A possible way to relate the effects of SARS-CoV-2 induced changes in transferrin to severe COVID-19 associated diseases

The potentially life-threatening Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is responsible for the coronavirus pandemic in 2019 (COVID-19). The transferrin as an essential component of iron-metabolism was suggested to be a link between iron transport associated diseases and COVID-19 infection. The effect of SARS-CoV-2 on human whole blood was studied by differential scanning calorimetry. The analysis and deconvolution of the thermal transition curves showed that the Tm of transferrin related second peak decreased by 5.16 {degrees}C (6.4%) in the presence of SARS-CoV-2 virus. The ratio of the under-curve area of the two main peaks was greatly affected while the total enthalpy of the heat denaturation was nearly unchanged in the presence of the virus. Based on the results it is possible to conclude that SARS-CoV-2 through binding to transferrin can influence its Fe3+ uptake by inducing thermodynamic changes. Transferrin may stay in iron-free apo-conformational state, which probably depends on the SARS-CoV-2 concentration. SARS-CoV-2 might induce disturbance in the erythropoiesis due to the free iron overload generated iron toxicity. As a late consequence iron toxicity related hepatocellular carcinoma can even develop. Our work can support the basic role of transferrin in COVID-19 related severe diseases.

The Algerian chapter of SARS-CoV-2 pandemic: An evolutionary, genetic, and epidemiological prospect of the first wave.

To explore the SARS-CoV-2 early pandemic in Algeria, a dataset comprising forty-three genomes originating from SARS-CoV-2 sampled from Algeria and other countries worldwide, from 24 December 2019 through 8 March 2020, of which, were thoroughly examined. While performing a multi-component analysis regarding the Algerian outbreak, the toolkit of phylogenetic, phylodynamic, haplotype analyses and genomic analysis were effectively implemented. We estimated the TMRCA in reference to the Algerian pandemic and highlighted both the introduction of the disease originating in France and the missing data depicted in the transmission loop. Most importantly, we unveiled mutational patterns, recombination events and the relatedness regarding the Algerian sequences to the dataset. Our results revealed the unique amino-acid replacement L129F in the orf3a gene in Algeria_EPI_ISL_418241. Additionally, a connection between Algeria_EPI_ISL_420037 and sequences originating from the USA was observed through a USA characteristic amino-acid replacement T1004I in the nsp3 gene, found in the aforementioned Algerian sequence. Lastly, we assessed the Algerian mitigation measures regarding disease containment using statistical analyses. Author summaryA novel human coronavirus, specifically SARS-CoV-2, emerged in China in late 2019. In Algeria, the contact tracing revealed the introduction of the disease originated in France, however, the intricate dynamics regarding the disease remain unexplored. In this study, we attempt to portray our perspective regarding the evolutionary, genetic and epidemiological aspects of the early pandemic in Algeria during the spring of 2020, through the use of time scaled phylogeny, phylodynamic and mutational pattern characterization and exploration. Additionally, we assessed the efficiency of the implemented mitigation measures using statistical analysis. The results supported the virus introduction from France and highlighted an Algerian characteristic amino-acid replacement in addition to a relatedness to the USA sequences. Moreover, we revealed an indirect contamination among the three sampled patients. Therefore, our analysis is a starting point for further investigations and emphasize the importance regarding intensive sequencing and genome exploration for mitigation measures implementation, and both drug and vaccine development.

The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro

BackgroundThe COVID-19 pandemic is an enormous threat for healthcare systems and economies worldwide that urgently demands effective preventive and therapeutic strategies. Unlike the development of vaccines and new drugs specifically targeting SARS-CoV-2, repurposing of approved or clinically tested drugs can provide an immediate solution. MethodsWe applied a novel computational approach to search among approved and clinically tested drugs from the DrugBank database. Candidates were selected based on Shannon entropy homology and predefined activity profiles of three small molecules with proven anti-SARS-CoV activity and a published data set. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 monkey kidney epithelial cells and reconstituted human nasal tissue. The effect on viral replication was assessed by quantification of viral genomes by droplet digital PCR. FindingsThe computational approach with four independent queries identified major drug families, most often and in overlapping fashion anti-infective, anti-inflammatory, anti-hypertensive, anti-histamine and neuroactive drugs. Azelastine, an histamine 1 receptor-blocker, was predicted in multiple screens, and based on its attractive safety profile and availability in nasal formulation, was selected for experimental testing. Azelastine significantly reduced cytopathic effect and SARS-CoV-2 infection of Vero E6 cells with an EC50 of [~]6 M both in a preventive and treatment setting. Furthermore, azelastine in a commercially available nasal spray tested at 5-fold dilution was highly potent in inhibiting viral propagation in SARS-CoV-2 infected reconstituted human nasal tissue. InterpretationsAzelastine, an anti-histamine, available in nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization with SARS-CoV-2. As such, it could be useful in reducing viral spread and prophylaxis of COVID-19. Ultimately, its potential benefit should be proven in clinical studies. Fundingprovided by the Hungarian government to the National Laboratory of Virology and by CEBINA GmbH.

Early transfusion of convalescent plasma improves the clinical outcome in severe SARS-CoV2 infection

Plasma harvested from convalescent COVID-19 patients (CCP) has been applied as first-line therapy in the early phase of the SARS-CoV2 pandemic through clinical studies using various protocols. We present data from a cohort of 267 hospitalized, severe COVID-19 patients who received CCP. No transfusion-related complications were reported, indicating the overall safety of CCP therapy. Patients who eventually died from COVID-19 received CCP significantly later (3.95 versus 5.22 days after hospital admission) and had higher interleukin 6 (IL-6) levels (28.9 pg/ml versus 102.5 pg/ml) than those who survived. In addition, CCP-transfusion caused a significant reduction in the overall inflammatory status of the patients regardless of the severity of disease or outcome, as evidenced by decreasing C-reactive protein, IL6 and ferritin levels. We conclude that, CCP-transfusion is a safe and effective supplementary treatment modality for hospitalized COVID-19 patients characterized by better expected outcome if applied as early as possible. We also observed that, IL-6 may be a suitable laboratory parameter for patient selection and monitoring of CCP therapy effectiveness.

Multiple SARS-CoV-2 introductions shaped the early outbreak in Central Eastern Europe: comparing Hungarian data to a worldwide sequence data-matrix

Severe Acute Respiratory Syndrome Coronavirus 2 is the third highly pathogenic human coronavirus in history. Since the emergence in Hubei province, China, during late 2019 the situation evolved to pandemic level. Following China, Europe was the second epicenter of the pandemic. To better comprehend the detailed founder mechanisms of the epidemic evolution in Central-Eastern Europe, particularly in Hungary, we determined the full-length SARS-CoV-2 genomes from 32 clinical samples collected from laboratory confirmed COVID-19 patients over the first month of disease in Hungary. We applied a haplotype network analysis on all available complete genomic sequences of SARS-CoV-2 from GISAID database as of the 21th of April, 2020. We performed additional phylogenetic and phylogeographic analyses to achieve the recognition of multiple and parallel introductory events into our region. Here we present a publicly available network imaging of the worldwide haplotype relations of SARS-CoV-2 sequences and conclude the founder mechanisms of the outbreak in Central-Eastern Europe.