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Iron transport protein is upregulated in SARS-CoV-2 infected cells
Transferrin identified as potential contributor to COVID-19 severity
FRANKFURT. The Institute of Medical Virology at Goethe-University, Frankfurt am Main, Germany, and the University of Kent’s School of Biosciences (UK) have identified that a glycoprotein known as transferrin may critically contribute to severe forms of COVID-19.
SARS-CoV-2 is the coronavirus that causes COVID-19. It is
currently not known why some individuals develop only mild or no symptoms when
infected, whilst others experience severe, life-threatening forms of the
disease. However, it is known that the risk of COVID-19 becoming severe
increases with age and is higher in males than in females. Many severe COVID-19
cases are characterised by increased blood clotting and thrombosis formation.
The team combined existing data on gene expression in humans with
cell culture research of SARS-CoV-2-infected cells to search for molecules
involved in blood coagulation that differ between females and males, change
with age, and are regulated in response to SARS-CoV-2 infection.
Out of more than 200 candidate factors, researchers identified a
glycoprotein called transferrin to be a procoagulant (a cause of blood
clotting) that increases with age, is higher in males than in females, and is
higher in SARS-CoV-2-infected cells. Hence, transferrin may have potential as a
biomarker for the early identification of COVID-19 patients at high risk of
severe disease.
Publication: Katie-May McLaughlin,
Marco Bechtel, Denisa Bojkova, Christian Münch, Sandra Ciesek, Mark N. Wass,
Martin Michaelis, Jindrich Cinatl, Jr.: COVID-19-Related
Coagulopathy - Is Transferrin a Missing Link? Diagnostics 2020, 10(8), 539;
https://doi.org/10.3390/diagnostics10080539
Further
information:
Prof. Dr. rer. nat. Jindrich Cinatl
Institute for Medical Virology
University Hospital Frankfurt
Tel.:
+49 69 6301-6409
E-mail:
cinatl@em.uni-frankfurt.de
Frankfurt scientists identify possible Achilles’ heel of SARS-CoV-2 virus
COVID-19 research: Anti-viral strategy with double effect
In the case of an infection, the SARS-CoV-2 virus must overcome various defense mechanisms of the human body, including its non-specific or innate immune defense. During this process, infected body cells release messenger substances known as type 1 interferons. These attract natural killer cells, which kill the infected cells.
One of the reasons the SARS-CoV-2 virus is so successful – and thus dangerous – is that it can suppress the non-specific immune response. In addition, it lets the human cell produce the viral protein PLpro (papain-like protease). PLpro has two functions: It plays a role in the maturation and release of new viral particles, and it suppresses the development of type 1 interferons. The German and Dutch researchers have now been able to monitor these processes in cell culture experiments. Moreover, if they blocked PLpro, virus production was inhibited and the innate immune response of the human cells was strengthened at the same time.
Professor Ivan Đikić, Director of the Institute of Biochemistry II at University Hospital Frankfurt and last author of the paper, explains: “We used the compound GRL-0617, a non-covalent inhibitor of PLpro, and examined its mode of action very closely in terms of biochemistry, structure and function. We concluded that inhibiting PLpro is a very promising double-hit therapeutic strategy against COVID-19. The further development of PLpro-inhibiting substance classes for use in clinical trials is now a key challenge for this therapeutic approach."
Another important finding from this work is that the viral protein PLpro of SARS-CoV-2 cleaves off ISG-15 (interferon-stimulated gene 15) from cellular proteins with a higher level of activity than the SARS equivalent, which leads to greater inhibition of type I interferon production. This is concordant with recent clinical observations which show that COVID-19 exhibits a reduced interferon response in comparison to other respiratory viruses such as influenza and SARS.
To understand in detail how inhibiting PLpro stops the virus, researchers in Frankfurt, Munich, Mainz, Freiburg and Leiden have worked closely together and pooled their biochemical, structural, IT and virological expertise.
Donghyuk Shin, postdoctoral researcher and first author of the paper, says: “Personally, I would like to underline the significance of science and research and in particular emphasize the potential generated by a culture of collaboration. When I saw our joint results, I was immensely grateful for being a researcher."
Professor Sandra Ciesek, Director of the Institute of Medical Virology at University Hospital Frankfurt, explains that the papain-like protease is an extremely attractive anti-viral goal for her as a physician because its inhibition would be a “double strike" against SARS-CoV-2. She highlights the excellent collaboration between the two institutes: “Especially when investigating a new clinical picture, everyone profits from interdisciplinary collaboration as well as different experiences and viewpoints."
Publication: Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Klaus-Peter Knobeloch, Krishnaraj Rajalingam, Huib Ovaa, Brenda Schulman, Jindrich Cinatl, Gerhard Hummer, Sandra Ciesek, Ivan Dikic. Inhibition of papain-like protease PLpro blocks 1 SARS-CoV-2 spread and 2 promotes anti-viral immunity. Nature, DOI 10.1038/s41586-020-2601-5, https://www.nature.com/articles/s41586-020-2601-5
Further information:
Professor Ivan Đikić
Director of the Institute of Biochemistry II of University Hospital Frankfurt
Group Leader at the Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt
Max Planck Fellow at Max Planck Institute of Biophysics, Frankfurt
Tel.: +49 (0)69 6301-5964, email: dikic@biochem2.uni-frankfurt.de, Twitter: @iDikic2
Goethe University physicists develop free covid-19 analysis website to compare the number of cases and deaths by country
Comparing covid-19 data worldwide with a click of the mouse
FRANKFURT. There is no lack of data on
global corona developments. But if you want to actively compare countries
yourself and relate case and death figures across countries, you can now get a
quick overview with just a few clicks – and gain surprising insights in the
process.
The new web service “Goethe Interactive
Covid-19 Analyzer“ which Fabian Schubert in the working group for the theory of
complex systems at the Institute for Theoretical Physics developed alongside
his dissertation is simple to use: go to the “Goethe Interactive Covid-19
Analyzer” website, click on the countries and number of cases in questions, and
drag the curves over each other. Congruent? The answer is immediately visible.
In the same way – depending on the individual question - the daily number of
cases or deaths, or the total number of infected or deceased individuals can be
compared. The underlying data for countries from “A” as in Afghanistan through
“Z” as in Zimbabwe is provided by the known covid-19 databases of the European Centre
for Disease Control” and the “Johns HopkinsCenter For Systems Science and Engineering.”
“Our interactive tool allows researchers,
journalists and other interested parties to quickly gain an overview of
outbreak developments,” explains Professor Claudius Gros, who studies the modelling
of covid-19 outbreaks himself at the Institute for Theoretical Physics, and who
as Schubert’s doctoral advisor encouraged him to develop the service tool.
Those who use the tool may also discover relationships that provide inspiration
for additional research on epidemic processes.
Gros, for example, was surprised that the
scaled trajectory curves of the case numbers from Germany and Spain “are almost
identical, although the two countries pursued significantly different lockdown
measures.” There are also interesting clues regarding the unexplained issue of
the number of unrecorded cases of corona infections. For Italy, the scaled
curve of covid-19 infections corresponds to the curve of corona deaths if the
daily case numbers are applied to the total numbers of the sick or the
deceased. “This indicates that the unrecorded case numbers may not have changed
significantly over the course of the outbreak – even though testing increased.”
The “Goethe Interactive Covid-19 Analyzer”
from the Institute for Theoretical Physics offers numerous options for combining
data per mouse click. “The page has only been live for a couple of days,” says Gros. It therefore remains to be seen
how many researchers and other interested parties will use the new analytical
tool. The first scientists have already indicated interest, however. And the theoretical
physicist is certain: “The website is certainly useful for the final papers and
doctoral dissertations on covid-19 that will soon be written. And also for
secondary school students who want to present a paper on corona.”
The new analytic tool is hosted on the
webserver of the Institute for
Theoretical Physics, which is also providing the necessary technical support.
Website: Goethe Interactive Covid-19 Analyzer: https://itp.uni-frankfurt.de/covid-19
Publication: Claudius Gros, Roser Valenti, Kilian Valenti, Daniel Gros, Strategies
for controlling the medical and socio-economic costs of the Corona pandemic (2020);
https://arxiv.org/abs/2004.00493
Further information: Prof. Dr. Claudius Gros, Institut für Theoretische Physik, Campus Riedberg, E-Mail gros07@itp.uni-frankfurt.de
Two research aircraft investigate reduced concentrations of pollutants in the air
BLUESKY scrutinizes the lockdown-altered atmosphere
FRANKFURT. The COVID-19 pandemic is not only
affecting almost every aspect of our daily lives, but also the environment. A
German team including atmosphere researchers around Prof. Joachim Curtius
(Goethe University Frankfurt) now wants to find out how strong these effects
are on the atmosphere. Over the next two weeks, as part of the BLUESKY research
programme, the scientists led by the Max Planck Institute for Chemistry and the
German Aerospace Center (Deutsches Zentrum für Luft- und Raumfahrt; DLR) will measure
concentrations of trace gases and pollutants in the air over European urban
areas and in the flight corridor to North America. The aim of these research
missions is to investigate how reduced emissions from industry and transport
are changing atmospheric chemistry and physics.
A German research team now wants to make
rapid use of this unusual situation for the BLUESKY project. Scientists from
DLR, the Max Planck Institute for Chemistry, Goethe University Frankfurt, and
the research centres at Jülich and Karlsruhe intend to use two DLR research
aircraft to conduct a globally unique investigation into the resulting changes
in Earth's atmosphere for the first time. DLR’s HALO and Falcon research
aircraft have been equipped with highly specialised instrumentation and will
fly over Germany, Italy, France, Great Britain and Ireland in the course of the
next two weeks. They will also fly over the North Atlantic, along the flight
corridor to North America.
“DLR is deploying part of its unique
research aircraft fleet to exploit an almost unique opportunity. During these
missions, the atmosphere will be analysed in a state that could be achieved in
the future with sustainable management of human activities. We will observe how
the environment changes with the ramp-up of industrial activities. This will
give us an entirely new perspective on the anthropogenic influence on Earth’s
atmosphere,” explains Rolf Henke, DLR Executive Board Member responsible for
aeronautics research. “Together with our partners, we are making a significant
contribution to redefining humankind’s activities once the pandemic is under
control.”
Coordinated research flights with two measurement
aircraft
Jos Lelieveld, Director of the Max Planck Institute
for Chemistry, wants to use the BLUESKY missions to clarify whether there is a
correlation between the clear blue sky during the lockdown and the prevalence
of aerosol particles in the atmosphere. “The unique blue sky of recent weeks
cannot be explained by meteorological conditions and the decrease in emissions
near the ground. Aircraft may have a greater impact on the formation of aerosol
particles than previously thought,” says the atmospheric researcher, who is the
Scientific Director of the HALO flights. Aerosols, microscopic particles in the
air that also influence cloud formation, are finely distributed. They scatter
and absorb solar radiation and thus also have an impact on the climate, because
they influence the radiation balance of the atmosphere. Aerosols are created,
amongst other ways, during the combustion of fossil fuels.
Christiane Voigt, Head of the Cloud
Physics Department at the DLR Institute of Atmospheric Physics and Scientific
Director of the Falcon flights, also sees a unique opportunity with BLUESKY.
“The current state of the atmosphere represents a kind of ‘zero point’ for
science. We will be able to measure a reference atmosphere that is only
slightly polluted with emissions from industry and transport, including
aviation. This gives us a unique opportunity to better understand the effects
of the anthropogenic emissions prior to the shutdown.” The atmospheric
physicist emphasises that, only through the cooperation of all the partners,
was it possible to plan and implement the scientifically and logistically
highly complex missions at very short notice.
Emissions from air transport, industry and road
traffic in urban areas
Voigt and her colleagues believe that the
BLUESKY data will provide a clearer picture of anthropogenic influences on the
composition of Earth’s atmosphere. With the equipment on board both research
aircraft, the BLUESKY scientists are investigating aircraft emissions such as
nitrogen oxides, sulphur dioxide and aerosols at cruising altitude, in addition
to the few remaining contrails. Among other things, they want to find out how
much these emissions have decreased over Europe and the North Atlantic flight
corridor. Approximately 30,000 aircraft fly over Europe every day, with
correspondingly significant emissions. The reduced air traffic will allow more
flexible flight routes for the measurements.
In addition, the researchers want to
investigate the reduced emission plumes from urban areas and clarify how
emissions are distributed at the atmospheric boundary layer. For example, the
BLUESKY scientists plan to fly over the Ruhr area and the regions around
Frankfurt am Main, Berlin and Munich. Flights over the Po Valley in Italy and
around Paris and London are also planned. “Close to cities and conurbations, we
will approach the atmospheric boundary layer at an altitude of one to two
kilometres, since emissions from road traffic and industry are concentrated
there,” explains Jos Lelieveld. “We are interested in how much the
concentrations of sulphur dioxide, nitrogen oxides, hydrocarbons and their
chemical reaction products, as well as ozone and aerosols, have changed.” He is
also very proud that the team is the first in the world to implement a
measurement campaign of this type.
Rapid preparations for flights – with special
infection control rules
In recent weeks, two DLR research aircraft
–measuring the Falcon 20E and the Gulfstream G550 HALO – have been successfully
converted at short notice for the BLUESKY missions. The conversions were
carried out at the DLR Flight Operations Facility in Oberpfaffenhofen.
“Numerous instruments have had to be installed and adapted, and the aircraft
modified for the upcoming missions,” says Burkard Wigger, Head of DLR Flight
Experiments. “Close cooperation between the various scientific organisations
has made it possible for these two research aircraft to operate simultaneously
under the challenging conditions resulting from the Coronavirus pandemic.”
The preparation, execution and follow-up
of the flights is being carried out in accordance with the current rules
regarding personal interactions and infection control. Joint flights by Falcon
and HALO are planned until the first half of June. The evaluation of the data
and the analysis of the results will then take several months. The analysis
will include comparative data from previous HALO research flight campaigns on
air traffic emissions and emissions from major cities and conurbations.
About HALO: The High Altitude and Long Range (HALO) research aircraft is a joint initiative of German environmental and climate research institutions. HALO is supported by grants from the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), the Helmholtz Association of German Research Centres, the Max Planck Society (MPG), the Leibniz Association, the Free State of Bavaria, the Karlsruhe Institute of Technology (KIT), the Forschungszentrum Jülich and the German Aerospace Center (DLR).
More information: Prof. Joachim Curtius, Institute for Atmospheric and Environmental Sciences, Goethe University Frankfurt, Phone: +49 (0)69 798-40258, curtius@iau.uni-frankfurt.de
Cell culture model: several compounds stop SARS-CoV-2 virus
Frankfurt researchers discover potential targets for COVID-19 therapy
FRANKFURT. A team of biochemists and virologists at
Goethe University and the Frankfurt University Hospital were able to observe how
human cells change upon infection with SARS-CoV-2, the virus causing COVID-19
in people. The scientists tested a series of compounds in laboratory models and
found some which slowed down or stopped virus reproduction. These results now
enable the search for an active substance to be narrowed down to a small number
of already approved drugs. (Nature DOI: 10.1038/s41586-020-2332-7).
Based on these findings, a US company reports that it is preparing clinical
trials. A Canadian company is also starting a clinical study
with a different substance.
Since the start of February, the Medical Virology of the Frankfurt University Hospital has been in possession of a SARS-CoV-2 infection cell culture system. The Frankfurt scientists in Professor Sandra Ciesek's team succeeded in cultivating the virus in colon cells from swabs taken from two infected individuals returning from Wuhan (Hoehl et al. NEJM 2020).
Using a technique developed at the
Institute for Biochemistry II at Goethe University Frankfurt, researchers from
both institutions were together able to show how a SARS-CoV-2 infection changes
the human host cells. The scientists used a particular form of mass
spectrometry called the mePROD method, which they had developed only a few
months previously. This method makes it possible to determine the amount and
synthesis rate of thousands of proteins within a cell.
The findings paint a picture of the
progression of a SARS-CoV-2 infection: whilst many viruses shut down the host's
protein production to the benefit of viral proteins, SARS-CoV-2 only slightly
influences the protein production of the host cell, with the viral proteins
appearing to be produced in competition to host cell proteins. Instead, a SARS-CoV-2
infection leads to an increased protein synthesis machinery in the cell. The researchers
suspected this was a weak spot of the virus and were indeed able to
significantly reduce virus reproduction using something known as translation
inhibitors, which shut down protein production.
Twenty-four hours after infection, the
virus causes distinct changes to the composition of the host proteome: while
cholesterol metabolism is reduced, activities in carbohydrate metabolism and in
modification of RNA as protein precursors increase. In line with this, the
scientists were successful in stopping virus reproduction in cultivated cells by
applying inhibitors of these processes. Similar success was achieved by using a
substance that inhibits the production of building blocks for the viral genome.
The findings have already created a stir on
the other side of the Atlantic: in keeping with common practise since the
beginning of the corona crisis, the Frankfurt researchers made these findings
immediately available on a preprint server and on the website of the Institute
for Biochemistry II (http://pqc.biochem2.de#coronavirus). Professor Ivan Dikic, Director of the
Institute, comments: “Both the culture of 'open science', in which we share our
scientific findings as quickly as possible, and the interdisciplinary collaboration
between biochemists and virologists contributed to this success. This project started
not even three months ago, and has already revealed new therapeutic approaches
to COVID-19."
Professor Sandra Ciesek, Director of the
Institute for Medical Virology at the University Hospital Frankfurt, explains:
“In a unique situation like this we also have to take new paths in research. An
already existing cooperation between the Cinatl and Münch laboratories made it
possible to quickly focus the research on SARS-CoV-2. The findings so far are a
wonderful affirmation of this approach of cross-disciplinary collaborations."
Among the substances that stopped viral
reproduction in the cell culture system was 2-Deoxy-D-Glucose (2-DG), which interferes
directly with the carbohydrate metabolism necessary for viral reproduction. The
US company Moleculin Biotech possesses a substance called WP1122, a prodrug
similar to 2-DG. Recently, Moleculin Biotech announced that they are preparing
a clinical trial with this substance based on the results from Frankfurt. https://www.moleculin.com/covid-19/.
Based on another one of the substances
tested in Frankfurt, Ribavirin, the Canadian company Bausch Health Americas is
starting a clinical study with 50 participants: https://clinicaltrials.gov/ct2/show/NCT04356677?term=04356677&draw=2&rank=1
Dr Christian Münch, Head of the Protein
Quality Control Group at the Institute for Biochemistry II and lead author, comments:
“Thanks to the mePROD-technology we developed, we were for the first time able
to trace the cellular changes upon infection over time and with high detail in
our laboratory. We were obviously aware of the potential scope of our findings.
However, they are based on a cell culture system and require further testing. The
fact that our findings may now immediately trigger further in vivo
studies with the purpose of drug development is definitely a great stroke of
luck." Beyond this, there are also other potentially interesting candidates
among the inhibitors tested, says Münch, some of which have already been
approved for other indications.
Professor Jindrich Cinatl from the
Institute of Medical Virology and lead author explains: “The successful use of
substances that are components of already approved drugs to combat SARS-CoV-2 is
a great opportunity in the fight against the virus. These substances are
already well characterised, and we know how they are tolerated by patients.
This is why there is currently a global search for these types of substances.
In the race against time, our work can now make an important contribution as to
which directions promise the fastest success."
Publication:
SARS-CoV-2 infected host cell proteomics
reveal potential therapy targets. Denisa Bojkova, Kevin Klann, Benjamin Koch,
Marek Widera, David Krause, Sandra Ciesek, Jindrich Cinatl, Christian Münch. Nature DOI: 10.1038/s41586-020-2332-7,
https://www.nature.com/articles/s41586-020-2332-7 (active starting 10am London time (BST), 5am US Eastern Time)
Images
may be
downloaded here: http://www.uni-frankfurt.de/88340061
Captions:
Dr. Christian Münch (Credit: Uwe Dettmar
for Goethe University Frankfurt)
Prof. Dr. rer. nat. Jindrich Cinatl (Credit:
University Hospital Frankfurt)
More
about the mePROD method: Biochemistry researchers at Goethe
University develop a new proteomics procedure https://aktuelles.uni-frankfurt.de/englisch/biochemistry-researchers-at-goethe-university-develop-new-protoeomics-procedure/
Further information:
Professor Dr. rer. nat. Jindrich Cinatl, Head of the Research Group Cinatl, Institute for Medical Virology, University Hospital Frankfurt am Main, Tel.
+49 69 6301-6409, E-mail: cinatl@em.uni-frankfurt.de,
Homepage: https://www.kgu.de/einrichtungen/institute/zentrum-der-hygiene/medizinische-virologie/forschung/research-group-cinatl/
Dr.
Christian Münch, Head of the Group Protein Quality Control, Institute for Biochemistry II, Goethe University Frankfurt am Main Tel: +49 69 6301 6599, E-Mail: ch.muench@em.uni-frankfurt.de,
Homepage:
https://www.biochem2.com/index.php/22-ibcii/pqc/130-frontpage-pqc
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