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1.
Int J Cardiol ; 2022 May 26.
Article in English | MEDLINE | ID: covidwho-1867210

ABSTRACT

INTRODUCTION: The respiratory illness triggered by severe acute respiratory syndrome virus-2 (SARS-CoV-2) is often particularly serious or fatal amongst patients with pre-existing heart conditions. Although the mechanisms underlying SARS-CoV-2-related cardiac damage remain elusive, inflammation (i.e. 'cytokine storm') and oxidative stress are likely involved. METHODS AND RESULTS: Here we sought to determine: 1) if cardiomyocytes are targeted by SARS-CoV-2 and 2) how inflammation and oxidative stress promote the viral entry into cardiac cells. We analysed pro-inflammatory and oxidative stress and its impact on virus entry and virus-associated cardiac damage from SARS-CoV-2 infected patients and compared it to left ventricular myocardial tissues obtained from non-infected transplanted hearts either from end stage heart failure or non-failing hearts (donor group). We found that neuropilin-1 potentiates SARS-CoV-2 entry into human cardiomyocytes, a phenomenon driven by inflammatory and oxidant signals. These changes accounted for increased proteases activity and apoptotic markers thus leading to cell damage and apoptosis. CONCLUSION: This study provides new insights into the mechanisms of SARS-CoV-2 entry into the heart and defines promising targets for antiviral interventions for COVID-19 patients with pre-existing heart conditions or patients with co-morbidities.

2.
J Infect Dis ; 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1831181

ABSTRACT

BACKGROUND: The contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. Importantly, the risk of fomite-based transmission has not been systematically addressed. Therefore, the aim of this study was to evaluate if confirmed hospitalized COVID-19 patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. METHODS: We initiated a single-center observational study including fifteen COVID-19 patients with a high baseline viral load (CT value ≤ 25). We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR and virus sequencing. RESULTS: Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral RNA on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2 %). While after coughing, no infectious virus could be recovered, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5 %). CONCLUSIONS: Transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but unlikely to occur in real-life scenarios and from droplet-contaminated fomites.

3.
Sci Rep ; 12(1): 7193, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1821611

ABSTRACT

The current Coronavirus Disease 19 (COVID-19) pandemic has exemplified the need for simple and efficient prevention strategies that can be rapidly implemented to mitigate infection risks. Various surfaces have a long history of antimicrobial properties and are well described for the prevention of bacterial infections. However, their effect on many viruses has not been studied in depth. In the context of COVID-19, several surfaces, including copper (Cu) and silver (Ag) coatings have been described as efficient antiviral measures that can easily be implemented to slow viral transmission. In this study, we detected antiviral properties against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) on surfaces, which were coated with Cu by magnetron sputtering as thin Cu films or as Cu/Ag ultrathin bimetallic nanopatches. However, no effect of Ag on viral titers was observed, in clear contrast to its well-known antibacterial properties. Further enhancement of Ag ion release kinetics based on an electrochemical sacrificial anode mechanism did not increase antiviral activity. These results clearly demonstrate that Cu and Ag thin film systems display significant differences in antiviral and antibacterial properties which need to be considered upon implementation.


Subject(s)
COVID-19 , Silver , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , Copper/chemistry , Copper/pharmacology , Humans , SARS-CoV-2 , Silver/chemistry , Silver/pharmacology
4.
Virus Res ; 316: 198791, 2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1815257

ABSTRACT

The emergence of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an unprecedented threat for the human population, necessitating rapid and effective intervention measures. Given the main infection route by airborne transmission, significant attention has been bestowed upon the use of antiseptic mouthrinses as a way to possibly reduce infectious viral titers. However, clinical evaluations are still sparse. Thus, we evaluated a wide variety of antiseptic agents that can be used as mouthrinses for their antiviral effects in vitro and their respective mode of action. One of the most promising antiseptic agents (benzalkoniumchloride, BAC) was used in a randomized placebo-controlled clinical trial with subsequent analysis of viral loads by RT-qPCR and virus rescue in cell culture. Mechanistic analysis revealed that treatment with BAC and other antiseptic agents efficiently inactivated SARS-CoV-2 in vitro by primarily disrupting the viral envelope, without affecting viral RNA integrity. However, the clinical application only resulted in a mild reduction of viral loads in the oral cavity. These results indicate that gargling with mouthrinses comprising single antiseptic agents may play a minor role towards a potential reduction of transmission rates and thus, these findings are of utmost importance when considering alternative COVID-19 prevention strategies.


Subject(s)
Anti-Infective Agents, Local , COVID-19 , Anti-Infective Agents, Local/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , SARS-CoV-2 , Viral Load
5.
Journal of Photochemistry and Photobiology ; : 100123, 2022.
Article in English | ScienceDirect | ID: covidwho-1814798

ABSTRACT

Microorganisms pose a serious threat for us humans, which is exemplified by the recent emergence of pathogens such as SARS-CoV-2 or the increasing number of multi-resistant pathogens such as MRSA. To control surface microorganisms and viruses, we investigated the disinfection properties of an AI-controlled robot, HERO21, equipped with eight 130-W low pressure UV-C mercury vapor discharge lamps emitting at a wavelength of 254 nm, which is strongly absorbed by DNA and RNA, thus inactivating illuminated microorganisms. Emissivity and spatial irradiance distribution of a single UV-C lamp unit was determined using a calibrated spectrometer and numerical simulation, respectively. The disinfection efficiency of single lamps is determined by microbiological tests using B. subtilis spores, which are known to be UV-C resistant. The required time for D99 disinfection and the corresponding UV-C irradiance dose amount to 60 s and 37.3 mJ•cm−2 at a distance of 1 m to the Hg-lamp, respectively. Spatially resolved irradiance produced by a disinfection unit consisting of eight lamps is calculated using results of one UV-C lamp characterization. This calculation shows that the UV-C robot HERO21 equipped with the mentioned UV-C unit causes an irradiance at λ=254 nm of 2.67 mJ•cm−2•s−1 at 1m and 0.29 mJ•cm−2•s−1 at 3 m distances. These values result in D99 disinfection times of 14 s and 129 s for B. subtilis spores, respectively. Similarly, human coronavirus 229E, structurally very similar to SARS-CoV-2, could be efficiently inactivated by 3-5 orders of magnitude within 10 - 30 s exposure time or doses of 2 - 6 mJ•cm−2, respectively. In conclusion, with the development of the HERO21 disinfection robot, we were able to determine the inactivation efficiency of bacteria and viruses on surfaces under laboratory conditions.

6.
iScience ; 25(5): 104293, 2022 May 20.
Article in English | MEDLINE | ID: covidwho-1804378

ABSTRACT

The nucleoside analog N4-hydroxycytidine (NHC) is the active metabolite of the prodrug molnupiravir, which has been approved for the treatment of COVID-19. SARS-CoV-2 incorporates NHC into its RNA, resulting in defective virus genomes. Likewise, inhibitors of dihydroorotate dehydrogenase (DHODH) reduce virus yield upon infection, by suppressing the cellular synthesis of pyrimidines. Here, we show that NHC and DHODH inhibitors strongly synergize in the inhibition of SARS-CoV-2 replication in vitro. We propose that the lack of available pyrimidine nucleotides upon DHODH inhibition increases the incorporation of NHC into nascent viral RNA. This concept is supported by the rescue of virus replication upon addition of pyrimidine nucleosides to the media. DHODH inhibitors increased the antiviral efficiency of molnupiravir not only in organoids of human lung, but also in Syrian Gold hamsters and in K18-hACE2 mice. Combining molnupiravir with DHODH inhibitors may thus improve available therapy options for COVID-19.

7.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332798

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing global pandemic. Despite the development of vaccines, which protect healthy people from severe and life-threatening COVID-19, the immunological responses of people with secondary immunodeficiencies to SARS-CoV-2 mRNA vaccines are currently not well understood. Human Immunodeficiency Virus (HIV), causing acquired immunodeficiency syndrome (AIDS), targets CD4+ T helper (Th) cells that orchestrate the immune response. Anti-retroviral therapy suppresses HIV burden and restores Th cell numbers. Here, we investigated the humoral and cellular immune responses elicited by the BTN162b2 vaccine in a cohort of people living with HIV (PLWH), who receive anti-retroviral therapy. While antibody responses in PLWH increased progressively after the first and second vaccination compared to baseline, they were reduced compared to HIV negative study participants (controls). CD8+ T cells exhibited a general activated phenotype and increased effector and effector memory compartments. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase and were comparable between PLWH and controls. In line with their reduced humoral response, the correlation between neutralizing antibodies and the CD4+ T cell response was decreased in PLWH compared to healthy controls. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4 T cell numbers do not necessarily interfere with cellular immune responses. Taken together, our data demonstrate that COVID-19 mRNA vaccination in PLWH results in potent cellular immune responses, but the reduced antibody responses suggest that booster vaccination might be required for preventing disease.

9.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330946

ABSTRACT

Background: The contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. Importantly, the risk of fomite-based transmission has not been systematically addressed. Methods: We initiated this single-center observational study to evaluate whether hospitalized COVID-19 patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. Fifteen hospitalized patients with a high baseline viral load (CT value ≤ 25) shortly after admission were included. We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR and virus sequencing. Results: Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral RNA on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2 %). While after coughing, no infectious virus could be recovered, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5 %). Conclusions: Transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but unlikely to occur in real-life scenarios and from droplet-contaminated fomites.

11.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-316864

ABSTRACT

The current Coronavirus Disease 19 (COVID-19) pandemic has exemplified the need for simple and efficient prevention strategies that can be rapidly implemented to mitigate infection risks. Various surfaces have a long history of antimicrobial properties and are well described for the prevention of bacterial infections. However, their effect on many viruses has not been studied in depth. In the context of COVID-19, several surfaces, including copper (Cu) and silver (Ag) coatings have been described as efficient antiviral measures that can easily be implemented to slow viral transmission. In this study, we detected antiviral properties against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) on surfaces, which were coated with Cu by magnetron sputtering. However, no effect of Ag on viral titers was observed, in clear contrast to its well-known antibacterial properties. Further enhancement of Ag ion release kinetics based on an electrochemical sacrificial anode mechanism did not increase antiviral activity. These results clearly demonstrate that Cu and Ag thin film systems display significant differences in antiviral and antibacterial properties which need to be considered upon implementation.

12.
SSRN;
Preprint in English | SSRN | ID: ppcovidwho-325736

ABSTRACT

Background: The effect of different modes of immunosuppressive therapy in autoimmune inflammatory rheumatic diseases (AIRD) remains unclear. We investigated the impact of immunosuppressive therapies on humoral and cellular responses after two dose vaccination. Methods: Patients with RA, axSpA or PsA treated with TNFi, IL-17i (b-), JAKi (ts-), or MTX (csDMARD) alone or in combination were included. Almost all patients received mRNA-based vaccine, 4 patients had a heterologous scheme. Neutralizing capacity (NC) and levels of IgG against SARS-CoV-2 spike-protein were evaluated together with quantification of activation markers on T-cells and their production of key cytokines 4 weeks after first and second vaccination. Findings: Overall, a total of 92 patients were included in the final study cohort with the median age of 50 years [IRQ: 39-56] and a 50% female ratio. 33·7% patients were on TNFi, 26·1% on IL-17i, 26·1% on JAKi, each group encompassing patients receiving drug inhibitors alone or in combination with MTX. 14·1% were treated with MTX alone. Although after first vaccination only 37·8% patients presented neutralizing antibodies, the majority (94·5%) showed neutralizing antibodies after second vaccination. Spike-protein specific IgG antibodies were found in 98·9% of all patients. Patients on IL17i developed the highest titers compared to the other modes of action. Co-administration of MTX led to lower titers compared to b/tsDMARD monotherapy. NC correlated well with IgG against SARS-CoV-2 spike-protein titers. T-cell immunity revealed similar frequencies of activated T-cells and cytokine profiles across therapies. Interpretation: Even after insufficient seroconversion for NC and IgG against SARS-CoV-2 spike-proteins in AIRD patients between different modes of action after first vaccination, a second vaccination covered almost all patients regardless of DMARDs therapy, with better outcomes in those on IL-17i. However, no difference of b-/ts- or cs-DMARD therapy was found on the cellular immune response. Funding Information: No funding was obtained. No author or any other person involved in the project or in the manuscript preparation has been paid to write this article.

13.
Front Immunol ; 13: 816220, 2022.
Article in English | MEDLINE | ID: covidwho-1686484

ABSTRACT

SARS-CoV-2 variants of concern (VOCs) can trigger severe endemic waves and vaccine breakthrough infections (VBI). We analyzed the cellular and humoral immune response in 8 patients infected with the alpha variant, resulting in moderate to fatal COVID-19 disease manifestation, after double mRNA-based anti-SARS-CoV-2 vaccination. In contrast to the uninfected vaccinated control cohort, the diseased individuals had no detectable high-avidity spike (S)-reactive CD4+ and CD8+ T cells against the alpha variant and wild type (WT) at disease onset, whereas a robust CD4+ T-cell response against the N- and M-proteins was generated. Furthermore, a delayed alpha S-reactive high-avidity CD4+ T-cell response was mounted during disease progression. Compared to the vaccinated control donors, these patients also had lower neutralizing antibody titers against the alpha variant at disease onset. The delayed development of alpha S-specific cellular and humoral immunity upon VBI indicates reduced immunogenicity against the S-protein of the alpha VOC, while there was a higher and earlier N- and M-reactive T-cell response. Our findings do not undermine the current vaccination strategies but underline a potential need for the inclusion of VBI patients in alternative vaccination strategies and additional antigenic targets in next-generation SARS-CoV-2 vaccines.


Subject(s)
/immunology , Antibodies, Neutralizing/blood , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , Antibody Affinity/immunology , COVID-19/mortality , Coronavirus M Proteins/immunology , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Male , Middle Aged , Phosphoproteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
14.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Article in English | MEDLINE | ID: covidwho-1671749

ABSTRACT

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2-infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.


Subject(s)
COVID-19/drug therapy , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Transcriptome , Virus Replication/drug effects , Animals , COVID-19/immunology , COVID-19/virology , Chlorocebus aethiops , Cloning, Molecular , Disease Models, Animal , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression Profiling , Gene Expression Regulation , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Mice , Protein Isoforms/classification , Protein Isoforms/genetics , Protein Isoforms/immunology , Protein Isoforms/pharmacology , Recombinant Proteins/classification , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/pharmacology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Signal Transduction , Vero Cells
15.
PLoS Biol ; 19(12): e3001490, 2021 12.
Article in English | MEDLINE | ID: covidwho-1595018

ABSTRACT

Over the past 20 years, 3 highly pathogenic human coronaviruses (HCoVs) have emerged-Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and, most recently, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-demonstrating that coronaviruses (CoVs) pose a serious threat to human health and highlighting the importance of developing effective therapies against them. Similar to other viruses, CoVs are dependent on host factors for their survival and replication. We hypothesized that evolutionarily distinct CoVs may exploit similar host factors and pathways to support their replication cycles. Herein, we conducted 2 independent genome-wide CRISPR/Cas-9 knockout (KO) screens to identify MERS-CoV and HCoV-229E host dependency factors (HDFs) required for HCoV replication in the human Huh7 cell line. Top scoring genes were further validated and assessed in the context of MERS-CoV and HCoV-229E infection as well as SARS-CoV and SARS-CoV-2 infection. Strikingly, we found that several autophagy-related genes, including TMEM41B, MINAR1, and the immunophilin FKBP8, were common host factors required for pan-CoV replication. Importantly, inhibition of the immunophilin protein family with the compounds cyclosporine A, and the nonimmunosuppressive derivative alisporivir, resulted in dose-dependent inhibition of CoV replication in primary human nasal epithelial cell cultures, which recapitulate the natural site of virus replication. Overall, we identified host factors that are crucial for CoV replication and demonstrated that these factors constitute potential targets for therapeutic intervention by clinically approved drugs.


Subject(s)
Autophagy/genetics , CRISPR-Cas Systems , Middle East Respiratory Syndrome Coronavirus/genetics , SARS-CoV-2/genetics , Antiviral Agents/pharmacology , Gene Knockdown Techniques , Host-Pathogen Interactions , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication
17.
J Infect Dis ; 223(6): 1114-1115, 2021 03 29.
Article in English | MEDLINE | ID: covidwho-1467334
19.
Viruses ; 13(10)2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438743

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). The availability of effective and well-tolerated antiviral drugs for the treatment of COVID-19 patients is still very limited. Traditional herbal medicines elicit antiviral activity against various viruses and might therefore represent a promising option for the complementary treatment of COVID-19 patients. The application of turmeric root in herbal medicine has a very long history. Its bioactive ingredient curcumin shows a broad-spectrum antimicrobial activity. In the present study, we investigated the antiviral activity of aqueous turmeric root extract, the dissolved content of a curcumin-containing nutritional supplement capsule, and pure curcumin against SARS-CoV-2. Turmeric root extract, dissolved turmeric capsule content, and pure curcumin effectively neutralized SARS-CoV-2 at subtoxic concentrations in Vero E6 and human Calu-3 cells. Furthermore, curcumin treatment significantly reduced SARS-CoV-2 RNA levels in cell culture supernatants. Our data uncover curcumin as a promising compound for complementary COVID-19 treatment. Curcumin concentrations contained in turmeric root or capsules used as nutritional supplements completely neutralized SARS-CoV-2 in vitro. Our data argue in favor of appropriate and carefully monitored clinical studies that vigorously test the effectiveness of complementary treatment of COVID-19 patients with curcumin-containing products.


Subject(s)
COVID-19/drug therapy , Curcumin/therapeutic use , SARS-CoV-2/drug effects , Animals , Antiviral Agents/therapeutic use , Cell Line , Chlorocebus aethiops , Curcuma/metabolism , Curcumin/metabolism , Dietary Supplements , Humans , Medicine, Traditional/methods , Plant Extracts/metabolism , Plant Extracts/therapeutic use , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vero Cells
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