , Inflammation/immunology , Inflammation/virology , Viral Proteins/immunology , Virus Diseases/immunology , Animals , Humans , Immunity, Innate , Inflammasomes/metabolism , Inflammation/metabolism , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism , Viral Proteins/metabolism , Virus Diseases/metabolism , Viruses/immunology , Viruses/metabolism
18.
Sci Rep ; 10(1): 16219, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-811544

ABSTRACT

COVID-19 pandemic has resulted in 16,114,449 cases with 646,641 deaths from the 217 countries, or territories as on July 27th 2020. Due to multifaceted issues and challenges in the implementation of the safety and preventive measures, inconsistent coordination between societies-governments and most importantly lack of specific vaccine to SARS-CoV-2, the spread of the virus that initially emerged at Wuhan is still uprising after taking a heavy toll on human life. In the present study, we mapped immunogenic epitopes present on the four structural proteins of SARS-CoV-2 and we designed a multi-epitope peptide based vaccine that, demonstrated a high immunogenic response with a vast application on world's human population. On codon optimization and in-silico cloning, we found that candidate vaccine showed high expression in E. coli and immune simulation resulted in inducing a high level of both B-cell and T-cell mediated immunity. The results predicted that exposure of vaccine by administrating three injections significantly subsidized the antigen growth in the system. The proposed candidate vaccine found promising by yielding desired results and hence, should be validated by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.


Subject(s)
Epitopes/immunology , Molecular Docking Simulation , Vaccines, Subunit/immunology , Viral Vaccines/immunology , Antigen-Antibody Complex/chemistry , Antigen-Antibody Complex/immunology , Antigens, Viral/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Coronavirus Nucleocapsid Proteins , Epitopes/chemistry , HLA Antigens/chemistry , HLA Antigens/immunology , Humans , Immunogenicity, Vaccine , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/immunology , Phosphoproteins , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Toll-Like Receptors/immunology , Vaccines, Subunit/chemistry , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/immunology , Viral Vaccines/chemistry
19.
Med Hypotheses ; 143: 110153, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-688792

ABSTRACT

Reports from various countries suggest that tobacco smoking might protect from SARS-CoV-2 infection, since the prevalence of smoking in COVID-19 hospitalized patients is lower than in the respective general population. Apart from nicotine or other chemicals contained in tobacco smoke, we propose that a single-stranded RNA virus that infects tobacco leaves, tobacco mosaic virus (TMV), might be implicated in this effect. TMV, though non-pathogenic, is found in smokers' airways, and stimulates adaptive and innate immunity, with release of specific antibodies and interferons. The latter may have preventive and/or therapeutic effects against COVID-19. If confirmed by epidemiological and interventional studies, this might lead to the use of TMV as an immunological adjuvant against SARS-CoV-2 infection and COVID-19 disease.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Models, Immunological , Pandemics , Pneumonia, Viral/immunology , Smokers , Tobacco Mosaic Virus/immunology , Tobacco Products/virology , Tobacco Smoking , Animals , Antibodies, Viral/biosynthesis , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disease Resistance , Humans , Interferons/biosynthesis , Mice , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Respiratory System/immunology , Respiratory System/virology , SARS-CoV-2 , Tobacco Mosaic Virus/isolation & purification , Tobacco Smoking/epidemiology , Toll-Like Receptors/immunology
20.
Front Immunol ; 11: 1409, 2020.
Article in English | MEDLINE | ID: covidwho-680017

ABSTRACT

As the world is severely affected by COVID-19 pandemic, the use of chloroquine and hydroxychloroquine in prevention or for the treatment of patients is allowed in multiple countries but remained at the center of much controversy in recent days. This review describes the properties of chloroquine and hydroxychloroquine, and highlights not only their anti-viral effects but also their important immune-modulatory properties and their well-known use in autoimmune diseases, including systemic lupus and arthritis. Chloroquine appears to inhibit in vitro SARS virus' replication and to interfere with SARS-CoV2 receptor (ACE2). Chloroquine and hydroxychloroquine impede lysosomal activity and autophagy, leading to a decrease of antigen processing and presentation. They are also known to interfere with endosomal Toll-like receptors signaling and cytosolic sensors of nucleic acids, which result in a decreased cellular activation and thereby a lower type I interferons and inflammatory cytokine secretion. Given the antiviral and anti-inflammatory properties of chloroquine and hydroxychloroquine, there is a rational to use them against SARS-CoV2 infection. However, the anti-interferon properties of these molecules might be detrimental, and impaired host immune responses against the virus. This duality could explain the discrepancy with the recently published studies on CQ/HCQ treatment efficacy in COVID-19 patients. Moreover, although these treatments could be an interesting potential strategy to limit progression toward uncontrolled inflammation, they do not appear per se sufficiently potent to control the whole inflammatory process in COVID-19, and more targeted and/or potent therapies should be required at least in add-on.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Hydroxychloroquine/therapeutic use , Pandemics , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2 , Antigen Presentation , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Humans , Lysosomes/immunology , Lysosomes/virology , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , SARS-CoV-2 , Toll-Like Receptors/immunology , Virus Replication/immunology
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