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    ADAM17 inhibition prevents neutrophilia MESHD and lung injury MESHD in a mouse model of Covid-19 MESHD

    Authors: Nathaniel L. Lartey; Salvador Valle-Reyes; Hilda Vargas-Robles; Karina E. Jiménez-Camacho; Idaira M. Guerrero-Fonseca; Ramón Castellanos-Martínez; Armando Montoya-García; Julio García-Cordero; Leticia Cedillo-Barrón; Porfirio Nava; Jessica G. Filisola-Villaseňor; Daniela Roa-Velázquez; Dan I. Zavala-Vargas; Edgar Morales-Ríos; Citlaltepetl Salinas-Lara; Eduardo Vadillo; Michael Schnoor

    doi:10.1101/2021.04.10.439288 Date: 2021-04-11 Source: bioRxiv

    Severe coronavirus disease MESHD coronavirus disease 2019 MESHD ( Covid-19 MESHD) is characterized by lung injury MESHD, cytokine storm and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe Covid-19 MESHD in infected individuals. Angiotensin-converting enzyme-2 ACE-2) is the receptor for SARS-CoV-2, the virus causing Covid-19 MESHD, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE-2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates Covid-19 MESHD-related lung inflammation MESHD. We employed a pre-clinical mouse model using intra-tracheal instillation of a combination of polyinosinic:polycytidylic acid (poly-I:C) and the receptor-binding domain of the SARS-CoV-2 spike PROTEIN protein (RBD-S) to mimic lung damage MESHD associated with Covid-19 MESHD. Histological analysis of inflamed mice confirmed the expected signs of lung injury MESHD including edema MESHD, fibrosis MESHD, vascular congestion and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill Covid-19 MESHD patients. Administration of the ADAM17 inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of pro-inflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17 inhibition. Thus, we propose inhibition of ADAM17 as a novel promising treatment strategy in SARS-CoV-2-infected MESHD individuals to prevent the progression towards severe Covid-19 MESHD.

    Sex differences in lung imaging and SARS-CoV-2 antibody responses in a COVID-19 MESHD golden Syrian hamster model

    Authors: Santosh Dhakal; Camilo A. Ruiz-Bedoya; Ruifeng Zhou; Patrick Creisher; Jason Villano; Kirsten Littlefield; Jennie Castillo; Paula Marinho; Anne Jedlicka; Alvaro Ordonez; Natalia Majewska; Michael Betenbaugh; Kelly Flavahan; Alice Mueller; Monika Looney; Darla Quijada; Filipa Mota; Sarah E. Beck; Jacqueline K Brockhurst; Alicia Braxton; Natalie Castell; Kelly A. Metcalf Pate; Petros C. Karakousis; Joseph L. Mankowski; Andrew Pekosz; Sanjay K Jain; Sabra L. Klein

    doi:10.1101/2021.04.02.438292 Date: 2021-04-04 Source: bioRxiv

    In the ongoing coronavirus disease MESHD coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) MESHD, more severe outcomes are reported in males compared with females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8-10 weeks of age) were inoculated intranasally with 105 TCID50 of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developing more extensive pneumonia MESHD as noted on chest computed tomography, and recovering more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage MESHD. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including IFNb and TNFa, were comparable between the sexes. However, during the recovery phase of infection, females mounted two-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S PROTEIN-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole inactivated SARS-CoV-2 and mutant S-RBDs MESHD, as well as virus neutralizing antibodies in plasma. The development of an animal model to study COVID-19 MESHD sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2 associated sex differences seen in the human population.

    Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike PROTEIN variants

    Authors: Satoshi Ikegame; Mohammed N. A. Siddiquey; Chuan-Tien Hung; Griffin Haas; Luca Brambilla; Kasopefoluwa Y. Oguntuyo; Shreyas Kowdle; Ariel Esteban Vilardo; Alexis Edelstein; Claudia Perandones; Jeremy P. Kamil; Benhur Lee

    doi:10.1101/2021.03.31.21254660 Date: 2021-04-02 Source: medRxiv

    The novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia MESHD outbreak in Wuhan, China. Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2 variants of concern (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus. All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic. Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B.1.1.7 (501Y.V1) and B.1.351 (501Y.V2). Using a replication-competent EGFP-reporter vesicular stomatitis virus MESHD ( VSV MESHD) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV MESHD-G, coupled with a clonal HEK-293T ACE2 HGNC TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that 8 out of 12 (75%) of serum samples from 12 recipients of the Russian Sputnik V Ad26 / Ad5 vaccine showed dose response curve slopes indicative of failure to neutralize rcVSV-CoV2-S: B.1.351. The same set of sera efficiently neutralized S from B.1.1.7 and showed only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of emergent SARS-CoV-2 variants may benefit from updated vaccines.

    A time series forecasting of the proportion of SARS-CoV-2 N501Y lineage in North America

    Authors: Elena Quinonez; Majid Vahed; Abdolrazagh Hashemi Shahraki; Mehdi Mirsaeidi

    doi:10.1101/2021.03.30.21254648 Date: 2021-03-31 Source: medRxiv

    Introduction: The outbreak of pneumonia MESHD known as SARS-COV-2 and newly-emerging South African (B.1.351), the United Kingdom (B.1.1.7) and Brazil (P.1) variants have led to a more infectious virus and potentially more substantial loss of neutralizing activity by natural infection or vaccine-elicited antibodies. Methods: We identified prevalent mutations using the spike receptor-binding domain (S-RBD) of SARS-CoV-2 deposited in the Nextstrain global database and comparing them to the Wuhan-Hu-1/2019 genomic sequence as a reference. Then we calculated the percentages of mutant genomes from the total regional subsample isolates from December 2019 to the end of January 2021. We developed two separate time series forecasting models for the SARS-CoV-2 B.1.1.7 variant. The computational model used the structure of the S-RBD to examine its interactions with the neutralizing antibody, named CV30 (isolated from a patient), and human angiotensin-converting enzyme 2 HGNC ( hACE-2 HGNC), based on a hybrid algorithm of template-based modeling to predict the affinity of S protein PROTEIN to the neutralizing antibodies and hACE-2 receptor. Results: The proportion of the B.1.1.7 strain in North America is growing fast. From these computations, it seems that the S-RBD and hACE-2 HGNC proteins are less favorable for the South African strain (K417N, E484K, and N501Y) as compared to the wild type structure and more favorable for B.1.1.7 and P.1 variants. In the present of crystallized CV30 neutralizing antibodies, docking scores suggest antibodies can be partially neutralize the B.1.1.7 variant, and, less efficiently, the B.1.351 and P.1 variants. Conclusion: The rapid evolution of SARS-CoV-2 has the potential to allow the newly-emerged B.1.351, and P.1 variants to escape from natural or vaccine-induced neutralizing immunity and viral spreading.

    A public vaccine-induced human antibody protects against SARS-CoV-2 and emerging variants

    Authors: Aaron J. Schmitz; Jackson S. Turner; Zhuoming Liu; Ishmael D. Aziati; Rita E. Chen; Astha Joshi; Traci L. Bricker; Tamarand L. Darling; Daniel C. Adelsberg; Wafaa B. Al Soussi; James Brett Case; Tingting Lei; Mahima Thapa; Fatima Amanat; Pei-Yong Shi; Rachel M. Presti; Florian Krammer; Goran Bajic; Sean P.J. Whelan; Michael S. Diamond; Adrianus C.M. Boon

    doi:10.1101/2021.03.24.436864 Date: 2021-03-25 Source: bioRxiv

    The emergence of antigenically distinct severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) variants with increased transmissibility is a public health threat. Some of these variants show substantial resistance to neutralization by SARS-CoV-2 infection MESHD- or vaccination-induced antibodies, which principally target the receptor binding domain (RBD) on the virus spike glycoprotein PROTEIN. Here, we describe 2C08, a SARS-CoV-2 mRNA vaccine-induced germinal center B cell-derived human monoclonal antibody that binds to the receptor binding motif within the RBD. 2C08 broadly neutralizes SARS-CoV-2 variants with remarkable potency and reduces lung inflammation MESHD, viral load, and morbidity in hamsters challenged with either an ancestral SARS-CoV-2 strain or a recent variant of concern. Clonal analysis identified 2C08-like public clonotypes among B cell clones responding to SARS-CoV-2 infection MESHD or vaccination in at least 20 out of 78 individuals. Thus, 2C08-like antibodies can be readily induced by SARS-CoV-2 vaccines MESHD and mitigate resistance by circulating variants of concern.

    Full Brain and Lung Prophylaxis against SARS-CoV-2 by Intranasal Lentiviral Vaccination in a New hACE2 HGNC Transgenic Mouse Model or Golden Hamsters

    Authors: Min-Wen Ku; Pierre Authie; Maryline Bourgine; Francois Anna; Amandine Noirat; Fanny Moncoq; Benjamin Vesin; Fabien Nevo; Jodie Lopez; Philippe Souque; Catherine Blanc; Sebastien Chardenoux; Ilta Lafosse; David Hardy; Kirill Nemirov; Francoise Guinet; Francina Langa Vives; Laleh Majlessi; Pierre Charneau

    doi:10.1101/2021.02.03.429211 Date: 2021-02-03 Source: bioRxiv

    Non-integrative, non-cytopathic and non-inflammatory lentivectors are particularly suitable for mucosal vaccination and recently emerge as a promising strategy to elicit sterilizing prophylaxis against SARS-CoV-2 in preclinical animal models. Here, we demonstrate that a single intranasal administration of a lentivector encoding a prefusion form of SARS-CoV-2 spike PROTEIN glycoprotein induces full protection of respiratory tracts and totally avoids pulmonary inflammation MESHD in the susceptible hamster model. More importantly, we generated a new transgenic mouse strain, expressing the human Angiotensin Converting Enzyme 2 HGNC, with unprecedent brain permissibility to SARS-CoV-2 replication and developing a lethal disease in <4 days post infection. Even though the neurotropism of SARS-CoV-2 MESHD is now well established, so far other vaccine strategies under development have not taken into account the protection of central nervous system. Using our highly stringent transgenic model, we demonstrated that an intranasal booster immunization with the developed lentivector vaccine candidate achieves full protection of both respiratory tracts and central nervous system against SARS-CoV-2.

    Bispecific antibody prevents SARS-CoV-2 escape and protects mice from disease

    Authors: Thomas L Williams; Maria T Colzani; Robyn GC Macrae; Emma L Robinson; Stuart Bloor; Edward JD Greenwood; Jun Ru Zhan; Gregory Strachan; Rhoda E Kuc; Duuamene Nyimanu; Janet J Maguire; Paul J Lehner; Sanjay Sinha; Anthony P Davenport; Valluri Anitha Lavanya; Mercy Rophina; S. Umadevi; Paras Sehgal; Avula Renuka Devi; A. Surekha; Pulala Chandra; Rajamadugu Hymavathy; P R Vanaja; Vinod Scaria; Sridhar Sivasubbu; Chloe Simela; Veronica French; Rachel Harris; Sharon A.M. Stevelink; Simon Wessely

    doi:10.1101/2021.01.22.427567 Date: 2021-01-22 Source: bioRxiv

    Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN (S) are among the most promising approaches against coronavirus disease 2019 MESHD ( COVID-19 MESHD). We developed a bispecific, IgG1-like molecule based on two antibodies derived from COVID-19 MESHD convalescent donors, C121 and C135. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, completely prevents S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 recognizes a broad panel of RBD variants and neutralizes SARS-CoV-2 and the escape mutants generated by the single monoclonals at sub-nanomolar concentrations. In a novel model of SARS-CoV-2 infection MESHD with lung inflammation MESHD, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

    Rapid protection from COVID-19 MESHD in nonhuman primates vaccinated intramuscularly but not intranasally with a single dose of a recombinant vaccine

    Authors: Wakako Furuyama; Kyle Shifflett; Amanda N Pinksi; Amanda J Griffin; Friederike Feldmann; Atsushi Okumura; Tylisha Gourdine; Allen Jankeel; Jamie Lovaglio; Patrick W Hanley; Tina Thomas; Chad S Clancy; Ilhem Messaoudi; Andrea Marzi; Martina Turroja; Kamille A West; Kristie Gordon; Katrina G Millard; Victor Ramos; Justin Da Silva; Jianliang Xu; Robert A Colbert; Roshni Patel; Juan P Dizon; Irina Shimeliovich; Anna Gazumyan; Marina Caskey; Pamela J Bjorkman; Rafael Casellas; Theodora Hatziioannou; Paul D Bieniasz; Michel C Nussenzweig

    doi:10.1101/2021.01.19.426885 Date: 2021-01-19 Source: bioRxiv

    The ongoing pandemic of Coronavirus disease 2019 MESHD ( COVID-19 MESHD) continues to exert a significant burden on health care systems worldwide. With limited treatments available, vaccination remains an effective strategy to counter transmission of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2). Recent discussions concerning vaccination strategies have focused on identifying vaccine platforms, number of doses, route of administration, and time to reach peak immunity against SARS-CoV-2. Here, we generated a single dose, fast-acting vesicular stomatitis MESHD virus-based vaccine derived from the licensed Ebola virus (EBOV) vaccine rVSV-ZEBOV, expressing the SARS-CoV-2 spike PROTEIN protein and the EBOV glycoprotein (VSV-SARS2-EBOV). Rhesus macaques vaccinated intramuscularly (IM) with a single dose of VSV-SARS2-EBOV were protected within 10 days and did not show signs of COVID-19 MESHD pneumonia MESHD. In contrast, IN vaccination MESHD resulted in limited immunogenicity and enhanced COVID-19 MESHD pneumonia MESHD compared to control animals. While IM and IN vaccination both induced neutralizing antibody titers MESHD, only IM vaccination resulted in a significant cellular immune response. RNA sequencing data bolstered these results by revealing robust activation of the innate and adaptive immune transcriptional signatures in the lungs of IM-vaccinated animals only. Overall, the data demonstrates that VSV-SARS2-EBOV is a potent single-dose COVID-19 MESHD vaccine candidate that offers rapid protection based on the protective efficacy observed in our study.

    Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces shedding of SARS-CoV-2 D614G in rhesus macaques

    Authors: Neeltje van Doremalen; Jyothi Purushotham; Jonathan Schulz; Myndi Holbrook; Trenton Bushmaker; Aaron Carmody; Julia Port; Kwe Claude Yinda; Atsushi Okumura; Greg Saturday; Fatima Amanat; Florian Krammer; Patrick Hanley; Brian Smith; Jamie Lovaglio; Sarah Anzick; Kent Barbian; Craig Martens; Sarah C Gilbert; Teresa Lambe; Vincent Munster; Michael Seilmaier; Clemens Wendtner; Reinhold Foerster; Bart Haagmans; Stephan Becker; Gerd Sutter; Asisa Volz

    doi:10.1101/2021.01.09.426058 Date: 2021-01-11 Source: bioRxiv

    Intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 protected rhesus macaques against pneumonia MESHD but did not reduce shedding of SARS-CoV-2. Here we investigate whether intranasally administered ChAdOx1 nCoV-19 reduces shedding, using a SARS-CoV-2 virus with the D614G mutation in the spike protein PROTEIN. Viral load in swabs obtained from intranasally vaccinated hamsters was significantly decreased compared to controls and no viral RNA or infectious virus was found in lung tissue, both in a direct challenge and a transmission model. Intranasal vaccination of rhesus macaques resulted in reduced shedding and a reduction in viral load in bronchoalveolar lavage and lower respiratory tract tissue. In conclusion, intranasal vaccination reduced shedding in two different SARS-CoV-2 animal models, justifying further investigation as a potential vaccination route for COVID-19 MESHD vaccines.

    Unravelling Vitamins as Wonder Molecules for Covid-19 MESHD Management via Structure-based Virtual Screening

    Authors: Medha Pandya; Sejal Shah; Dhanalakshmi Menamadathil; Ayushman Gadnayak; Tanzil Juneja; Amisha Patel; Kajari Das; Jayashankar Das

    doi:10.21203/rs.3.rs-144177/v1 Date: 2021-01-09 Source: ResearchSquare

    The emergence situation of coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic has realised the global scientific communities to develop strategies for immediate priorities and long-term approaches for utilization of existing knowledge and resources which can be diverted to pandemic preparedness planning. Lack of proper vaccine candidate and therapeutic management has accelerated the researchers to repurpose the existing drugs with known preclinical and toxicity MESHD profiles, which can easily enter Phase 3 or 4 or can be used directly in clinical settings. We focused to justify even exploration of supplements, nutrients and vitamins to dampen the disease burden of the current pandemic may play a crucial role for its management. We have explored structure based virtual screening of 15 vitamins against non-structural ( NSP3 HGNC NSP3 PROTEIN, NSP5 PROTEIN NSP5 HGNC, ORF7a PROTEIN, NSP12 PROTEIN, ORF3a PROTEIN), structural (Spike & Hemagglutinin esterase) and host protein furin HGNC. The in silico analysis exhibited that vitamin B12, Vitamin B9, Vitamin D3 determined suitable binding while vitamin B15 manifested remarkable H-bond interactions with all targets. Vitamin B12 bestowed the lowest energies with human furin HGNC and SARS-COV-2 RNA dependent RNA polymerase PROTEIN. Furin HGNC mediated cleavage of the viral spike glycoprotein PROTEIN is directly related to enhanced virulence of SARS-CoV-2. In contrast to these, vitamin B12 showed zero affinity with SARS-CoV-2 spike PROTEIN protein. These upshots intimate that Vitamin B12 could be the wonder molecule to shrink the virulence by hindering the furin HGNC mediated entry of spike to host cell. These identified molecules may effectively assist in SARS-CoV-2 therapeutic management to boost the immunity by inhibiting the virus imparting relief in lung inflammation MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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