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1.
Viruses ; 12(5)2020 05 24.
Article in English | MEDLINE | ID: covidwho-1726014

ABSTRACT

Feline infectious peritonitis (FIP) is a viral disease with a high morbidity and mortality by the FIP virus (FIPV, virulent feline coronavirus). Several antiviral drugs for FIP have been identified, but many of these are expensive and not available in veterinary medicine. Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. We investigated whether HCQ in association with interferon-ω (IFN-ω) is effective for FIPV in vitro. A total of 100 µM of HCQ significantly inhibited the replication of types I and II FIPV. Interestingly, the combination of 100 µM of HCQ and 104 U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. Our study suggested that HCQ and rfIFN-ω are applicable for treatment of FIP. Further clinical studies are needed to verify the combination of HCQ and rIFN-ω will be effective and safe treatment for cats with FIP.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus, Feline/drug effects , Hydroxychloroquine/pharmacology , Interferon Type I/pharmacology , Analysis of Variance , Animals , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Cats , Cell Line/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Coronavirus, Feline/pathogenicity , Drug Combinations , Feline Infectious Peritonitis/drug therapy , Feline Infectious Peritonitis/virology , Fluorescent Antibody Technique/veterinary , Hydroxychloroquine/therapeutic use , Hydroxychloroquine/toxicity , Interferon Type I/therapeutic use , Interferon Type I/toxicity , Virulence
2.
mBio ; 11(3)2020 05 22.
Article in English | MEDLINE | ID: covidwho-1723548

ABSTRACT

Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antiviral Agents/pharmacology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/virology , Disease Models, Animal , Female , Ferrets , Humans , Hydroxychloroquine/therapeutic use , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , United States , United States Food and Drug Administration , Viral Load
3.
Br J Nutr ; 127(8): 1172-1179, 2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1665637

ABSTRACT

Zn deficiency compromises its biological functions, its effect on the immune system and its antiviral activity, increasing vulnerability to infectious diseases. This narrative review aims at presenting and discussing functional aspects and possible mechanisms involved in the potential role of Zn in the immune response and antiviral activity for coronavirus infectious disease-19 (COVID-19) prevention and control. The searches were conducted in PubMed and Science Direct databases, using clinical trials, experimental studies in animals and humans, case-control studies, case series, letters to the editor, and review articles published in English, without restrictions on year of publication. Search approach was based on using the terms: 'zinc', 'COVID-19', 'antiviral agents', 'immunologic factors' and 'respiratory tract infections'. Literature shows the importance of Zn as an essential mineral immunomodulator with relevant antiviral activity in the body. Thus, although there is still a scarcity of studies evaluating Zn supplementation in patients with COVID-19, the results on the topic show the necessity of controlling Zn mineral deficiency, as well as maintaining its homoeostasis in the body in order to strengthen the immune system and improve the prevention of highly complex viral infections, such as that of the COVID-19.


Subject(s)
COVID-19 , Communicable Diseases , Virus Diseases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Communicable Diseases/drug therapy , Humans , Zinc/therapeutic use
4.
Rev Med Virol ; 31(6): e2236, 2021 11.
Article in English | MEDLINE | ID: covidwho-1573896

ABSTRACT

Modifications in HLA-I expression are found in many viral diseases. They represent one of the immune evasion strategies most widely used by viruses to block antigen presentation and NK cell response, and SARS-CoV-2 is no exception. These alterations result from a combination of virus-specific factors, genetically encoded mechanisms, and the status of host defences and range from loss or upregulation of HLA-I molecules to selective increases of HLA-I alleles. In this review, I will first analyse characteristic features of altered HLA-I expression found in SARS-CoV-2. I will then discuss the potential factors underlying these defects, focussing on HLA-E and class-I-related (like) molecules and their receptors, the most documented HLA-I alterations. I will also draw attention to potential differences between cells transfected to express viral proteins and those presented as part of authentic infection. Consideration of these factors and others affecting HLA-I expression may provide us with improved possibilities for research into cellular immunity against viral variants.


Subject(s)
Antigenic Variation , COVID-19/immunology , Clonal Anergy , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/genetics , Alleles , COVID-19/pathology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Cytotoxicity, Immunologic , Gene Expression , Histocompatibility Antigens Class I/genetics , Humans , Immunity, Cellular , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily C/immunology , NK Cell Lectin-Like Receptor Subfamily D/genetics , NK Cell Lectin-Like Receptor Subfamily D/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology
5.
EXCLI J ; 20: 781-791, 2021.
Article in English | MEDLINE | ID: covidwho-1527045

ABSTRACT

The disruption of antioxidant defense has been demonstrated in severe acute respiratory syndrome due to SARS-CoV infection. Selenium plays a major role in decreasing the ROS produced in response to various viral infections. Selenoprotein enzymes are essential in combating oxidative stress caused due to excessive generation of ROS. Selenium also has a role in inhibiting the activation of NF-κB, thus alleviating inflammation. In viral infections, selenoproteins have also been found to inhibit type I interferon responses, modulate T cell proliferation and oxidative burst in macrophages, and inhibit viral transcriptional activators. Potential virally encoded selenoproteins have been identified by computational analysis in different viral genomes like HIV-1, Japanese encephalitis virus (JEV), and hepatitis C virus. This review discusses the role and the possible mechanisms of selenium, selenoproteins, and virally encoded selenoproteins in the pathogenicity of viral infections. Identification of potential selenoproteins in the COVID 19 genome by computational tools will give insights further into their role in the pathogenesis of viral infections.

6.
J Virol ; 95(17): e0080721, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1486516

ABSTRACT

The membrane fusion between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host cells is essential for the initial step of infection; therefore, the host cell membrane components, including sphingolipids, influence the viral infection. We assessed several inhibitors of the enzymes pertaining to sphingolipid metabolism, against SARS-CoV-2 spike protein (S)-mediated cell-cell fusion and viral infection. N-(4-Hydroxyphenyl) retinamide (4-HPR), an inhibitor of dihydroceramide Δ4-desaturase 1 (DES1), suppressed cell-cell fusion and viral infection. The analysis of sphingolipid levels revealed that the inhibition efficiencies of cell-cell fusion and viral infection in 4-HPR-treated cells were consistent with an increased ratio of saturated sphinganine-based lipids to total sphingolipids. We investigated the relationship of DES1 with the inhibition efficiencies of cell-cell fusion. The changes in the sphingolipid profile induced by 4-HPR were mitigated by the supplementation with exogenous cell-permeative ceramide; however, the reduced cell-cell fusion could not be reversed. The efficiency of cell-cell fusion in DES1 knockout (KO) cells was at a level comparable to that in wild-type (WT) cells; however, the ratio of saturated sphinganine-based lipids to the total sphingolipids was higher in DES1 KO cells than in WT cells. 4-HPR reduced cell membrane fluidity without any significant effects on the expression or localization of angiotensin-converting enzyme 2, the SARS-CoV-2 receptor. Therefore, 4-HPR suppresses SARS-CoV-2 S-mediated membrane fusion through a DES1-independent mechanism, and this decrease in membrane fluidity induced by 4-HPR could be the major cause for the inhibition of SARS-CoV-2 infection. IMPORTANCE Sphingolipids could play an important role in SARS-CoV-2 S-mediated membrane fusion with host cells. We studied the cell-cell fusion using SARS-CoV-2 S-expressing cells and sphingolipid-manipulated target cells, with an inhibitor of the sphingolipid metabolism. 4-HPR (also known as fenretinide) is an inhibitor of DES1, and it exhibits antitumor activity and suppresses cell-cell fusion and viral infection. 4-HPR suppresses membrane fusion through a decrease in membrane fluidity, which could possibly be the cause for the inhibition of SARS-CoV-2 infection. There is accumulating clinical data on the safety of 4-HPR. Therefore, it could be a potential candidate drug against COVID-19.


Subject(s)
Cell Membrane/metabolism , Fenretinide/pharmacology , Membrane Fluidity/drug effects , Oxidoreductases/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Cell Fusion , Cell Membrane/genetics , Gene Knockout Techniques , HEK293 Cells , Humans , Membrane Fluidity/genetics , Oxidoreductases/deficiency , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
7.
Int J Mol Med ; 47(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1448967

ABSTRACT

Circular RNAs (circRNAs) are a class of non­coding RNAs with a circular, covalent structure that lack both 5' ends and 3' poly(A) tails, which are stable and specific molecules that exist in eukaryotic cells and are highly conserved. The role of circRNAs in viral infections is being increasingly acknowledged, since circRNAs have been discovered to be involved in several viral infections (such as hepatitis B virus infection and human papilloma virus infection) through a range of circRNA/microRNA/mRNA regulatory axes. These findings have prompted investigations into the potential of circRNAs as targets for the diagnosis and treatment of viral infection­related diseases. The aim of the present review was to systematically examine and discuss the role of circRNAs in several common viral infections, as well as their potential as diagnostic markers and therapeutic targets.


Subject(s)
MicroRNAs/genetics , RNA, Circular/physiology , RNA, Messenger/genetics , Virus Diseases/genetics , Biomarkers/analysis , Humans , RNA, Circular/genetics , Virus Diseases/diagnosis , Virus Diseases/therapy , Virus Diseases/virology
8.
Antioxidants (Basel) ; 10(3)2021 Mar 16.
Article in English | MEDLINE | ID: covidwho-1389268

ABSTRACT

Various studies have shown that certain flavonoids, flavonoid-containing plant extracts, and foods can improve human health. Experimental studies showed that flavonoids have the capacity to alter physiological processes as well as cellular and molecular mechanisms associated with their antioxidant properties. An important function of flavonoids was determined in the cardiovascular system, namely their capacity to lower blood pressure and to improve endothelial function. (-)-Epicatechin and taxifolin are two flavonoids with notable antihypertensive effects and multiple beneficial actions in the cardiovascular system, but they also possess antiviral effects, which may be of particular importance in the ongoing pandemic situation. Thus, this review is focused on the current knowledge of (-)-epicatechin as well as (+)-taxifolin and/or (-)-taxifolin-modified biological action and underlining molecular mechanisms determined in preclinical studies, which are relevant not only to the treatment of hypertension per se but may provide additional antiviral benefits that could be relevant to the treatment of hypertensive subjects with SARS-CoV-2 infection.

9.
Mar Drugs ; 19(1)2020 Dec 24.
Article in English | MEDLINE | ID: covidwho-1389434

ABSTRACT

Compromised lung function is a feature of both infection driven and non-infective pathologies. Viral infections-including the current pandemic strain SARS-CoV-2-that affect lung function can cause both acute and long-term chronic damage. SARS-CoV-2 infection suppresses innate immunity and promotes an inflammatory response. Targeting these aspects of SARS-CoV-2 is important as the pandemic affects greater proportions of the population. In clinical and animal studies, fucoidans have been shown to increase innate immunity and decrease inflammation. In addition, dietary fucoidan has been shown to attenuate pulmonary damage in a model of acute viral infection. Direct inhibition of SARS-CoV-2 in vitro has been described, but is not universal. This short review summarizes the current research on fucoidan with regard to viral lung infections and lung damage.


Subject(s)
COVID-19/drug therapy , Lung/drug effects , Polysaccharides/pharmacology , SARS-CoV-2 , Animals , COVID-19/immunology , Humans , Lung/physiology , Lung Diseases/drug therapy , Polysaccharides/therapeutic use , Virus Diseases/drug therapy
10.
Front Physiol ; 11: 802, 2020.
Article in English | MEDLINE | ID: covidwho-1389234

ABSTRACT

We dissect the mechanism of SARS-CoV-2 in human lung host from the initial phase of receptor binding to viral replication machinery. Two independent lung protein interactome were constructed to reveal the signaling process on receptor activation and host protein hijacking machinery in the pathogenesis of virus. Further, we test the functional role of the hubs derived from the interactome. Most hubs proteins were differentially regulated on SARS-CoV-2 infection. Also, the proteins in viral replication hubs were related with cardiovascular disease, diabetes and hypertension confirming the vulnerability and severity of infection in the risk individual. Additionally, the hub proteins were closely linked with other viral infection, including MERS and HCoVs which suggest similar infection pattern in SARS-CoV-2. We identified five hubs that interconnect both networks that show the preparation of optimal environment in the host for viral replication process upon receptor attachment. Interestingly, we propose that seven potential miRNAs, targeting the intermediate phase that connects receptor and viral replication process a better choice as a drug for SARS-CoV-2.

11.
Front Immunol ; 11: 607314, 2020.
Article in English | MEDLINE | ID: covidwho-1389171

ABSTRACT

Acute lung injury (ALI) is an important cause of morbidity and mortality after viral infections, including influenza A virus H1N1, SARS-CoV, MERS-CoV, and SARS-CoV-2. The angiotensin I converting enzyme 2 (ACE2) is a key host membrane-bound protein that modulates ALI induced by viral infection, pulmonary acid aspiration, and sepsis. However, the contributions of ACE2 sequence variants to individual differences in disease risk and severity after viral infection are not understood. In this study, we quantified H1N1 influenza-infected lung transcriptomes across a family of 41 BXD recombinant inbred strains of mice and both parents-C57BL/6J and DBA/2J. In response to infection Ace2 mRNA levels decreased significantly for both parental strains and the expression levels was associated with disease severity (body weight loss) and viral load (expression levels of viral NA segment) across the BXD family members. Pulmonary RNA-seq for 43 lines was analyzed using weighted gene co-expression network analysis (WGCNA) and Bayesian network approaches. Ace2 not only participated in virus-induced ALI by interacting with TNF, MAPK, and NOTCH signaling pathways, but was also linked with high confidence to gene products that have important functions in the pulmonary epithelium, including Rnf128, Muc5b, and Tmprss2. Comparable sets of transcripts were also highlighted in parallel studies of human SARS-CoV-infected primary human airway epithelial cells. Using conventional mapping methods, we determined that weight loss at two and three days after viral infection maps to chromosome X-the location of Ace2. This finding motivated the hierarchical Bayesian network analysis, which defined molecular endophenotypes of lung infection linked to Ace2 expression and to a key disease outcome. Core members of this Bayesian network include Ace2, Atf4, Csf2, Cxcl2, Lif, Maml3, Muc5b, Reg3g, Ripk3, and Traf3. Collectively, these findings define a causally-rooted Ace2 modulatory network relevant to host response to viral infection and identify potential therapeutic targets for virus-induced respiratory diseases, including those caused by influenza and coronaviruses.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Lung/virology , Virus Diseases/genetics , Animals , Bayes Theorem , Epithelial Cells/virology , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Respiratory Mucosa/virology , Signal Transduction/genetics
12.
Eur J Clin Pharmacol ; 76(11): 1615-1618, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1384377

ABSTRACT

AIM: SARS-CoV-2 infection has been divided by scientific opinion into three phases: the first as asymptomatic or slightly symptomatic and the second and the third with greater severity, characterized by a hyperinflammatory and fibrotic state, responsible for lung lesions, in some cases fatal. The development of antiviral drugs directed against SARS-CoV-2 and effective vaccines is progressing; meanwhile, the best pharmacological objective is related to the management of all the complications caused by this viral infection, mainly controlling the inflammatory and fibrotic state and preventing the infection from moving into the most serious phases. SUBJECT AND METHOD: Describe the scientific rationale related to the use of an antifibrotic therapy with pirfenidone, as monotherapy and/or in combination with anti-inflammatory drugs to manage and control complications of SARS-CoV-2 infection. RESULTS: Based on the scientific literature and epidemiological results and considering the pathophysiological, biological, and molecular characteristics of SARS-CoV-2, an antifibrotic drug such as pirfenidone as monotherapy or in combination with anti-inflammatory drugs can be (acting early, at the right doses and at the right time) therapeutically effective to avoid serious complications during viral infection. The same approach can also be effective as postinfection therapy in patients with residual pulmonary fibrotic damage. Management of inflammation and fibrotic status with a combination therapy of pirfenidone and IL-6 or IL-1 inhibitors could represent a pharmacological synergy with added value. CONCLUSION: In this article, we consider the role of antifibrotic therapy with pirfenidone in patients with SARS-CoV-2 infection on going or in the stage of postinfection with pulmonary fibrotic consequences. The scientific rationale for its use is also described.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/etiology , Pyridones/therapeutic use , Betacoronavirus , COVID-19 , Drug Therapy, Combination , Humans , Inflammation/drug therapy , Interleukin-1/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Pandemics , SARS-CoV-2
13.
J Virol ; 95(17): e0080721, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1381151

ABSTRACT

The membrane fusion between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host cells is essential for the initial step of infection; therefore, the host cell membrane components, including sphingolipids, influence the viral infection. We assessed several inhibitors of the enzymes pertaining to sphingolipid metabolism, against SARS-CoV-2 spike protein (S)-mediated cell-cell fusion and viral infection. N-(4-Hydroxyphenyl) retinamide (4-HPR), an inhibitor of dihydroceramide Δ4-desaturase 1 (DES1), suppressed cell-cell fusion and viral infection. The analysis of sphingolipid levels revealed that the inhibition efficiencies of cell-cell fusion and viral infection in 4-HPR-treated cells were consistent with an increased ratio of saturated sphinganine-based lipids to total sphingolipids. We investigated the relationship of DES1 with the inhibition efficiencies of cell-cell fusion. The changes in the sphingolipid profile induced by 4-HPR were mitigated by the supplementation with exogenous cell-permeative ceramide; however, the reduced cell-cell fusion could not be reversed. The efficiency of cell-cell fusion in DES1 knockout (KO) cells was at a level comparable to that in wild-type (WT) cells; however, the ratio of saturated sphinganine-based lipids to the total sphingolipids was higher in DES1 KO cells than in WT cells. 4-HPR reduced cell membrane fluidity without any significant effects on the expression or localization of angiotensin-converting enzyme 2, the SARS-CoV-2 receptor. Therefore, 4-HPR suppresses SARS-CoV-2 S-mediated membrane fusion through a DES1-independent mechanism, and this decrease in membrane fluidity induced by 4-HPR could be the major cause for the inhibition of SARS-CoV-2 infection. IMPORTANCE Sphingolipids could play an important role in SARS-CoV-2 S-mediated membrane fusion with host cells. We studied the cell-cell fusion using SARS-CoV-2 S-expressing cells and sphingolipid-manipulated target cells, with an inhibitor of the sphingolipid metabolism. 4-HPR (also known as fenretinide) is an inhibitor of DES1, and it exhibits antitumor activity and suppresses cell-cell fusion and viral infection. 4-HPR suppresses membrane fusion through a decrease in membrane fluidity, which could possibly be the cause for the inhibition of SARS-CoV-2 infection. There is accumulating clinical data on the safety of 4-HPR. Therefore, it could be a potential candidate drug against COVID-19.


Subject(s)
Cell Membrane/metabolism , Fenretinide/pharmacology , Membrane Fluidity/drug effects , Oxidoreductases/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Cell Fusion , Cell Membrane/genetics , Gene Knockout Techniques , HEK293 Cells , Humans , Membrane Fluidity/genetics , Oxidoreductases/deficiency , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
14.
Curr Diabetes Rev ; 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1367728

ABSTRACT

The article has been withdrawn at the request of the authors and editor of the journal Current Diabetes Reviews, due to incoherent content.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submit-ting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

15.
J Virol ; 95(17): e0080721, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1350004

ABSTRACT

The membrane fusion between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host cells is essential for the initial step of infection; therefore, the host cell membrane components, including sphingolipids, influence the viral infection. We assessed several inhibitors of the enzymes pertaining to sphingolipid metabolism, against SARS-CoV-2 spike protein (S)-mediated cell-cell fusion and viral infection. N-(4-Hydroxyphenyl) retinamide (4-HPR), an inhibitor of dihydroceramide Δ4-desaturase 1 (DES1), suppressed cell-cell fusion and viral infection. The analysis of sphingolipid levels revealed that the inhibition efficiencies of cell-cell fusion and viral infection in 4-HPR-treated cells were consistent with an increased ratio of saturated sphinganine-based lipids to total sphingolipids. We investigated the relationship of DES1 with the inhibition efficiencies of cell-cell fusion. The changes in the sphingolipid profile induced by 4-HPR were mitigated by the supplementation with exogenous cell-permeative ceramide; however, the reduced cell-cell fusion could not be reversed. The efficiency of cell-cell fusion in DES1 knockout (KO) cells was at a level comparable to that in wild-type (WT) cells; however, the ratio of saturated sphinganine-based lipids to the total sphingolipids was higher in DES1 KO cells than in WT cells. 4-HPR reduced cell membrane fluidity without any significant effects on the expression or localization of angiotensin-converting enzyme 2, the SARS-CoV-2 receptor. Therefore, 4-HPR suppresses SARS-CoV-2 S-mediated membrane fusion through a DES1-independent mechanism, and this decrease in membrane fluidity induced by 4-HPR could be the major cause for the inhibition of SARS-CoV-2 infection. IMPORTANCE Sphingolipids could play an important role in SARS-CoV-2 S-mediated membrane fusion with host cells. We studied the cell-cell fusion using SARS-CoV-2 S-expressing cells and sphingolipid-manipulated target cells, with an inhibitor of the sphingolipid metabolism. 4-HPR (also known as fenretinide) is an inhibitor of DES1, and it exhibits antitumor activity and suppresses cell-cell fusion and viral infection. 4-HPR suppresses membrane fusion through a decrease in membrane fluidity, which could possibly be the cause for the inhibition of SARS-CoV-2 infection. There is accumulating clinical data on the safety of 4-HPR. Therefore, it could be a potential candidate drug against COVID-19.


Subject(s)
Cell Membrane/metabolism , Fenretinide/pharmacology , Membrane Fluidity/drug effects , Oxidoreductases/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Cell Fusion , Cell Membrane/genetics , Gene Knockout Techniques , HEK293 Cells , Humans , Membrane Fluidity/genetics , Oxidoreductases/deficiency , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
16.
Virus Res ; 286: 198040, 2020 09.
Article in English | MEDLINE | ID: covidwho-1328562

ABSTRACT

The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human C-C chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed.


Subject(s)
Flavivirus/pathogenicity , HIV Infections/immunology , Receptors, CCR5/genetics , Receptors, CCR5/immunology , Virus Diseases/immunology , Animals , Flavivirus/classification , Genetic Variation , Genotype , HIV-1 , Humans , Mice
17.
Biochimie ; 179: 237-246, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1326916

ABSTRACT

The anti-malarial drug Chloroquine (CQ) and its derivative hydroxychloroquine have shown antiviral activities in vitro against many viruses, including coronaviruses, dengue virus and the biosafety level 4 Nipah and Hendra paramyxoviruses. The in vivo efficacy of CQ in the treatment of COVID-19 is currently a matter of debate. CQ is a lysosomotrophic compound that accumulates in lysosomes, as well as in food vacuoles of Plasmodium falciparum. In the treatment of malaria, CQ impairs the digestion and growth of the parasite by increasing the pH of the food vacuole. Similarly, it is assumed that the antiviral effects of CQ results from the increase of lysosome pH and the inhibition of acidic proteases involved in the maturation of virus fusion protein. CQ has however other effects, among which phospholipidosis, characterized by the accumulation of multivesicular bodies within the cell. The increase in phospholipid species particularly concerns bis(monoacylglycero)phosphate (BMP), a specific lipid of late endosomes involved in vesicular trafficking and pH-dependent vesicle budding. It was shown previously that drugs like progesterone, the cationic amphiphile U18666A and the phospholipase inhibitor methyl arachidonyl fluoro phosphonate (MAFP) induce the accumulation of BMP in THP-1 cells and decrease cell infection by human immunodeficiency virus. HIV viral particles were found to be retained into large endosomal-type vesicles, preventing virus spreading. Since BMP was also reported to favour virus entry through hijacking of the endocytic pathway, we propose here that BMP could play a dual role in viral infection, with its antiviral effects triggered by lysosomotropic drugs like CQ.


Subject(s)
Antiviral Agents/pharmacology , Chloroquine/pharmacology , Endocytosis/drug effects , Endosomes/drug effects , Endosomes/metabolism , Lysophospholipids/metabolism , Monoglycerides/metabolism , SARS-CoV-2/drug effects , Humans , SARS-CoV-2/physiology
18.
Viruses ; 13(4)2021 04 15.
Article in English | MEDLINE | ID: covidwho-1208346

ABSTRACT

Many factors impact the host response to influenza virus infection and vaccination. Ferrets have been an indispensable reagent for influenza virus research for almost one hundred years. One of the most significant and well-known factors affecting human disease after infection is host age. Another significant factor is the virus, as strain-specific disease severity is well known. Studying age-related impacts on viral infection and vaccination outcomes requires an animal model that reflects both the physiological and immunological changes that occur with human aging, and sensitivity to differentially virulent influenza viruses. The ferret is uniquely susceptible to a plethora of influenza viruses impacting humans and has proven extremely useful in studying the clinical and immunological pictures of influenza virus infection. Moreover, ferrets developmentally have several of the age-related physiological changes that occur in humans throughout infancy, adulthood, old age, and pregnancy. In this review, we discuss ferret susceptibility to influenza viruses, summarize previous influenza studies using ferrets as models of age, and finally, highlight the application of ferret age models in the pursuit of prophylactic and therapeutic agents to address age-related influenza disease severity.


Subject(s)
Ferrets/virology , Immunity , Orthomyxoviridae Infections/virology , Age Factors , Animals , Female , Humans , Influenza Vaccines , Pregnancy , Risk Factors , Vaccination
19.
Pharmacol Res ; 157: 104849, 2020 07.
Article in English | MEDLINE | ID: covidwho-1318926

ABSTRACT

Taking anti-inflammatory drugs, including non-steroidal (NSAIDs), during Covid-19 infection, how much is risky? The French Minister of Health, who has raised an alarm on a possible risk deriving from the use of ibuprofen for the control of fever and other symptoms during the disease, opened the debate a few days ago. In this paper we examine available evidence from preclinical and clinical studies that had analysed the role of COX in the inflammatory process and the effects of NSAIDs in patients with infections. Most of the published studies that suggested not protective effects of NSAIDs were mainly performed in vitro or on animals. Therefore, their meaning in humans is to be considered with great caution. Based also on data suggesting protective effects of NSAIDs, we concluded that currently there is no evidence suggesting a correlation between NSAIDs and a worsening of infections. Further studies will be certainly needed to better define the role of NSAIDs and particularly COX2 inhibitors in patients with infections. In the meantime, we must wait for results of the revision started by the PRAC on May 2019 on the association ibuprofen/ketoprofen​​​​​​ and worsening of infections. Since nowadays no scientific evidence establishes a correlation between NSAIDS and worsening of COVID-19, patients should be advice against any NSAIDs self-medication when COVID-19 like symptoms are present.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents/adverse effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Virus Diseases/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Humans , Pandemics , SARS-CoV-2
20.
Viruses ; 13(2)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1298428

ABSTRACT

The nuclear factor κB (NF-κB) family are the master transcription factors that control cell proliferation, apoptosis, the expression of interferons and proinflammatory factors, and viral infection. During viral infection, host innate immune system senses viral products, such as viral nucleic acids, to activate innate defense pathways, including the NF-κB signaling axis, thereby inhibiting viral infection. In these NF-κB signaling pathways, diverse types of ubiquitination have been shown to participate in different steps of the signal cascades. Recent advances find that viruses also modulate the ubiquitination in NF-κB signaling pathways to activate viral gene expression or inhibit host NF-κB activation and inflammation, thereby facilitating viral infection. Understanding the role of ubiquitination in NF-κB signaling during viral infection will advance our knowledge of regulatory mechanisms of NF-κB signaling and pave the avenue for potential antiviral therapeutics. Thus, here we systematically review the ubiquitination in NF-κB signaling, delineate how viruses modulate the NF-κB signaling via ubiquitination and discuss the potential future directions.


Subject(s)
Interferons/immunology , NF-kappa B/metabolism , Ubiquitination , Ubiquitins/immunology , Virus Diseases/immunology , Animals , Humans , Protein Binding , Signal Transduction/immunology , Structure-Activity Relationship , Transcriptional Activation/immunology , Virus Diseases/virology
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