Cutting-edge molecular tools reveal potential COVID-19 diagnostic and therapeutic targets

Date:
November 11, 2021
Source:
Elsevier
Summary:
Advanced next-generation sequencing of autopsy tissues has
furthered molecular understanding of SARS-CoV-2 infection and
COVID-19 disease mechanisms, researchers report.



FULL STORY ========================================================================== Using some of the most advanced molecular sequencing tools available to evaluate COVID-19 rapid autopsy tissues, researchers have identified four
major regulatory pathways, specific molecular effectors behind COVID-19 symptoms, and differences that drive diverging clinical courses among individual patients.

This research may pave the way for a more personalized and effective
approach to COVID-19 diagnosis and treatment, researchers explain in
a new study published in The American Journal of Pathology, published
by Elsevier.


========================================================================== "From the time that COVID-19 first hit New York City in March 2020,
the Department of Pathology at Mount Sinai made a commitment to uncompromisingly perform as many autopsies as was needed to better
understand what causes this complex and devastating illness," explained
lead investigator Carlos Cordon- Cardo, MD, PhD, Professor and Chairman, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School
of Medicine at Mount Sinai Hospital, New York, NY, USA. "It was clear
to us that beyond the very valuable study of these tissues under the microscope, we would need to dissect the molecular pathways that drive
the disease and underlie the diverse clinical complications seen in our patients." Rapid autopsies were performed on tissues from two decedents
with different symptomology using multi-scale RNA next-generation
sequencing methods to provide unprecedented molecular resolution of COVID-19-induced damage.

Assessing cells individually and integrating histology and molecular information enabled researchers to capture the unique features of each patient's illness.

Patient 1 was a male in his 60s with a complex medical history whose hospitalization lasted for over a month. Patient 2, also a male in his
60s, had diabetes and heart failure who died shortly after admission.

Bulk RNA sequencing evaluation in Patient 1 revealed viral RNA in the nasopharynx and lung, but not in the olfactory bulb, prefrontal cortex, oropharynx, salivary gland, heart, liver, or kidney. Comparison of
the infected and uninfected tissues revealed four major regulatory
pathways. Effectors within these pathways could constitute novel
therapeutic targets, such as the complement receptor C3AR1, which can
be involved in the development of hyperinflammatory and hypercoagulable
states, and decorin, whichplays an important role in the extracellular
matrix and could affect the regulation of signaling, autophagy, and
macrophage activation and fibrosis in response to chronic injury. These
are all critical aspects of severe COVID-19 disease and potentially
long-term COVID as well.

Single-nuclei RNA sequencing of olfactory bulb and prefrontal cortex in
Patient 1 highlighted greater diversity of coronavirus receptors than
is routinely evaluated. Examination of multiple coronavirus-associated receptors revealed only scattered expression of angiotensin converting
enzyme 2 (ACE2) in rare cells and robust expression of basigin (BSG) throughout. Though significant attention has been paid to the role of
ACE2, these results provide evidence of infection potential in the brain
via alternative receptors.

Finally, digital spatial profiling was performed on lung and lymph
node tissues from both patients, comparing patients with different characteristics and disease courses. The results showed distinct molecular phenotypes that may be related to early- versus late-stage COVID-19.

The researchers note that the potential diagnostic and prognostic
markers and therapeutic targets revealed in this study could not have
been uncovered through other methods. Current COVID-19 therapies are
generally focused on either the virus itself, with antiviral medications
and hyperimmune sera, or nonspecific approaches to the inflammatory and coagulopathic challenges, such as steroids and blood thinners.

"In order to develop new classes of therapeutics that can synergize with existing treatments and act on the key effectors driving these symptoms,
it is critical to gain a more detailed, molecular understanding of the pathophysiology of severe COVID-19," concluded lead author Elisabet
Pujadas, MD, PhD, also of the Department of Pathology, Molecular and
Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York,
NY, USA.

The authors have dedicated this work to the memory of co-author
Mary E. Fowkes, MD, PhD, "whose passion and leadership profoundly
shaped our contributions to the understanding and treatment of this
disease." Dr. Fowkes was one of the few pathologists who volunteered
to perform autopsies on COVID-19 victims early in the pandemic. She and
her team discovered the presence of significant blood clots in the brain
and other organs in patients hospitalized with COVID-19.

Their discovery led to increased use of blood thinners as a COVID-19
treatment and improved outcomes for some patients.

========================================================================== Story Source: Materials provided by Elsevier. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Elisabet Pujadas, Michael Beaumont, Hardik Shah, Nadine Schrode,
Nancy
Francoeur, Sanjana Shroff, Clare Bryce, Zachary Grimes, Jill
Gregory, Ryan Donnelly, Mary E. Fowkes, Kristin G. Beaumont,
Robert Sebra, Carlos Cordon-Cardo. Molecular Profiling of
Coronavirus Disease 2019 (COVID-19) Autopsies Uncovers Novel
Disease Mechanisms. The American Journal of Pathology, 2021; DOI:
10.1016/j.ajpath.2021.08.009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211111130314.htm

--- up 2 hours, 54 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)