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1.
researchsquare; 2022.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-2222184.v1

ABSTRACT

Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. To address this issue, we performed a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We found that soluble and transcriptional markers of systemic inflammation peaked during the first week after symptom onset and correlated directly with the upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4+ and CD8+ T cells correlated inversely with various inflammatory markers and UA-VLs. In addition, we observed high frequencies of activated CD4+ and CD8+ T cells in acutely infected nasopharyngeal tissue, many of which expressed genes encoding various effector molecules, such as cytotoxic proteins and IFN-γ. The presence of functionally active T cells in the infected epithelium was further linked with common patterns of gene expression among virus-susceptible target cells and better local control of SARS-CoV-2. Collectively, these results identified an immune correlate of protection against SARS-CoV-2, which could inform the development of more effective vaccines to combat the acute and chronic illnesses attributable to COVID-19.

2.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.04.27.21256133

ABSTRACT

Background: In the 2nd year of the Covid-19 pandemic, knowledge about the dynamics of the infection in the general population is still limited. Such information is essential for health planners, as many of those infected show no or only mild symptoms and thus, escape the surveillance system. We therefore aimed to describe the course of the pandemic in the Munich general population living in private households from April 2020 to January 2021. Methods: The KoCo19 baseline study took place from April to June 2020 including 5313 participants (age 14 years and above). From November 2020 to January 2021, we could again measure SARS-CoV-2 antibody status in 4,433 of the baseline participants (response 83%). Participants were offered a self-sampling kit to take a capillary blood sample (dry blood spot; DBS). Blood was analysed using the Elecsys(R) Anti-SARS-CoV-2 assay (Roche). Questionnaire information on socio-demographics and potential risk factors assessed at baseline was available for all participants. In addition, follow-up information on health-risk taking behaviour and number of personal contacts outside the household (N=2768) as well as leisure time activities (N=1263) were collected in summer 2020. Results: Weighted and adjusted (for specificity and sensitivity) SARS-CoV-2 sero-prevalence at follow-up was 3.6% (95% CI 2.9-4.3%) as compared to 1.8% (95% CI 1.3-3.4%) at baseline. 91% of those tested positive at baseline were also antibody-positive at follow-up. While sero-prevalence increased from early November 2021 to January 2021, no indication of geospatial clustering across the city of Munich was found, although cases clustered within households. Taking baseline result and time to follow-up into account, men and participants in the age group 20-34 years were at the highest risk of sero-positivity. In the sensitivity analyses, differences in health-risk taking behaviour, number of personal contacts and leisure time activities partly explained these differences. Conclusion: The number of citizens in Munich with SARS-CoV-2 antibodies was still below 5% during the 2nd wave of the pandemic. Antibodies remained present in the majority of baseline participants. Besides age and sex, potentially confounded by differences in behaviour, no major risk factors could be identified. Non-pharmaceutical public health measures are thus still important.

3.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.01.13.21249735

ABSTRACT

BackgroundSerosurveys are essential to understand SARS-CoV-2 exposure and enable population-level surveillance, but currently available tests need further in-depth evaluation. We aimed to identify testing-strategies by comparing seven seroassays in a population-based cohort. MethodsWe analysed 6,658 samples consisting of true-positives (n=193), true-negatives (n=1,091), and specimens of unknown status (n=5,374). For primary testing, we used Euroimmun-Anti-SARS-CoV-2-ELISA-IgA/IgG and Roche-Elecsys-Anti-SARS-CoV-2; and virus-neutralisation, GeneScript(R)cPass, VIRAMED-SARS-CoV-2-ViraChip(R), and Mikrogen-recomLine-SARS-CoV-2-IgG, including common-cold CoVs, for confirmatory testing. Statistical modelling generated optimised assay cut-off-thresholds. FindingsSensitivity of Euroimmun-anti-S1-IgA was 64.8%, specificity 93.3%; for Euroimmun-anti-S1-IgG, sensitivity was 77.2/79.8% (manufacturers/optimised cut-offs), specificity 98.0/97.8%; Roche-anti-N sensitivity was 85.5/88.6%, specificity 99.8/99.7%. In true-positives, mean and median titres remained stable for at least 90-120 days after RT-PCR-positivity. Of true-positives with positive RT-PCR (<30 days), 6.7% did not mount detectable seroresponses. Virus-neutralisation was 73.8% sensitive, 100.0% specific (1:10 dilution). Neutralisation surrogate tests (GeneScript(R)cPass, Mikrogen-recomLine-RBD) were >94.9% sensitive, >98.1% specific. Seasonality had limited effects; cross-reactivity with common-cold CoVs 229E and NL63 in SARS-CoV-2 true-positives was significant. ConclusionOptimised cut-offs improved test performances of several tests. Non-reactive serology in true-positives was uncommon. For epidemiological purposes, confirmatory testing with virus-neutralisation may be replaced with GeneScript(R)cPass or recomLine-RBD. Head-to-head comparisons given here aim to contribute to the refinement of testing-strategies for individual and public health use.

4.
ssrn; 2021.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3745128

ABSTRACT

Background: Population-based studies investigating the dynamics of the SARS-CoV-2 pandemic are needed. Here, we report on baseline findings from April through June 2020 of a prospective cohort study in Munich, Germany.Methods: We drew a representative sample of 2994 private households. The 5313 participating household members 14 years and older completed questionnaires and provided blood samples. SARS-CoV-2 seropositivity was defined as Roche N pan-Ig ≥ 0·4218. We adjusted the prevalence for the sampling design, sensitivity, and specificity. We investigated risk factors for SARS-CoV-2 seropositivity and geospatial transmission patterns by generalized linear mixed models and permutation tests.Findings: Seropositivity for SARS-CoV-2 specific antibodies was 1·82% (95% confidence interval (CI) 1·28-2·37%) as compared to 0·46% PCR-positive cases officially registered in Munich. Loss of the sense of smell or taste was associated with seropositivity (odds ratio (OR) 47·4; 95% CI 7·2-307·0) and infections clustered within households. Participants suffering from respiratory allergies (OR 2·7; 95% CI 0·9-8·6) and working in high-risk jobs (OR 2·0; 95% CI 0·5-6·7) showed non-significantly increased odds for SARS-CoV-2 seropositivity.Interpretation: Applying a validated assay, we demonstrate a low SARS-CoV-2 seroprevalence in the Munich population 14 years and older towards the end of the first pandemic wave. However, we noted official sub-registration at this early stage of the pandemic.Funding: Bavarian State Ministry of Science and the Arts, University Hospital of LMU Munich, Helmholtz Centre Munich, University of Bonn, and University of Bielefeld.Declaration of Interests: FF, TF, DM, LO, and VT report grants from the Bavarian State Ministry of Science and the Arts during the conduct oft he study. TF reports grants from the University Hospital of LMU Munich, Helmholtz Center Munich, University of Bonn, University of Bielefeld, and German Ministry for Education and Research during the conduct of the study. JH reports grants from the German Federal Ministry of Education and Research during the conduct of the study. MH and AW report personal fees and non-financial support, LO and MP report non-financial support from Roche Diagnostics. MH, LO, MP, and AW report non-financial support from Euroimmun, Viramed, and Mikrogen. MH, MP, and AW report grants, non-financial support, and other from German Center for Infection Research (DZIF). FF, MH, LO, MP, VT, and AW report grants and non-financial support from the Government of Bavaria. MH, LO, MP, and AW report non-financial support from BMW, Mercedes Benz, Munich Police, and Accenture. MH and AW report personal fees and non-financial support from Dr. Box Betrobox during the conduct of the study. LO and MP report non-financial support from Dr. Box Betrobox. MH and AW have a patent Sample System for Sputum Diagnostics of SARS-CoV-2 pending. DM reports to be a a sub-investigator on a Phase I SARS-CoV-2 vaccine trial and on a Phase I rabies vaccine trial, both sponsored by CureVac AG. MP and AW report non-financial support from Dr. Becker MVZ. VT reports support from CureVac AG outside the submitted work. AW reports personal fees and other from Haeraeus Sensors. AW reports non-financial support from Bruker Daltronics outside the submitted work. AW is involved in other different patents and companies not in relation with the serology of SARS-CoV-2. All other authors report nothing to disclose.Ethics Approval Statement: Prior to study initiation, this study had been approved by therespective Institutional Review Board.

5.
Marek Ostaszewski; Anna Niarakis; Alexander Mazein; Inna Kuperstein; Robert Phair; Aurelio Orta-Resendiz; Vidisha Singh; Sara Sadat Aghamiri; Marcio Luis Acencio; Enrico Glaab; Andreas Ruepp; Gisela Fobo; Corinna Montrone; Barbara Brauner; Goar Frishman; Julia Somers; Matti Hoch; Shailendra Kumar Gupta; Julia Scheel; Hanna Borlinghaus; Tobias Czauderna; Falk Schreiber; Arnau Montagud; Miguel Ponce de Leon; Akira Funahashi; Yusuke Hiki; Noriko Hiroi; Takahiro G Yamada; Andreas Drager; Alina Renz; Muhammad Naveez; Zsolt Bocskei; Daniela Bornigen; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.26.356014

ABSTRACT

We hereby describe a large-scale community effort to build an open-access, interoperable, and computable repository of COVID-19 molecular mechanisms - the COVID-19 Disease Map. We discuss the tools, platforms, and guidelines necessary for the distributed development of its contents by a multi-faceted community of biocurators, domain experts, bioinformaticians, and computational biologists. We highlight the role of relevant databases and text mining approaches in enrichment and validation of the curated mechanisms. We describe the contents of the map and their relevance to the molecular pathophysiology of COVID-19 and the analytical and computational modelling approaches that can be applied to the contents of the COVID-19 Disease Map for mechanistic data interpretation and predictions. We conclude by demonstrating concrete applications of our work through several use cases.

6.
Reut Falach; Liat Bar-On; Shlomi Lazar; Tamar Kadar; Ohad Mazor; Moshe Aftalion; David Gur; Ohad Shifman; Ofir Israeli; Inbar Cohen-Gihon; Galia Zaida; Hila Gutman; Yentl Evgy; Yaron Vagima; Efi Makdasi; Dana Stein; Ronit Rosenfeld; Ron Alcalay; Eran Zahavy; Haim Levy; Itai Glinert; Amir Ben-Shmuel; Tomer Israely; Sharon Melamed; Boaz Politi; Hagit Achdout; Shmuel Yitzhaky; Chanoch Kronman; Tamar Sabo; Alina Renz; Muhammad Naveez; Zsolt Bocskei; Daniela Bornigen; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.358614

ABSTRACT

Severe manifestations of COVID-19 are mostly restricted to persons with comorbidities, and they form a significantly high proportion of those which develop life-endangering lung injury. Nevertheless, COVID-19 animal models established to date are not based on preexistence of comorbidities. Here we report that mild pulmonary injury induced by administration of acute-lung-injury stimulants, renders outbred CD-1 mice to be sensitive to SARS-CoV-2. Following intranasal pretreatment of mice with low doses of ricin or bleomycin, SARS-CoV-2 infection caused a severe disease manifested by sustained body loss and mortality rates of >50%. Low-dose-ricin pretreated mice displayed markedly higher levels of viral RNA than mice not pretreated with ricin, not only in the nasal turbinate, trachea and lungs but also in the serum and heart. The deleterious effects of SARS-CoV-2 infection in ricin-pretreated mice were effectively alleviated by passive transfer of polyclonal and monoclonal antibodies generated against SARS-CoV-2 or SARS-CoV-2 RBD. Notably, viral cell entry in the sensitized mice model seems to involve viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. In summary, we present a novel animal model in mice that express native murine ACE2 yet are susceptible to genetically unaltered SARS-CoV-2, for the study of comorbidity-dependent COVID-19 pathology and treatment.

7.
Boris Bonaventure; Antoine Rebendenne; Francisco Garcia de Gracia; Marine Tauziet; Joe McKellar; Ana Luiza Chaves Valadão; Valérie Courgnaud; Eric Bernard; Laurence Briant; Nathalie Gros; Wassila Djilli; Mary Arnaud-Arnould; Hugues Parrinello; Stéphanie Rialle; Olivier Moncorgé; Caroline Goujon; Ronit Rosenfeld; Ron Alcalay; Eran Zahavy; Haim Levy; Itai Glinert; Amir Ben-Shmuel; Tomer Israely; Sharon Melamed; Boaz Politi; Hagit Achdout; Shmuel Yitzhaky; Chanoch Kronman; Tamar Sabo; Alina Renz; Muhammad Naveez; Zsolt Bocskei; Daniela Bornigen; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.359356

ABSTRACT

Genome-wide CRISPR/Cas9 knock-out genetic screens are powerful approaches to unravel new regulators of viral infections. With the aim of identifying new cellular inhibitors of HIV-1, we have developed a strategy in which we took advantage of the ability of type 1 interferon (IFN) to potently inhibit HIV-1 infection, in order to create a cellular environment hostile to viral replication. This approach led to the identification of the DEAD-box RNA helicase DDX42 as an intrinsic inhibitor of HIV-1. Depletion of endogenous DDX42 using siRNA or CRISPR/Cas9 knock-out increased HIV-1 infection, both in model cell lines and in physiological targets of HIV-1, primary CD4+ T cells and monocyte-derived macrophages (MDMs), and irrespectively of the IFN treatment. Similarly, the overexpression of a dominant-negative mutant of DDX42 positively impacted HIV-1 infection, whereas wild-type DDX42 overexpression potently inhibited HIV-1 infection. The positive impact of endogenous DDX42 depletion on HIV-1 infection was directly correlated to an increase in viral DNA accumulation. Interestingly, proximity ligation assays showed that DDX42, which can be mainly found in the nucleus but is also present in the cytoplasm, was in the close vicinity of HIV-1 Capsid during infection of primary monocyte-derived macrophages. Moreover, we show that DDX42 is also able to substantially decrease infection with other retroviruses and retrotransposition of long interspersed elements-1 (LINE-1). Finally, we reveal that DDX42 potently inhibits other pathogenic viruses, including Chikungunya virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

8.
Tiangang Liu; Jia-Qi Li; Minjian Huang; Ya-Nan Zhang; Ran Liu; Zhe-Rui Zhang; Qiu-Yan Zhang; Yong Wang; Jing Liu; Zixin Deng; Bo Zhang; Han-Qing Ye; Hugues Parrinello; Stéphanie Rialle; Olivier Moncorgé; Caroline Goujon; Ronit Rosenfeld; Ron Alcalay; Eran Zahavy; Haim Levy; Itai Glinert; Amir Ben-Shmuel; Tomer Israely; Sharon Melamed; Boaz Politi; Hagit Achdout; Shmuel Yitzhaky; Chanoch Kronman; Tamar Sabo; Alina Renz; Muhammad Naveez; Zsolt Bocskei; Daniela Bornigen; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.27.354563

ABSTRACT

Infections with zoonotic viruses, such as flaviviruses, influenza virus, and the SARS-CoV-2 pandemic coronavirus constitute an increasing global risk. Hence, an urgent need exists for the development of broad-spectrum antivirals to prevent such outbreaks. Here, we show that the maduramycin and CP-80,219 aglycone polyether ionophores exhibit effective broad-spectrum antiviral activity, against various viruses, including Japanese encephalitis virus (JEV), Dengue virus (DENV), Zika virus (ZIKV), and Chikungunya virus (CHIKV), while also exhibiting promising activity against PR8 influenza virus and SARS-CoV-2. Moreover, liposome-encapsulated maduramycin and CP-80,219 provide full protection for mice from infection with JEV in vivo. Mechanistic studies suggest that aglycone polyether ionophores primarily inhibit the viral replication step without blocking endosome acidification to promote the fusion between viral and cellular membranes. The successful application of liposomes containing aglycone polyether ionophores in JEV-infected mice offers hope to the development of broad-spectrum antiviral drugs like penicillin back to 1940s.

9.
Katarzyna Polak; Noémie Greze; Maëlle Lachat; Delphine Merle; Steve Chiumento; Christelle Bertrand-Gaday; Bernadette Trentin; Robert Z. Mamoun; Gamze Tumentemur; Sevda Demir; Utku Seyis; Recai Kuzay; Muhammer Elek; Gurcan Ertop; Serap Arbak; Merve Acikel Elmas; Cansu Hemsinlioglu; Ozden Hatirnaz Ng; Sezer Akyoney; Ilayda Sahin; Cavit Kerem Kayhan; Fatma Tokat; Gurler Akpinar; Murat Kasap; Ayse Sesin Kocagoz; Ugur Ozbek; Dilek Telci; Fikrettin Sahin; Koray Yalcin; Siret Ratip; Umit Ince; Guldal Suyen; Ercument Ovali; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.357137

ABSTRACT

Extracellular vesicles (EVs) emerge as essential mediators of intercellular communication. DNA vaccines encoding antigens presented on EVs efficiently induce T-cell responses and EV-based vaccines containing the Spike (S) proteins of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) are highly immunogenic in mice. Thus, EVs may serve as vaccine platforms against emerging diseases, going beyond traditional strategies, with the antigen displayed identically to the original protein embedded in the viral membrane and presented as such to the immune system. Compared to their viral and pseudotyped counterparts, EV-based vaccines overcome many safety issues including pre-existing immunity against these vectors. Here, we applied our technology in natural EV's engineering, to express the S proteins of SARS-CoV-2 embedded in the EVs, which mimic the virus with its fully native spikes. Immunizations with a two component CoVEVax vaccine, comprising DNA vector (DNAS-EV) primes, allowing in situ production of Spike harbouring EVs, and a boost using S-EVs produced in mammalian cells, trigger potent neutralizing and cellular responses in mice, in the absence of any adjuvants. CoVEVax would be the prototype of vaccines, where the sole exchange of the envelope proteins on EVs leads to the generation of new vaccine candidates against emerging viruses.

10.
Da-Yuan Chen; Nazimuddin Khan; Brianna J. Close; Raghuveera K. Goel; Benjamin Blum; Alexander H. Tavares; Devin Kenney; Hasahn L. Conway; Jourdan K. Ewoldt; Sebastian Kapell; Vipul C. Chitalia; Nicholas A. Crossland; Christopher S. Chen; Darrell N. Kotton; Susan C. Baker; John H. Connor; Florian Douam; Andrew Emili; Mohsan Saeed; Ilayda Sahin; Cavit Kerem Kayhan; Fatma Tokat; Gurler Akpinar; Murat Kasap; Ayse Sesin Kocagoz; Ugur Ozbek; Dilek Telci; Fikrettin Sahin; Koray Yalcin; Siret Ratip; Umit Ince; Guldal Suyen; Ercument Ovali; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.27.358259

ABSTRACT

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we performed global proteomic analysis of the virus-host interface in a newly established panel of phenotypically diverse, SARS-CoV-2-infectable human cell lines representing different body organs. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cell lines and primary-like cardiomyocytes, and found that several pathway components were targeted by SARS-CoV-2 leading to cellular desensitization to interferon. These findings indicate that the suppression of interferon signaling is a mechanism widely used by SARS-CoV-2 in diverse tissues to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19.

11.
Alison Green; Glyn Roberts; Timothy Tobery; Carol Vincent; Matteo Barili; Carolyn Jones; Kiyoshi Kita; Kouichi Morita; Jiro Yasuda; Sebastian Kapell; Vipul C. Chitalia; Nicholas A. Crossland; Christopher S. Chen; Darrell N. Kotton; Susan C. Baker; John H. Connor; Florian Douam; Andrew Emili; Mohsan Saeed; Ilayda Sahin; Cavit Kerem Kayhan; Fatma Tokat; Gurler Akpinar; Murat Kasap; Ayse Sesin Kocagoz; Ugur Ozbek; Dilek Telci; Fikrettin Sahin; Koray Yalcin; Siret Ratip; Umit Ince; Guldal Suyen; Ercument Ovali; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.359257

ABSTRACT

Background: saliva is established to contain high counts SARS-CoV-2 virus and contact with saliva droplets, contaminated surfaces or airborne particles are sources of viral transmission. The generation of infective aerosols during clinical procedures is of particular concern. Therefore, a fuller understanding of the potential of mouthwash to reduce viral counts and modulate the risk of transmission in medical professional and public context is an important research topic. Method: we determined the virucidal activity of four anti-bacterial mouthwashes against a surrogate for SARS-CoV-2, Human CoV-SARS 229E, using a standard ASTM suspension test, with dilution and contact times applicable to recommended mouthwash use. Results: the mouthwash formulated with 0.07% Cetylpyridinium Chloride exhibited virucidal effects providing a [≥]3.0 log reduction HCoV-229E viral count. Mouthwashes containing 15.7% ethanol, 0.2% zinc sulphate heptahydrate and a mix of enzymes and proteins did not demonstrate substantive virucidal activity in this test. Conclusion: mouthwash containing 0.07% Cetylpyridinium Chloride warrants further laboratory and clinical assessment to determine their potential benefit in reducing the risk of SARS-CoV-2.

12.
Goran Kokic; Hauke Sven Hillen; Dimitry Tegunov; Christian Dienemann; Florian Seitz; Jana Schmitzova; Lucas Farnung; Aaron Siewert; Claudia Hoebartner; Patrick Cramer; Bo Zhang; Han-Qing Ye; Hugues Parrinello; Stéphanie Rialle; Olivier Moncorgé; Caroline Goujon; Ronit Rosenfeld; Ron Alcalay; Eran Zahavy; Haim Levy; Itai Glinert; Amir Ben-Shmuel; Tomer Israely; Sharon Melamed; Boaz Politi; Hagit Achdout; Shmuel Yitzhaky; Chanoch Kronman; Tamar Sabo; Alina Renz; Muhammad Naveez; Zsolt Bocskei; Daniela Bornigen; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.358481

ABSTRACT

Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analogue and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3'-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3'-nucleotide of the RNA product is matched with the template base, and this may prevent proofreading by the viral 3'-exonuclease that recognizes mismatches. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.

13.
Xiaoquan Li; Petr Lidsky; Yinghong Xiao; Chien-Ting Wu; Miguel Garcia-Knight; Junjiao Yang; Tsuguhisa Nakayama; Jayakar V. Nayak; Peter K. Jackson; Raul Andino; Xiaokun Shu; Nicholas A. Crossland; Christopher S. Chen; Darrell N. Kotton; Susan C. Baker; John H. Connor; Florian Douam; Andrew Emili; Mohsan Saeed; Ilayda Sahin; Cavit Kerem Kayhan; Fatma Tokat; Gurler Akpinar; Murat Kasap; Ayse Sesin Kocagoz; Ugur Ozbek; Dilek Telci; Fikrettin Sahin; Koray Yalcin; Siret Ratip; Umit Ince; Guldal Suyen; Ercument Ovali; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.359042

ABSTRACT

More than a million people have now died from COVID-19, because of infection with the SARS-CoV-2 coronavirus. Currently, the FDA has approved remdesivir, an inhibitor of SARS-CoV-2 replication, to treat COVID-19, though very recent data from WHO showed little if any COVID19 protective effect. Here we report that ethacridine, a safe and potent antiseptic use in humans, effectively inhibits SARS-CoV-2, at very low concentrations (EC50 ~ 0.08 M). Ethacridine was identified through a high-throughput screening of an FDA-approved drug library in living cells using a fluorescent assay. Interestingly, the main mode of action of ethacridine is to inactivate virus particles, preventing binding to the host cells. Thus, our work has identified a potent drug with a distinct mode of action against SARS-CoV-2.

14.
Raife Dilek Turan; Cihan Tastan; Derya Dilek Kancagi; Bulut Yurtsever; Gozde Sir Karakus; Samed Ozer; Selen Abanuz; Didem Cakirsoy; Gamze Tumentemur; Sevda Demir; Utku Seyis; Recai Kuzay; Muhammer Elek; Gurcan Ertop; Serap Arbak; Merve Acikel Elmas; Cansu Hemsinlioglu; Ozden Hatirnaz Ng; Sezer Akyoney; Ilayda Sahin; Cavit Kerem Kayhan; Fatma Tokat; Gurler Akpinar; Murat Kasap; Ayse Sesin Kocagoz; Ugur Ozbek; Dilek Telci; Fikrettin Sahin; Koray Yalcin; Siret Ratip; Umit Ince; Guldal Suyen; Ercument Ovali; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.356667

ABSTRACT

The SARS-CoV-2 virus caused one of the severest pandemic around the world. The vaccine development for urgent use became more of an issue during the pandemic. An inactivated virus formulated vaccines such as Hepatitis A, inactivated polio, and influenza has been proven to be a reliable approach for immunization for long years. In this pandemic, we produced an inactivated SARS-CoV-2 vaccine candidate by modification of the oldest but the most experienced method that can be produced quickly and tested easily rather than the recombinant vaccines. Here, we optimized an inactivated virus vaccine which includes the gamma irradiation process for the inactivation as an alternative to classical chemical inactivation methods so that there is no extra purification required. Also, we applied the vaccine candidate (OZG-38.61.3) using the intradermal route in mice which decreased the requirement of a higher concentration of inactivated virus for proper immunization unlike most of the classical inactivated vaccine treatments. Thus, the novelty of our vaccine candidate (OZG-38.61.3) is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. We first determined the efficiency and safety dose (either 1013 or 1014 viral copy per dose) of the OZG-38.61.3 in Balb/c mice. Next, to test the immunogenicity and protective efficacy of the OZG-38.61.3, we immunized human ACE2-encoding transgenic mice and infected them with a dose of infective SARS-CoV-2 virus for the challenge test. We showed that the vaccinated mice showed lowered SARS-CoV-2 viral copy number in oropharyngeal specimens along with humoral and cellular immune responses against the SARS-CoV-2, including the neutralizing antibodies similar to those shown in Balb/c mice without substantial toxicity. This study encouraged us towards a new promising strategy for inactivated vaccine development (OZG-38.61.3) and the Phase 1 clinical trial for the COVID-19 pandemic.

15.
Antoine Rebendenne; Ana Luiza Chaves Valadão; Marine Tauziet; Ghizlane Maarifi; Boris Bonaventure; Rémi Planès; Joe McKellar; Sébastien Nisole; Mary Arnaud-Arnould; Olivier Moncorgé; Caroline Goujon; Nicholas A. Crossland; Christopher S. Chen; Darrell N. Kotton; Susan C. Baker; John H. Connor; Florian Douam; Andrew Emili; Mohsan Saeed; Ilayda Sahin; Cavit Kerem Kayhan; Fatma Tokat; Gurler Akpinar; Murat Kasap; Ayse Sesin Kocagoz; Ugur Ozbek; Dilek Telci; Fikrettin Sahin; Koray Yalcin; Siret Ratip; Umit Ince; Guldal Suyen; Ercument Ovali; Liam Fergusson; Marta Conti; Marius Rameil; Vanessa Nakonecnij; Jakob Vanhoefer; Leonard Schmiester; Muying Wang; Emily E Ackerman; Jason E Shoemaker; Jeremy Zucker; Kristie L Oxford; Jeremy Teuton; Ebru Kocakaya; Gokce Yagmur Summak; Kristina Hanspers; Martina Kutmon; Susan Coort; Lars Eijssen; Friederike Ehrhart; Rex D. A. B.; Denise Slenter; Marvin Martens; Robin Haw; Bijay Jassal; Lisa Matthews; Marija Orlic-Milacic; Andrea Senff-Ribeiro; Karen Rothfels; Veronica Shamovsky; Ralf Stephan; Cristoffer Sevilla; Thawfeek Mohamed Varusai; Jean-Marie Ravel; Vera Ortseifen; Silvia Marchesi; Piotr Gawron; Ewa Smula; Laurent Heirendt; Venkata Satagopam; Guanming Wu; Anders Riutta; Martin Golebiewski; Stuart Owen; Carole Goble; Xiaoming Hu; Rupert Overall; Dieter Maier; Angela Bauch; John A Bachman; Benjamin M Gyori; Carlos Vega; Valentin Groues; Miguel Vazquez; Pablo Porras; Luana Licata; Marta Iannuccelli; Francesca Sacco; Denes Turei; Augustin Luna; Ozgun Babur; Sylvain Soliman; Alberto Valdeolivas; Marina Esteban-Medina; Maria Pena-Chilet; Tomas Helikar; Bhanwar Lal Puniya; Anastasia Nesterova; Anton Yuryev; Anita de Waard; Dezso Modos; Agatha Treveil; Marton Laszlo Olbei; Bertrand De Meulder; Aurelien Naldi; Aurelien Dugourd; Laurence Calzone; Chris Sander; Emek Demir; Tamas Korcsmaros; Tom C Freeman; Franck Auge; Jacques S Beckmann; Jan Hasenauer; Olaf Wolkenhauer; Egon Willighagen; Alexander R Pico; Chris Evelo; Lincoln D Stein; Henning Hermjakob; Julio Saez-Rodriguez; Joaquin Dopazo; Alfonso Valencia; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; - the COVID-19 Disease Map Community.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.28.358945

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic coronavirus to spill over to humans in less than 20 years, after SARS-CoV-1 in 2002-2003 and Middle East respiratory syndrome (MERS)-CoV in 2012. SARS-CoV-2 is the etiologic agent of coronavirus disease 19 (COVID-19), which ranges from mild respiratory symptoms to severe lung injury and death in the most severe cases. The COVID-19 pandemic is currently a major health issue worldwide. Immune dysregulation characterized by altered innate cytokine responses is thought to contribute to the pathology of COVID-19 patients, which is a testimony of the fundamental role of the innate immune response against SARS-CoV-2. Here, we further characterized the host cell antiviral response against SARS-CoV-2 by using primary human airway epithelia and immortalized model cell lines. We mainly focused on the type I and III interferon (IFN) responses, which lead to the establishment of an antiviral state through the expression of IFN-stimulated genes (ISGs). Our results demonstrate that both primary airway epithelial cells and model cell lines elicit a robust immune response characterized by a strong induction of type I and III IFN through the detection of viral pathogen molecular patterns (PAMPs) by melanoma differentiation associated gene (MDA)-5. However, despite the high levels of type I and III IFNs produced in response to SARS-CoV-2 infection, the IFN response was unable to control viral replication, whereas IFN pre-treatment strongly inhibited viral replication and de novo production of infectious virions. Taken together, these results highlight the complex and ambiguous interplay between viral replication and the timing of IFN responses.

16.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.04.19.20071597

ABSTRACT

Epidemiological models are widely used to analyse the spread of diseases such as the global COVID-19 pandemic caused by SARS-CoV-2. However, all models are based on simplifying assumptions and on sparse data. This limits the reliability of parameter estimates and predictions. In this manuscript, we demonstrate the relevance of these limitations by performing a study of the COVID-19 outbreak in Wuhan, China. We perform parameter estimation, uncertainty analysis and model selection for a range of established epidemiological models. Amongst others, we employ Markov chain Monte Carlo sampling, parameter and prediction profile calculation algorithms. Our results show that parameter estimates and predictions obtained for several established models on the basis of reported case numbers can be subject to substantial uncertainty. More importantly, estimates were often unrealistic and the confidence / credibility intervals did not cover plausible values of critical parameters obtained using different approaches. These findings suggest, amongst others, that several models are oversimplistic and that the reported case numbers provide often insufficient information.

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