Understanding lung damage in patients with COVID-19

Date:
August 11, 2021
Source:
Max Delbru"ck Center for Molecular Medicine in the Helmholtz
Association
Summary:
A severe course of COVID-19 disease is not caused by the direct
destruction of the lung due to the multiplication of the virus. New
research shows that inflammatory processes and the endothelium of
the lung are involved.



FULL STORY ==========================================================================
A severe course of COVID-19 disease is not caused by the direct
destruction of the lung due to the multiplication of the virus. As
researchers from Berlin report in the journal Nature Communications, inflammatory processes and the endothelium of the lung are involved.


========================================================================== Researchers from around the globe have spent the past 18 months
trying to understand COVID-19, the disease caused by the SARS-CoV-2 coronavirus. Capable of causing acute lung failure, the disease is
known to wreak havoc on both the lungs and other organs and organ
systems. Unfortunately, drug-based treatment options remain limited. One
of the difficulties has been the fact that COVID-19 is caused by an
errant and sometimes exaggerated immune response. In order to identify therapeutic targets, researchers need to gain a detailed understanding
of the underlying mechanisms, both in terms of how they work and where
in the body they occur. Patient-centered approaches are rather limited
in their scope.

This particularly applies to the study of disease mechanisms during the
early phase of infection. Biomaterials, which are needed for this type
of research, can usually be harvested only after a patient has been
admitted to hospital.

Furthermore, it is virtually impossible to obtain lung tissue samples from patients with mild or moderate disease and pneumonia, as the harvesting procedure would place these patients at too great a risk. What is left,
then, is the analysis of tissues harvested from COVID-19 patients after
their death.

Under the leadership of Prof. Dr. Martin Witzenrath, Deputy Head of
Charite''s Department of Infectious Diseases and Respiratory Medicine, the researchers used available patient samples to obtain valuable information
on both disease mechanisms and disease progression. The researchers
searched for a suitable model which might enable them to also study compartments of the lungs not easily accessible in patients but necessary
in order to study the early phase of the disease. Hamster models have
proven extremely useful, both as part of international research efforts
into COVID-19 and research pertaining to SARS- CoV-1. "We wanted to know whether we could use these models to develop new treatment options and
tried to replicate findings from patient samples. We were remarkably
successful in this regard," says Prof. Witzenrath, the study's co- last
author. "We were primarily interested in the lung's endothelial cells,
which line the pulmonary blood vessels and form a barrier there. In severe COVID-19 cases, this barrier becomes dysfunctional, a development which eventually results in lung failure." Syrian hamster is most important
animal model for COVID Working alongside researchers from the MDC's Berlin Institute for Medical Systems Biology (BIMSB), virologists and veterinary surgeons from Freie Universita"t Berlin, as well as data experts from the Berlin Institute of Health (BIH), the researchers were able to describe
the detailed characteristics of SARS-CoV-2 infection in an animal
model. They subsequently corroborated their findings using data sets
pertaining to patient samples. The purpose of this analysis is to make
what is currently the most important, non- transgenic animal model for
the study of COVID-19 available for research aimed at developing future treatments. Hamsters contract the same virus variants as humans. They also develop similar disease symptoms, and severe disease will result in damage
to the lungs. Symptoms and progression of COVID-19, however, vary between different species of hamster. While symptoms usually remain moderate in
Syrian hamsters, Roborovski hamsters will develop severe disease.

The reasons for this and the processes which take place in the cells
of the lungs were demonstrated as part of experiments conducted at the
BIMSB. These included single-cell analyses during which individual cells obtained from a particular sample were loaded onto a chip, where they
were first barcoded and then encapsulated into minute droplets of aqueous fluid. Once prepared, single cells can undergo RNA sequencing, a process
used to establish the sequence of genetic building blocks which a cell
has just read. Thanks to barcoding, this RNA was later identifiable
as originating from a particular cell, enabling the researchers to
determine cellular function at the single-cell level with a high degree
of accuracy. "We were able to observe how certain cells involved in lung immunity -- namely monocytes and monocyte-derived macrophages -- ingest
the virus and subsequently show a very pronounced response. They send
out biological messengers which then elicit a very strong inflammatory response. In our model, this is quickly brought under control by T cells, another type of immune cell which is dispatched for this very purpose. In severe COVID-19, however, this does not happen," explains the study's
co-first author Dr.

Geraldine Nouailles, a researcher at Charite''s Department of Infectious Diseases and Respiratory Medicine. She adds: "A fast and efficient
T cell response is crucial to successful recovery from COVID-19."
While COVID-19 prompts the immune system to go into overdrive, SARS-CoV- 2 initially displays a low rate of replication in the lungs and respiratory tract. "The destruction of lung tissue seen in severe COVID-19 is not
a direct result of viral propagation inside cells, but of the strong inflammatory response," explains fellow co-first author Dr. Emanuel
Wyler, a researcher at the MDC. He adds: "This also appears to apply
to the cells of the vasculature, in particular the lung's endothelial
cells. They show a very strong response to the virus but are neither
infected by it nor destroyed in the process." If the disease is severe,
blood vessels can become obstructed and vessel walls unstable, resulting
in acute lung failure. It does not appear likely, however, that this blood vessel damage also plays a part in moderate COVID-19. "That COVID-19
activates the endothelium -- a type of protective barrier lining blood
vessels which, amongst other things, also controls a range of processes
in the lung's micro blood vessels -- did not come as a surprise. What did
come as a surprise, however, was that these cells are also the active
driver of inflammation," says Prof. Witzenrath. "Given their key role
in disease progression, these cells could be targeted using one of two therapeutic strategies. One is to use substances which are capable of
sealing the endothelial barrier. The other is to use substances which
calm the endothelium.

One of these is already the target of research conducted in our
Collaborative Research Center SFB-TR84, where we were able to show
that it is effective in pneumonia and ventilated patients." Other anti-inflammatory drugs currently being tested as treatments for
COVID-19 target the immune response itself. They are also effective
against monocytes and macrophages and temper their activity.

Now that their model has been validated, the researchers hope to use
it to help develop safe and effective treatments for patients with
COVID-19. The aim is to reduce the number of patients who develop
severe lung injury. The multidisciplinary team of researchers are
currently analyzing the responses of different cell types observed in Roborovski dwarf hamsters. The researchers want to establish why the
infection produces severe disease in these animals, and why it is not self-limiting as is the case in Syrian hamsters. "We hope this will guide
us to a possible explanation for why some people develop severe COVID-19
but others do not," says Dr. Nouailles. As a first step, the researchers
will need to decipher the dwarf hamster's genome. The fact that hamsters
have traditionally been regarded as somewhat exotic by the animal research community explains the existence of numerous knowledge gaps.

"Information from our current study has enabled us to close some of
these gaps.

This represents major progress, including in terms of a more conscious and targeted approach to the use of animals in medical research," explains
co-last author Dr. Jakob Trimpert, a virologist and veterinary surgeon
from Freie Universita"t Berlin. In addition to developing the COVID-19
hamster models, Dr.

Trimpert and his team also worked with Freie Universita"t Berlin's
Department of Veterinary Pathology. Performing the necessary
histopathological analyses (microscopic examination of infected lung
tissue) under the leadership of Prof.

Dr. Achim Gruber, the team's work represents a crucial contribution to
the study's published findings.

About this study Funding for this study was provided by: the German
Research Foundation (DFG) - - via the SFB-TR84 Collaborative Research
Center; the Federal Ministry of Education and Research (BMBF) -- via
the CAPSyS-COVID, PROVID, and NAPKON (National Pandemic Cohort Network
of the Network University Medicine/ Nationales Forschungsnetzwerk der Universita"tsmedizin zu Covid-19, NUM) projects; and the Berlin Institute
of Health (BIH) at Charite' -- via the CM- COVID project.

========================================================================== Story Source: Materials provided by Max_Delbru"ck_Center_for_Molecular_Medicine_in_the
Helmholtz_Association. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Geraldine Nouailles, Emanuel Wyler, Peter Pennitz, Dylan Postmus,
Daria
Vladimirova, Julia Kazmierski, Fabian Pott, Kristina Dietert,
Michael Muelleder, Vadim Farztdinov, Benedikt Obermayer,
Sandra-Maria Wienhold, Sandro Andreotti, Thomas Hoefler, Birgit
Sawitzki, Christian Drosten, Leif E. Sander, Norbert Suttorp,
Markus Ralser, Dieter Beule, Achim D.

Gruber, Christine Goffinet, Markus Landthaler, Jakob Trimpert,
Martin Witzenrath. Temporal omics analysis in Syrian hamsters
unravel cellular effector responses to moderate COVID-19. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-25030-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210811162842.htm

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