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2.
Eur J Neurol ; 28(10): 3503-3516, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1608969

ABSTRACT

OBJECTIVE: The outbreak of the SARS-CoV-2 pandemic, caused by a previously unknown infectious agent, posed unprecedented challenges to healthcare systems and unmasked their vulnerability and limitations worldwide. Patients with long-term immunomodulatory/suppressive therapies, as well as their physicians, were and are concerned about balancing the risk of infection and effects of disease-modifying therapy. Over the last few months, knowledge regarding SARS-CoV-2 has been growing tremendously, and the first experiences of infections in patients with multiple sclerosis (MS) have been reported. METHODS: This review summarizes the currently still limited knowledge about SARS-CoV-2 immunology and the commonly agreed modes of action of approved drugs in immune-mediated diseases of the central nervous system (MS and neuromyelitis optica spectrum disorder). Specifically, we discuss whether immunosuppressive/immunomodulatory drugs may increase the risk of SARS-CoV-2 infection and, conversely, may decrease the severity of a COVID-19 disease course. RESULTS: At present, it can be recommended in general that none of those therapies with a definite indication needs to be stopped per se. A possibly increased risk of infection for most medications is accompanied by the possibility to reduce the severity of COVID-19. CONCLUSIONS: Despite the knowledge gain over the last few months, current evidence remains limited, and, thus, further clinical vigilance and systematic documentation is essential.


Subject(s)
COVID-19 , Multiple Sclerosis , Neuromyelitis Optica , Humans , Multiple Sclerosis/drug therapy , Multiple Sclerosis/epidemiology , Neuromyelitis Optica/epidemiology , Pandemics , SARS-CoV-2
3.
Biophys J ; 120(14): 2880-2889, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1606842

ABSTRACT

Coronaviruses have caused multiple epidemics in the past two decades, in addition to the current COVID-19 pandemic that is severely damaging global health and the economy. Coronaviruses employ between 20 and 30 proteins to carry out their viral replication cycle, including infection, immune evasion, and replication. Among these, nonstructural protein 16 (Nsp16), a 2'-O-methyltransferase, plays an essential role in immune evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA to enhance translation efficiency and distinguish self from other. Unlike human CMTr1, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity. The requirement of this binding partner presents two questions that we investigate in this manuscript. First, how does Nsp10 activate Nsp16? Although experimentally derived structures of the active Nsp16/Nsp10 complex exist, structures of inactive, monomeric Nsp16 have yet to be solved. Therefore, it is unclear how Nsp10 activates Nsp16. Using over 1 ms of molecular dynamics simulations of both Nsp16 and its complex with Nsp10, we investigate how the presence of Nsp10 shifts Nsp16's conformational ensemble to activate it. Second, guided by this activation mechanism and Markov state models, we investigate whether Nsp16 adopts inactive structures with cryptic pockets that, if targeted with a small molecule, could inhibit Nsp16 by stabilizing its inactive state. After identifying such a pocket in SARS-CoV2 Nsp16, we show that this cryptic pocket also opens in SARS-CoV1 and MERS but not in human CMTr1. Therefore, it may be possible to develop pan-coronavirus antivirals that target this cryptic pocket.

4.
Rev Med Virol ; 31(5): 1-14, 2021 09.
Article in English | MEDLINE | ID: covidwho-1575050

ABSTRACT

Of all the nutrients, vitamin A has been the most extensively evaluated for its impact on immunity. There are three main forms of vitamin A, retinol, retinal and retinoic acid (RA) with the latter being most biologically active and all-trans-RA (ATRA) its main derivative. Vitamin A is a key regulator of the functions of various innate and adaptive immune cells and promotes immune-homeostasis. Importantly, it augments the interferon-based innate immune response to RNA viruses decreasing RNA virus replication. Several clinical trials report decreased mortality in measles and Ebola with vitamin A supplementation.During the Covid-19 pandemic interventions such as convalescent plasma, antivirals, monoclonal antibodies and immunomodulator drugs have been tried but most of them are difficult to implement in resource-limited settings. The current review explores the possibility of mega dose vitamin A as an affordable adjunct therapy for Covid-19 illness with minimal reversible side effects. Insight is provided into the effect of vitamin A on ACE-2 expression in the respiratory tract and its association with the prognosis of Covid-19 patients. Vitamin A supplementation may aid the generation of protective immune response to Covid-19 vaccines. An overview of the dosage and safety profile of vitamin A is presented along with recommended doses for prophylactic/therapeutic use in randomised controlled trials in Covid-19 patients.


Subject(s)
COVID-19/immunology , COVID-19/prevention & control , Vitamin A/administration & dosage , Animals , COVID-19/virology , Humans , Immunity/drug effects , Immunomodulation/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Vitamin A/analysis
5.
Front Vet Sci ; 7: 570748, 2020.
Article in English | MEDLINE | ID: covidwho-1573664

ABSTRACT

The novel coronavirus (SARS-CoV-2) infection (COVID-19) has raised considerable concern on the entire planet. On March 11, 2020, COVID-19 was categorized by the World Health Organization (WHO) as a pandemic infection, and by March 18, 2020, it has spread to 146 countries. The first internal defense line against numerous diseases is personalized immunity. Although it cannot be claimed that personalized nutrition will have an immediate impact on a global pandemic, as the nutritional interventions required a long time to induce beneficial outcomes on immunity development, nutritional strategies are still able to clarify and have a beneficial influence on the interplay between physiology and diet, which could make a positive contribution to the condition in the next period. As such, a specific goal for every practitioner is to evaluate different tests to perceive the status of the patient, such as markers of inflammation, insulin regulation, and nutrient status, and to detect possible imbalances or deficiencies. During the process of disease development, the supplementation and addition of different nutrients and nutraceuticals can influence not only the viral replication but also the cellular mechanisms. It is essential to understand that every patient has its individual needs. Even though many nutrients, nutraceuticals, and drugs have beneficial effects on the immune response and can prevent or ameliorate viral infections, it is essential to detect at what stage in COVID-19 progression the patient is at the moment and decide what kind of nutrition intervention is necessary. Furthermore, understanding the pathogenesis of coronavirus infection is critical to make proper recommendations.

6.
Viral Immunol ; 34(3): 165-173, 2021 04.
Article in English | MEDLINE | ID: covidwho-1569564

ABSTRACT

The current pandemic is caused by the coronavirus disease 2019 (COVID-19), which is, in turn, induced by a novel coronavirus (SARS-CoV-2) that triggers an acute respiratory disease. In recent years, the emergence of SARS-CoV-2 is the third highly pathogenic event and large-scale epidemic affecting the human population. It follows the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. This novel SARS-CoV-2 employs the angiotensin-converting enzyme 2 (ACE2) receptor, like SARS-CoV, and spreads principally in the respiratory tract. The viral spike (S) protein of coronaviruses facilities the attachment to the cellular receptor, entrance, and membrane fusion. The S protein is a glycoprotein and is critical to elicit an immune response. Glycosylation is a biologically significant post-translational modification in virus surface proteins. These glycans play important roles in the viral life cycle, structure, immune evasion, and cell infection. However, it is necessary to search for new information about viral behavior and immunological host's response after SARS-CoV-2 infection. The present review discusses the implications of the CoV-2 S protein glycosylation in the SARS-CoV-2/ACE2 interaction and the immunological response. Elucidation of the glycan repertoire on the spike protein can propel research for the development of an appropriate vaccine.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/physiology , Glycosylation , Humans , SARS-CoV-2/chemistry , SARS-CoV-2/genetics
9.
Angiogenesis ; 24(3): 677-693, 2021 08.
Article in English | MEDLINE | ID: covidwho-1549443

ABSTRACT

Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak.

10.
Pan Afr Med J ; 38: 93, 2021.
Article in French | MEDLINE | ID: covidwho-1547720

ABSTRACT

Introduction: SARS-CoV-2 serology tests could play a crucial role in estimating the prevalence of COVID-19. The purpose of this study was to estimate the prevalence of COVID-19 among travellers and workers in Bukavu, a city in eastern Democratic Republic of the Congo. Methods: between May and August 2020, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test (Cellex, Inc., USA), lateral flow immunoassay was used to rapidly detect and differentiate antibodies against SARS-CoV-2 among travellers and workers seeking medical certification. Results: among the 684 residents of the city of Bukavu screened for COVID-19 (4.2% Hispanic, 2.8% other African, 0.9% Asian), the seroprevalence anti-SARS-CoV-2 antibodies was 40.8% (IgG+/IgM+: 34.6%; IgG+/IgM-: 0.5%; IgG-/IgM+: 5.4%). Cumulative seroprevalence of anti-SARS-CoV-2 IgG antibodies increased from 24.5% to 35.2% from May to August 2020. Independent predictors of SARS-CoV-2 antibodies were age > 60 years [adjusted OR = 2.07(1.26-3.38)] and non-membership of the medical staff [adjusted OR = 2.28 (1.22-4.26)]. Thirteen point nine percent of patients seropositive for SARS-CoV-2 antibodies were symptomatic and hospitalized. Conclusion: this study shows a very high seroprevalence of SARS-CoV-2 antibodies among travellers and workers in Bukavu, a city in eastern Democratic Republic of the Congo, which may positively affect community immunity in the study population. Thus, the management of COVID-19 should be contextualized according to local realities.


Subject(s)
Antibodies, Viral/blood , COVID-19/epidemiology , SARS-CoV-2/isolation & purification , Travel , Adult , Age Factors , Aged , COVID-19/diagnosis , Democratic Republic of the Congo/epidemiology , Female , Hospitalization/statistics & numerical data , Humans , Immunoassay , Male , Middle Aged , SARS-CoV-2/immunology , Seroepidemiologic Studies
11.
Jpn J Infect Dis ; 74(6): 530-536, 2021 Nov 22.
Article in English | MEDLINE | ID: covidwho-1534555

ABSTRACT

It is important to determine the inflammatory biomarkers in the severity of coronavirus disease 2019 (COVID-19) with the emergence of the pandemic. Galectins and prostaglandins play important roles in the regulation of immune and inflammatory responses. Therefore, this study aimed to investigate Galectin-1 (Gal-1), Galectin-3 (Gal-3), and prostaglandin E2 (PGE2) levels in patients with COVID-19. Serum concentrations of Gal-1, Gal-3, and PGE2 were measured using enzyme-linked immunosorbent assay on 84 patients with COVID-19 (severe = 29 and nonsevere = 55) and 56 healthy controls. In this study, increased levels of Gal-1 (median, 9.86, 6.35, and 3.67 ng/mL), Gal-3 (median, 415.31, 326.33, and 243.13 pg/mL), and PGE2 (median, 193.17, 192.58, and 124.62 pg/mL) levels were found in patients with COVID-19 than in healthy controls (P < 0.001 for all). In the severe disease group, Gal-3 levels were higher, while no differences were noted in Gal-1 and PGE2 levels (P = 0.011, P = 0.263, and P = 0.921, respectively). Serum levels of Gal-1 were positively correlated with those of Gal-3 (P = 0.871 and P < 0.001). Gal-3, C-reactive protein, lymphocyte count, and age were found as independent predictors of disease severity (P = 0.002, P = 0.001, P = 0.007, and P = 0.003, respectively). With the emergence of effective drug needs in the COVID-19 pandemic, differentiation of severe disease is important. Therefore, Gal-3 could be a potential prognostic biomarker of COVID-19.

12.
Int J Biol Sci ; 17(4): 1079-1087, 2021.
Article in English | MEDLINE | ID: covidwho-1524445

ABSTRACT

Fibrinogen-associated protein (FREP) family is a family of proteins with a fibrin domain at the carboxyl terminus. Recent investigations illustrated that two members of FREP family, fibrinogen-like protein-1 (FGL1) and fibrinogen-like protein-2 (FGL2), play crucial roles in cancer by regulating the proliferation, invasion, and migration of tumor cells, or regulating the functions of immune cells in tumor microenvironment. Meanwhile, they are potential targets for medical intervention of tumor development. In this review, we discussed the structure, and the roles of FGL1 and FGL2 in tumors, especially the roles in regulating immune cell functions.

13.
Emerg Microbes Infect ; 10(1): 365-375, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1490458

ABSTRACT

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.


Subject(s)
Hepatitis E/immunology , Human papillomavirus 16/immunology , Human papillomavirus 18/immunology , Papillomavirus Infections/immunology , Papillomavirus Vaccines/immunology , Vaccines, Synthetic/immunology , Viral Hepatitis Vaccines/immunology , Adolescent , Adult , Aged , Antibodies, Viral/immunology , Female , Hepatitis E/prevention & control , Hepatitis E/virology , Human papillomavirus 16/genetics , Human papillomavirus 18/genetics , Humans , Immunity , Immunoglobulin G/immunology , Male , Middle Aged , Papillomavirus Infections/prevention & control , Papillomavirus Infections/virology , Papillomavirus Vaccines/administration & dosage , Papillomavirus Vaccines/adverse effects , Papillomavirus Vaccines/genetics , Vaccination/adverse effects , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/genetics , Viral Hepatitis Vaccines/administration & dosage , Viral Hepatitis Vaccines/adverse effects , Viral Hepatitis Vaccines/genetics , Young Adult
14.
Aging Clin Exp Res ; 33(7): 2031-2041, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1491488

ABSTRACT

BACKGROUND: The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has re-ignited interest in the possible role of vitamin D in modulation of host responses to respiratory pathogens. Indeed, vitamin D supplementation has been proposed as a potential preventative or therapeutic strategy. Recommendations for any intervention, particularly in the context of a potentially fatal pandemic infection, should be strictly based on clinically informed appraisal of the evidence base. In this narrative review, we examine current evidence relating to vitamin D and COVID-19 and consider the most appropriate practical recommendations. OBSERVATIONS: Although there are a growing number of studies investigating the links between vitamin D and COVID-19, they are mostly small and observational with high risk of bias, residual confounding, and reverse causality. Extrapolation of molecular actions of 1,25(OH)2-vitamin D to an effect of increased 25(OH)-vitamin D as a result of vitamin D supplementation is generally unfounded, as is the automatic conclusion of causal mechanisms from observational studies linking low 25(OH)-vitamin D to incident disease. Efficacy is ideally demonstrated in the context of adequately powered randomised intervention studies, although such approaches may not always be feasible. CONCLUSIONS: At present, evidence to support vitamin D supplementation for the prevention or treatment of COVID-19 is inconclusive. In the absence of any further compelling data, adherence to existing national guidance on vitamin D supplementation to prevent vitamin D deficiency, predicated principally on maintaining musculoskeletal health, appears appropriate.


Subject(s)
COVID-19 , Vitamin D Deficiency , Humans , SARS-CoV-2 , Vitamin D , Vitamins
15.
Pharmaceutics ; 13(5)2021 May 01.
Article in English | MEDLINE | ID: covidwho-1457507

ABSTRACT

Subunit vaccines based on antigen-encoding nucleic acids have shown great promise for antigen-specific immunization against cancer and infectious diseases. Vaccines require immunostimulatory adjuvants to activate the innate immune system and trigger specific adaptive immune responses. However, the incorporation of immunoadjuvants into nonviral nucleic acid delivery systems often results in fairly complex structures that are difficult to mass-produce and characterize. In recent years, minimalist approaches have emerged to reduce the number of components used in vaccines. In these approaches, delivery materials, such as lipids and polymers, and/or pDNA/mRNA are designed to simultaneously possess several functionalities of immunostimulatory adjuvants. Such multifunctional immunoadjuvants encode antigens, encapsulate nucleic acids, and control their pharmacokinetic or cellular fate. Herein, we review a diverse class of multifunctional immunoadjuvants in nucleic acid subunit vaccines and provide a detailed description of their mechanisms of adjuvanticity and induction of specific immune responses.

16.
Vaccines (Basel) ; 8(3)2020 Sep 22.
Article in English | MEDLINE | ID: covidwho-1438751

ABSTRACT

In modern vaccines, adjuvants can be sophisticated immunological tools to promote robust and long-lasting protection against prevalent diseases. However, there is an urgent need to improve immunogenicity of vaccines in order to protect mankind from life-threatening diseases such as AIDS, malaria or, most recently, COVID-19. Therefore, it is important to understand the cellular and molecular mechanisms of action of vaccine adjuvants, which generally trigger the innate immune system to enhance signal transition to adaptive immunity, resulting in pathogen-specific protection. Thus, improved understanding of vaccine adjuvant mechanisms may aid in the design of "intelligent" vaccines to provide robust protection from pathogens. Various commonly used clinical adjuvants, such as aluminium salts, saponins or emulsions, have been identified as activators of inflammasomes - multiprotein signalling platforms that drive activation of inflammatory caspases, resulting in secretion of pro-inflammatory cytokines of the IL-1 family. Importantly, these cytokines affect the cellular and humoral arms of adaptive immunity, which indicates that inflammasomes represent a valuable target of vaccine adjuvants. In this review, we highlight the impact of different inflammasomes on vaccine adjuvant-induced immune responses regarding their mechanisms and immunogenicity. In this context, we focus on clinically relevant adjuvants that have been shown to activate the NLRP3 inflammasome and also present various experimental adjuvants that activate the NLRP3-, NLRC4-, AIM2-, pyrin-, or non-canonical inflammasomes and could have the potential to improve future vaccines. Together, we provide a comprehensive overview on vaccine adjuvants that are known, or suggested, to promote immunogenicity through inflammasome-mediated signalling.

17.
J Clin Invest ; 130(11): 6151-6157, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1435146

ABSTRACT

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.


Subject(s)
Betacoronavirus , Complement Membrane Attack Complex , Coronavirus Infections , Extracellular Traps , Neutrophils , Pandemics , Pneumonia, Viral , Thromboplastin , Thrombosis , Aged , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Complement Activation/drug effects , Complement Membrane Attack Complex/immunology , Complement Membrane Attack Complex/metabolism , Coronavirus Infections/blood , Coronavirus Infections/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Peptides, Cyclic/pharmacology , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/blood , Receptor, Anaphylatoxin C5a/immunology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Thrombin/immunology , Thrombin/metabolism , Thromboplastin/immunology , Thromboplastin/metabolism , Thrombosis/blood , Thrombosis/immunology , Thrombosis/virology
18.
Res Sq ; 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1417405

ABSTRACT

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

19.
Front Immunol ; 12: 624293, 2021.
Article in English | MEDLINE | ID: covidwho-1394756

ABSTRACT

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which interacts with a wide range of organic molecules of endogenous and exogenous origin, including environmental pollutants, tryptophan metabolites, and microbial metabolites. The activation of AHR by these agonists drives its translocation into the nucleus where it controls the expression of a large number of target genes that include the AHR repressor (AHRR), detoxifying monooxygenases (CYP1A1 and CYP1B1), and cytokines. Recent advances reveal that AHR signaling modulates aspects of the intrinsic, innate and adaptive immune response to diverse microorganisms. This review will focus on the increasing evidence supporting a role for AHR as a modulator of the host response to viral infection.


Subject(s)
Adaptive Immunity , Immunity, Innate , Receptors, Aryl Hydrocarbon/metabolism , Virus Diseases/virology , Viruses/immunology , Active Transport, Cell Nucleus , Animals , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Ligands , Signal Transduction , Virus Diseases/genetics , Virus Diseases/immunology , Virus Diseases/metabolism , Viruses/genetics , Viruses/pathogenicity
20.
Int J Mol Sci ; 22(9)2021 Apr 27.
Article in English | MEDLINE | ID: covidwho-1390655

ABSTRACT

The identification of thrombospondin-1 as an angiogenesis inhibitor in 1990 prompted interest in its role in cancer biology and potential as a therapeutic target. Decreased thrombospondin-1 mRNA and protein expression are associated with progression in several cancers, while expression by nonmalignant cells in the tumor microenvironment and circulating levels in cancer patients can be elevated. THBS1 is not a tumor suppressor gene, but the regulation of its expression in malignant cells by oncogenes and tumor suppressor genes mediates some of their effects on carcinogenesis, tumor progression, and metastasis. In addition to regulating angiogenesis and perfusion of the tumor vasculature, thrombospondin-1 limits antitumor immunity by CD47-dependent regulation of innate and adaptive immune cells. Conversely, thrombospondin-1 is a component of particles released by immune cells that mediate tumor cell killing. Thrombospondin-1 differentially regulates the sensitivity of malignant and nonmalignant cells to genotoxic stress caused by radiotherapy and chemotherapy. The diverse activities of thrombospondin-1 to regulate autophagy, senescence, stem cell maintenance, extracellular vesicle function, and metabolic responses to ischemic and genotoxic stress are mediated by several cell surface receptors and by regulating the functions of several secreted proteins. This review highlights progress in understanding thrombospondin-1 functions in cancer and the challenges that remain in harnessing its therapeutic potential.


Subject(s)
Neoplasms , Thrombospondin 1/physiology , Tumor Microenvironment/physiology , Animals , Cell Adhesion , Cell Movement , Humans , Integrins/metabolism , Mice , Neoplasms/blood supply , Neoplasms/immunology , Neoplasms/pathology , Neovascularization, Pathologic/metabolism , Neovascularization, Physiologic/genetics , T-Lymphocytes/immunology , Thrombospondin 1/genetics , Thrombospondin 1/metabolism
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