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1.
Bioorg Med Chem ; 46: 116356, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1347508

ABSTRACT

The ongoing COVID-19 pandemic, periodic recurrence of viral infections, and the emergence of challenging variants has created an urgent need of alternative therapeutic approaches to combat the spread of viral infections, failing to which may pose a greater risk to mankind in future. Resilience against antiviral drugs or fast evolutionary rate of viruses is stressing the scientific community to identify new therapeutic approaches for timely control of disease. Host metabolic pathways are exquisite reservoir of energy to viruses and contribute a diverse array of functions for successful replication and pathogenesis of virus. Targeting the host factors rather than viral enzymes to cease viral infection, has emerged as an alternative antiviral strategy. This approach offers advantage in terms of increased threshold to viral resistance and can provide broad-spectrum antiviral action against different viruses. The article here provides substantial review of literature illuminating the host factors and molecular mechanisms involved in innate/adaptive responses to viral infection, hijacking of signalling pathways by viruses and the intracellular metabolic pathways required for viral replication. Host-targeted drugs acting on the pathways usurped by viruses are also addressed in this study. Host-directed antiviral therapeutics might prove to be a rewarding approach in controlling the unprecedented spread of viral infection, however the probability of cellular side effects or cytotoxicity on host cell should not be ignored at the time of clinical investigations.


Subject(s)
Antiviral Agents/pharmacology , Positive-Strand RNA Viruses/drug effects , Animals , Cytokines/metabolism , Frameshifting, Ribosomal/drug effects , Frameshifting, Ribosomal/physiology , Glycosylation/drug effects , Humans , Immunity/drug effects , Immunity/physiology , Lipid Metabolism/drug effects , Lipid Metabolism/physiology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/physiology , Polyamines/metabolism , Positive-Strand RNA Viruses/physiology , Signal Transduction/drug effects , Signal Transduction/physiology , Ubiquitination/drug effects , Ubiquitination/physiology
2.
PLoS One ; 16(8): e0255335, 2021.
Article in English | MEDLINE | ID: covidwho-1341502

ABSTRACT

The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.


Subject(s)
COVID-19/pathology , Dinoprostone/blood , Immunity , Adolescent , Adult , Animals , COVID-19/blood , COVID-19/immunology , Case-Control Studies , Cells, Cultured , Chlorocebus aethiops , Dinoprostone/pharmacology , Dinoprostone/physiology , Disease Progression , Female , Humans , Immunity/drug effects , Immunity/physiology , Male , Middle Aged , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Vero Cells , Young Adult
4.
Nat Med ; 27(3): 454-462, 2021 03.
Article in English | MEDLINE | ID: covidwho-1319036

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2.


Subject(s)
Antibodies, Viral/blood , COVID-19/epidemiology , SARS-CoV-2/immunology , Adolescent , Adult , Age of Onset , Aged , Antibodies, Neutralizing/analysis , Antibodies, Neutralizing/blood , Antibodies, Viral/analysis , Asymptomatic Infections , COVID-19/blood , COVID-19/pathology , Carrier State/blood , Carrier State/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Humans , Immunity/physiology , Immunoglobulin A/blood , Immunoglobulin G/blood , Infant , Infant, Newborn , Male , Middle Aged , Pandemics , Severity of Illness Index , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/epidemiology , Young Adult
5.
Womens Health (Lond) ; 17: 17455065211022262, 2021.
Article in English | MEDLINE | ID: covidwho-1259152

ABSTRACT

In COVID-19 disease, are reported gender differences in relation to severity and death. The aim of this review is to highlight gender differences in the immune response to COVID-19. The included studies were identified using PubMed, until 30 October 2020. The search included the following keywords: SARS-CoV-2, COVID-19, gender, age, sex, and immune system. Literature described that females compared to males have greater inflammatory, antiviral, and humoral immune responses. In female, estrogen is a potential ally to alleviate SARS-COV-2 disease. In male, testosterone reduces vaccination response and depresses the cytokine response. In the older patients, and in particular, in female older patients, it has been reported a progressive functional decline in the immune systems. Differences by gender were reported in infection diseases, including SARS-CoV-2. These data should be confirmed by the other epidemiological studies.


Subject(s)
Aging/immunology , COVID-19/immunology , Immune System/physiology , Immunity/physiology , Sex Factors , Estrogens/metabolism , Female , Humans , Male , SARS-CoV-2/immunology , Severity of Illness Index , Testosterone/metabolism , Vaccination
6.
Curr Res Transl Med ; 69(2): 103289, 2021 05.
Article in English | MEDLINE | ID: covidwho-1179993

ABSTRACT

Elevated PCT level in COVID-19 was associated with higher risk of severe disease and higher risk of overall mortality. An increased PCT level of PCT in COVID-19 patients especially in severe cases would be assumed as bacterial coinfection. Could PCT level increase in SARS-CoV-2 infection without bacterial coinfection? Several SARS-CoV-2 proteins activate STAT3-dependent transcriptional pathways particularly in monocytes, that could lead to increased PCT production. STAT3α isoform could cause increased ACE2 expression, resulting more SARS-CoV-2 infected cells and further production of PCT.


Subject(s)
Bacterial Infections/diagnosis , COVID-19/diagnosis , Coinfection/diagnosis , Procalcitonin/blood , SARS-CoV-2/immunology , Bacterial Infections/blood , Bacterial Infections/complications , Biomarkers/blood , COVID-19/blood , COVID-19/complications , COVID-19/immunology , Coinfection/blood , Coinfection/complications , Humans , Immunity/physiology , Monocytes/metabolism , Monocytes/virology , Predictive Value of Tests , Procalcitonin/metabolism , STAT3 Transcription Factor/metabolism , Severity of Illness Index , Signal Transduction/immunology
7.
J Nanobiotechnology ; 19(1): 59, 2021 Feb 25.
Article in English | MEDLINE | ID: covidwho-1105715

ABSTRACT

Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.


Subject(s)
COVID-19 Vaccines/therapeutic use , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/biosynthesis , COVID-19 Vaccines/immunology , Humans , Immunity/physiology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Vaccination/methods , Vaccines, Virus-Like Particle/biosynthesis , Vaccines, Virus-Like Particle/immunology , Vaccines, Virus-Like Particle/therapeutic use
8.
J Clin Pharmacol ; 61(8): 987-1000, 2021 08.
Article in English | MEDLINE | ID: covidwho-1103313

ABSTRACT

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), numerous research has been undertaken to delineate the various effects of the virus which manifests in many ways all over the body. The association between the SARS-CoV-2 invasion mechanism and the renin-angiotensin-aldosterone system (RAAS) receptors, created many debates about the possible consequences of using RAAS-modulating drugs including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) during the pandemic. Many clinical studies were conducted to assess the outcomes of coronavirus disease 2019 (COVID-19) in patients who use ACEi/ARBs following the arguments claiming to discontinue these drugs as a precautionary measure. Although several studies mainly analyzed the outcomes of the disease, this review aimed to compare specific blood markers in both groups of COVID-19 patients to gain better insight into the interaction of ACEi/ARBs with different body functions during the infection. Several databases were searched using a combination of keywords followed by screening and data extraction. Only 28 studies met our inclusion criteria, the majority of which showed no significant difference between the inflammation markers of COVID-19 patients who used or did not use ACEi/ARBs. Interestingly, 6 studies reported lower inflammatory markers in COVID-19 patients who used ACEi/ARBs, and 6 studies reported better outcomes among the same group. We therefore concluded that the use of ACEi/ARBs may not lead to worse prognosis of COVID-19 and may even play a protective role against the hyperinflammatory response associated with COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19 , Immunity , Renin-Angiotensin System/immunology , SARS-CoV-2/physiology , COVID-19/diagnosis , COVID-19/immunology , COVID-19/metabolism , Humans , Immunity/drug effects , Immunity/physiology , Prognosis , Protective Factors
9.
Curr Opin Pulm Med ; 27(3): 193-198, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1101917

ABSTRACT

PURPOSE OF REVIEW: The wide spectrum of COVID-19 clinical manifestations demonstrates the determinant role played by the individual immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the course of the disease. Thanks to the large number of published data, we are beginning to understand the logic of the human response to a virus adapted to bat immunity. RECENT FINDINGS: Impairment of types I and III interferon responses may facilitate the occurrence of severe COVID-19 with reduced antiviral activity associated to potent inflammation. The human T and B-cell germline repertoire contain the specificities able to react against SARS-CoV-2 antigens. Although inflammation disrupts the structure of germinal centers, memory T and B cells can be found in the blood of patients after mild and severe COVID 19. SUMMARY: Further studies are indispensable to better understand the human immune response to SARS-CoV-2. The diversity of the individual reaction may contribute to explain the clinical manifestation spectrum. Immunological memory can be demonstrated in patients, convalescent from mild, moderate, or severe COVID-19, but we do not know whether asymptomatic individuals have memory of the virus. Tailored vaccination protocols may be needed for individuals with previous SAS-CoV-2 infection.


Subject(s)
COVID-19 Vaccines/pharmacology , COVID-19 , Immunity/physiology , SARS-CoV-2/immunology , Asymptomatic Infections , COVID-19/immunology , COVID-19/physiopathology , COVID-19/prevention & control , Humans , Immunologic Memory , Severity of Illness Index
11.
Brain Behav Immun ; 91: 649-667, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064858

ABSTRACT

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.


Subject(s)
Stroke Rehabilitation/methods , Stroke/immunology , Stroke/physiopathology , Animals , Brain Ischemia/drug therapy , Comorbidity , Disease Models, Animal , Humans , Immunity/immunology , Immunity/physiology , Inflammation/immunology , Neuroprotection/immunology , Neuroprotection/physiology , Outcome Assessment, Health Care , Reperfusion/methods , Reperfusion/trends
12.
Respir Med ; 175: 106204, 2020 12.
Article in English | MEDLINE | ID: covidwho-1023739

ABSTRACT

COVID-19, the novel coronavirus pandemic, has already spread around the globe affecting more than 18 million people. As previously observed with other coronaviruses, SARS-CoV-2 deeply dysregulate the immune system eliciting respiratory failure and a state of systemic hyperinflammation in severely ill individuals. Immunotherapy is often used to downgrade the detrimental effects of the disease sustained by high-level of cytokines. Those treatments, however, are known to undermine patients' ability to contain tuberculosis (TB) infection. This study aims to describe interferon-γ release assay (IGRA) results in severe COVID-19 patients eligible for immunosuppressive treatment. Aggregate data were gathered from five hospitals in Milan, Italy, from March 1 to May 15, 2020 and retrospectively analyses. Results were summarized using absolute frequencies and percentages and compared using a two-sided Chi-squared test. Overall, 462 COVID-19 patients were eligible for immunosuppressive therapy, among which 335 were tested using IGRA testing. More than one-third of them (122/335; 36.4%) had an indeterminate IGRA result because of insufficient immune response to mitogen control, 19 (5.7%) tested positive and 194 (57.9) negative. The majority of patients with lymphocytopenia (i.e., total lymphocyte count [TLC] below 1000 cells/mm3) had indeterminate IGRAs (81/155; 52.3%). The proportion becomes even higher in patients with severe lymphocytopenia (i.e., TLC<500 cells/mm3) (36/57; 63%). Our results suggest a possible negative impact of COVID-19 related immune dysregulation on TB infection assessment and management. Close monitoring of individuals with or without retesting of individuals with indeterminate IGRAs and further basic science investigations should to be sought to better comprehend their implication on TB epidemiology.


Subject(s)
COVID-19/therapy , Interferon-gamma Release Tests/methods , Latent Tuberculosis/diagnosis , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Female , Humans , Immunity/physiology , Interferon-gamma Release Tests/statistics & numerical data , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Italy/epidemiology , Latent Tuberculosis/epidemiology , Latent Tuberculosis/immunology , Latent Tuberculosis/prevention & control , Lymphopenia/immunology , Male , Retrospective Studies , SARS-CoV-2/genetics , Severity of Illness Index
13.
Immunity ; 53(3): 510-523, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-761744

ABSTRACT

Integrated immunometabolic responses link dietary intake, energy utilization, and storage to immune regulation of tissue function and is therefore essential for the maintenance and restoration of homeostasis. Adipose-resident leukocytes have non-traditional immunological functions that regulate organismal metabolism by controlling insulin action, lipolysis, and mitochondrial respiration to control the usage of substrates for production of heat versus ATP. Energetically expensive vital functions such as immunological responses might have thus evolved to respond accordingly to dietary surplus and deficit of macronutrient intake. Here, we review the interaction of dietary intake of macronutrients and their metabolism with the immune system. We discuss immunometabolic checkpoints that promote healthspan and highlight how dietary fate and regulation of glucose, fat, and protein metabolism might affect immunity.


Subject(s)
Adipose Tissue/metabolism , Diet , Energy Metabolism/physiology , Immune System/physiology , Immunity/physiology , Caloric Restriction , Dietary Fats , Glucose/metabolism , Humans , Leukocytes/immunology , Macrophages/immunology , Obesity/pathology
14.
Biomed Pharmacother ; 135: 111233, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1009323

ABSTRACT

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has led to the ongoing global pandemic. Although most patients experience no or only mild symptoms, some patients can develop severe illness, such as progressive pneumonia, acute respiratory distress syndrome, secondary hemophagocytic lymphohistiocytosis and multiple organ failure caused by cytokine release syndrome. A majority of COVID-19 patients also develop gastrointestinal symptoms. These can present special challenges to the management of patients with inflammatory bowel disease (IBD) due to potential interactions between the immune response related to SARS-CoV-2 infection and dysregulated immunity associated with IBD. In this context, the pathogenesis of COVID-19 is reviewed in order to address these questions regarding immune interactions between COVID-19 and IBD.


Subject(s)
COVID-19/epidemiology , COVID-19/physiopathology , Immunity/physiology , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/physiopathology , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/immunology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/physiopathology , Humans , Immunity/drug effects , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology
15.
Cytometry B Clin Cytom ; 100(1): 33-41, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1006421

ABSTRACT

Over a remarkably short period of time, a great deal of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has been acquired, through the focused and cooperative effort of the international scientific community. Much has become known about how the immune response is coordinated to fight infection, and how it becomes dysregulated in severe disease. In this review, we take an in-depth look at the many immune features associated with the host response to SARS-CoV2, as well as those that appear to mark severe disease.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/immunology , Flow Cytometry/methods , Fluorescent Antibody Technique/methods , SARS-CoV-2/immunology , Biomarkers/analysis , COVID-19/pathology , COVID-19/therapy , Chemokines/analysis , Chemokines/metabolism , Cytokines/analysis , Cytokines/metabolism , Fluorescent Antibody Technique/trends , Host-Pathogen Interactions/immunology , Humans , Immunity/physiology , Metabolomics/methods , Metabolomics/trends , Risk Assessment , Severity of Illness Index
16.
Trends Microbiol ; 29(3): 224-237, 2021 03.
Article in English | MEDLINE | ID: covidwho-989295

ABSTRACT

Pathogens usurp host pathways to generate a permissive environment for their propagation. The current spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection presents the urgent need to understand the complex pathogen-host interplay for effective control of the virus. SARS-CoV-2 reorganizes the host cytoskeleton for efficient cell entry and controls host transcriptional processes to support viral protein translation. The virus also dysregulates innate cellular defenses using various structural and nonstructural proteins. This results in substantial but delayed hyperinflammation alongside a weakened interferon (IFN) response. We provide an overview of SARS-CoV-2 and its uniquely aggressive life cycle and discuss the interactions of various viral proteins with host signaling pathways. We also address the functional changes in SARS-CoV-2 proteins, relative to SARS-CoV. Our comprehensive assessment of host signaling in SARS-CoV-2 pathogenesis provides some complex yet important strategic clues for the development of novel therapeutics against this rapidly emerging worldwide crisis.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , COVID-19/metabolism , Humans , Immunity/physiology , Life Cycle Stages , Signal Transduction/physiology , Viral Proteins/genetics , Viral Proteins/metabolism
20.
Endocr Metab Immune Disord Drug Targets ; 20(6): 807-811, 2020.
Article in English | MEDLINE | ID: covidwho-689779
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