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1.
QJM ; 2023 Jan 20.
Article in English | MEDLINE | ID: covidwho-2311734

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock, or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NLRP3 inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the pro-inflammatory cytokines IL-1ß and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.

2.
Med (N Y) ; 2(2): 113-114, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-2275991

ABSTRACT

Iron deficiency has been linked to impaired humoral immunity to vaccines. In this issue of Med, Frost et al. demonstrate the importance of serum iron levels for lymphocyte function during vaccination and infection, pointing to iron supplementation as a strategy to boost vaccine efficacy, including against COVID19.1.


Subject(s)
COVID-19 , Hepcidins , COVID-19/prevention & control , Humans , Immunity, Humoral , Iron , Vaccination , Vaccine Efficacy
3.
Curr Opin Immunol ; 80: 102268, 2022 Nov 25.
Article in English | MEDLINE | ID: covidwho-2233156

ABSTRACT

The metabolite itaconate (ITA) and its derivatives, both chemically synthesized and endogenous, have emerged as immunoregulators, with roles in limiting inflammation but also having effects on bacterial and viral infection. Some members of the ITA family have been shown to target and inhibit multiple processes in macrophages with recently identified targets, including NLRP3, JAK1, ten-eleven translocation-2 dioxygenases, and TFEB, a key transcription factor for lysosomal biogenesis. They have also been shown to target multiple bacteria, inhibiting their replication, as well as having antiviral effects against viruses such as SARS-CoV2, Zika virus, and Influenza virus. The importance of ITA is highlighted by the fact that several pathogens have developed mechanisms to evade ITA and can manipulate ITA for their own gain. Two newly discovered isomers of ITA, mesaconate and citraconate, are also discussed, which also have immunomodulatory effects. ITA continues to be a fascination, both in terms of inflammation but also as an antibacterial and antiviral agent, with therapeutic potential in immune and inflammatory diseases.

4.
Clinical Spectroscopy ; 4:100022-100022, 2022.
Article in English | EuropePMC | ID: covidwho-1842696

ABSTRACT

Vibrational spectroscopic techniques, both infrared absorption and Raman scattering, are high precision, label free analytical techniques which have found applications in fields as diverse as analytical chemistry, pharmacology, forensics and archeometrics and, in recent times, have attracted increasing attention for biomedical applications. As analytical techniques, they have been applied to the characterisation of viruses as early as the 1970 s, and, in the context of the coronavirus disease 2019 (COVID-19) pandemic, have been explored in response to the World Health Organisation as novel methodologies to aid in the global efforts to implement and improve rapid screening of viral infection. This review considers the history of the application of vibrational spectroscopic techniques to the characterisation of the morphology and chemical compositions of viruses, their attachment to, uptake by and replication in cells, and their potential for the detection of viruses in population screening, and in infection response monitoring applications. Particular consideration is devoted to recent efforts in the detection of severe acute respiratory syndrome coronavirus 2, and monitoring COVID-19.

5.
Biochem J ; 479(6): 731-750, 2022 03 31.
Article in English | MEDLINE | ID: covidwho-1764226

ABSTRACT

The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional 'waterfall' model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1ß and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.


Subject(s)
COVID-19 Drug Treatment , Thrombosis , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Humans , Inflammation/complications , Pyroptosis , SARS-CoV-2 , Thromboinflammation , Thromboplastin/metabolism
6.
Crit Rev Clin Lab Sci ; 59(7): 445-459, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1740611

ABSTRACT

A plethora of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic tests are available, each with different performance specifications, detection methods, and targets. This narrative review aims to summarize the diagnostic technologies available and how they are best selected to tackle SARS-CoV-2 infection as the pandemic evolves. Seven key settings have been identified where diagnostic tests are being deployed: symptomatic individuals presenting for diagnostic testing and/or treatment of COVID-19 symptoms; asymptomatic individuals accessing healthcare for planned non-COVID-19-related reasons; patients needing to access emergency care (symptom status unknown); patients being discharged from healthcare following hospitalization for COVID-19; healthy individuals in both single event settings (e.g. airports, restaurants, hotels, concerts, and sporting events) and repeat access settings (e.g. workplaces, schools, and universities); and vaccinated individuals. While molecular diagnostics remain central to SARS-CoV-2 testing strategies, we have offered some discussion on the considerations for when other tools and technologies may be useful, when centralized/point-of-care testing is appropriate, and how the various additional diagnostics can be deployed in differently resourced settings. As the pandemic evolves, molecular testing remains important for definitive diagnosis, but increasingly widespread point-of-care testing is essential to the re-opening of society.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19 Testing , COVID-19/diagnosis , Pandemics , Point-of-Care Testing , Sensitivity and Specificity
7.
Curr Res Pharmacol Drug Discov ; 2: 100048, 2021.
Article in English | MEDLINE | ID: covidwho-1372950

ABSTRACT

Dexamethasone, a corticosteroid, has been approved for use in the treatment of severe COVID-19, which is characterised by hyperinflammation and associated lung damage. However, dexamethasone shows no clinical benefit in the treatment of less severe disease, and prolonged treatment may lead to immunosuppression and an increased risk of opportunistic infections. Hence there is a need for more specific anti-inflammatory therapies which also prevent severe disease. The NLRP3 inflammasome is an intracellular signalling complex which is responsible for the cleavage and release of the cytokines IL-1ß and IL-18 and has also been shown to be inhibited by dexamethasone. NLRP3 inflammasome activation is strongly correlated with COVID-19 severity and part of dexamethasone's clinical effect in COVID-19 may be via NLRP3 inhibition. Specific NLRP3 inhibitors are currently undergoing clinical trials for the treatment of COVID-19. In this review, we evaluate the evidence supporting the use of dexamethasone and speculate on the potential use of NLRP3 inhibitors to treat COVID-19 as a more specific approach that may not have the liabilities of dexamethasone.

8.
Immunother Adv ; 1(1): ltab013, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1303911

ABSTRACT

The COVID-19 crisis has emphasised the need for antiviral therapies to combat current and future viral zoonoses. Recent studies have shown that immune cells such as macrophages are the main contributors to the inflammatory response seen in the later inflammatory phase of COVID-19. Immune cells in the context of a viral infection such as SARS-CoV-2 undergo metabolic reprogramming to elicit these pro-inflammatory effector functions. The evidence of metabolic reprogramming in COVID-19 offers opportunities for metabolites with immunomodulatory properties to be investigated as potential therapies to combat this hyper-inflammatory response. Recent research indicates that the metabolite itaconate, previously known to be broadly antibacterial, may have both antiviral and immunomodulatory potential. Furthermore, low itaconate levels have shown to correlate with COVID-19 disease severity, potentially implicating its importance in the disease. The antiviral potential of itaconate has encouraged researchers to synthesise itaconate derivatives for antiviral screening, with some encouraging results. This review summarises the antiviral and immunomodulatory potential of immunometabolic modulators including metformin, peroxisome proliferator-activated receptor agonists and TEPP-46 as well as itaconate, and its derivatives and their potential use as broad spectrum anti-viral agents.

10.
Virus Res ; 287: 198094, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-680841

ABSTRACT

The past century has witnessed major advances in the control of many infectious diseases, yet outbreaks and epidemics caused by (re-) emerging RNA viruses continue to pose a global threat to human health. As illustrated by the global COVID19 pandemic, high healthcare costs, economic disruption and loss of productivity reinforce the unmet medical need to develop new antiviral strategies to combat not only the current pandemic but also future viral outbreaks. Pivotal for effective anti-viral defense is the innate immune system, a first line host response that senses and responds to virus infection. While molecular details of the innate immune response are well characterized, this research field is now being revolutionized with the recognition that cell metabolism has a major impact on the antiviral and inflammatory responses to virus infections. A detailed understanding of the role of metabolic regulation with respect to antiviral and inflammatory responses, together with knowledge of the strategies used by viruses to exploit immunometabolic pathways, will ultimately change our understanding and treatment of pathogenic viral diseases. INITIATE is a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN), with the goal to train 15 early stage PhD researchers (ESRs) to become experts in antiviral immunometabolism (https://initiate-itn.eu/). To this end, INITIATE brings together a highly complementary international team of academic and corporate leaders from 7 European countries, with outstanding track records in the historically distinct research fields of virology, immunology and metabolism. The ESRs of INITIATE are trained in these interdisciplinary research fields through individual investigator-driven research projects, specialized scientific training events, workshops on academia-industry interactions, outreach & communication. INITIATE will deliver a new generation of creative and entrepreneurial researchers who will be able to face the inevitable future challenges in combating viral diseases.


Subject(s)
Betacoronavirus/immunology , Biomedical Research/methods , Coronavirus Infections/drug therapy , Education, Medical/methods , Immunity, Innate/immunology , Pneumonia, Viral/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/economics , Delivery of Health Care/economics , Delivery of Health Care/methods , Host-Pathogen Interactions/physiology , Humans , Pandemics/economics , Pneumonia, Viral/economics , SARS-CoV-2
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