What this study adds
- This study presents insights into the possible mechanisms by which
thalidomide and lenalidomide would suppress the cytokine storm and
immune response
- Thalidomide and its derivative lenalidomide modulate expression of
several genes and key pathways aberrantly regulated in SARS-coV-2
infected tissues.
- There is a similarity in gene expression profiles of SARS-coV2
infected tissues with systemic lupus erythematosus
Abstract
Background and Purpose : SARS-coV-2 pandemic continues to cause
an unprecedented global destabilization. There is an urgent need to
develop vaccines or identify molecules to treat severe cases and
repurposing of drugs is the best approach at this hour. Thalidomide,
despite having an infamous history has been successfully repurposed and
tested for various disease conditions including inflammatory diseases
and tumor. Few reports emphasize the use of thalidomide with a
SARS-coV-2 pneumonia patient being successfully treated with
thalidomide.
Experimental Approach: A meta-analysis comparing the
transcriptomes of SARS-coV-2 infected tissues with thalidomide and
lenalidomide-induced transcriptomic changes in transformed lung,
endothelial and hematopoietic models was performed.
Key Results: Thalidomide and lenalidomide exhibited pleiotropic
effects affecting a range of biological processes including
inflammation, immune response, angiogenesis, MAPK signaling, NOD-like
receptor signaling, TLR signaling, leukocyte differentiation and innate
immunity, the processes which are aberrantly regulated in severe
COVID-19 patients. In addition, we show the similarities between the
expression profiles of SARS-coV-2 infected lung and systemic lupus
erythematous.
Conclusion and Implications: The present study recommends
thalidomide analogs as a “better fit” to treat severe cases of novel
viral infections, healing the damaged network by compensating the
impairment caused by the Coronavirus disease-2019 (COVID-19).
Abbreviations : COVID-19 - Coronavirus Disease -19; BALF –
Broncho-alveolar lavage fluid; PBMC – Peripheral Blood Mononuclear
Cell; DEG- Differentially Expressed Genes; GSEA – Gene Set Enrichment
Analysis; SLE – Systemic Lupus Erythematosus; TLR – Toll-like
Receptor; HUVEC – Human Umbilical Vein Endothelial Cell
Introduction
Novel coronavirus, SARS-coV-2 has been posing devastating effects on a
global scale with a soaring number of infections and an alarming rate of
mortality. Despite tremendous efforts, development of effective vaccines
or anti-viral medications is months away leaving repurposing of drugs
with known safety and efficacy profiles as the only viable choice.
COVID-19 is clinically very challenging since the novel coronavirus
triggers multi-organ turbulence devastating the homeostasis of the human
system. Once the SARS-CoV-2 virus enters the respiratory tract, there
are four different stages of the infection from symptoms to multi-organ
failures. Phase I starts with
the
ACE2 receptor-mediated viral entry through nasal and oral routes
followed by
host
immune system alert simultaneously with active viral replication in the
upper respiratory tract (Phase II). Next, Phase III coincides with minor
cytokine storm in the alveoli releasing the inflammatory cytokines
making the blood vessels leaky around the air sac, and ultimately the
second cytokine storm arrives with uncontrolled inflammatory and
life-threatening symptoms, acute respiratory distress syndrome (ARDS),
seizure, severe hypoxia and severed organ toxicity (Phase IV)1,2. Manifestation of the bi-phasic cytokine storm
occurs through the activation of a series of cytokines including
granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced
protein 10 (CXCL10), monocyte chemoattractant protein 1 (MCP1),
macrophage inflammatory protein 1α (MIP-1α), tumour necrosis factor α
(TNF-α), interleukin (IL)-2R and IL-6 overwhelming the system leading to
indiscriminate damages in multiple organs 3–5. There
is an increased amount of blood vessel growth in the lungs of COVID-19
patients compared to severe influenza 6. Due to such
multi-layers of problems associated with the COVID-19 infections,
researchers around the world are desperately in search for a drug, which
would able to tackle all or few of these COVID-19 hallmarks.
Thalidomide, a small molecule drug, was marketed with an intent to
relieve morning sickness in pregnant women. However, this resulted in an
unexpected misfortune that resulted in the birth of several children
with defects due to in-utero exposure 7. Later,
thalidomide became a game changer for its the multi-faced
pharmacological effects such as immunomodulation, anti-inflammation,
anti-angiogenesis, and anti-viral effects 8. At this
point of time, the world needs a “smart” solution. Thalidomide
increases the hope for treating COVID-19 patients 9.
Chen et al reports successful treatment of SARS-coV-2 associated
pneumonia with combinatory treatment of thalidomide and a low-dose
glucocorticoid 10 Two clinical trials, NCT04273581 and
NCT04273529 have been registered to check the efficacy of thalidomide in
treating COVID-19 patients. The adverse effects of thalidomide and its
analogs are well documented. Various genes aberrantly expressed in
SARS-coV-2 affected lungs are known targets of thalidomide (Table S1).
Extensive information available on thalidomide’s mechanisms, their
efficacy and safety in hemophagocytic syndrome-induced cytokine storm11 and idiopathic pulmonary fibrosis12, severe H1N1 and paraquat poisoning lung injury13,14 argue for the possible action of thalidomide on
COVID-19 induced lung effects and cytokine storm.
Transcriptome-based approach to connect diseases with drug responses is
a recognized strategy in drug repurposing 15. With the
fast-growing literature on SARS-coV-2 infections, we performed
meta-analysis of whole transcriptome signatures of lungs, PBMC, BALF
from SARS-coV-2 affected patients and A549 cells and compared with the
gene expression signatures of thalidomide or lenalidomide-treated A549
(transformed adenocarcinoma cells), hematopoietic and endothelial cells.
We hereby provide possible mechanistic actions of thalidomide in
treating the SARS-coV-2 pathology. In addition, we suggest that the
derivatives of thalidomide, lenalidomide and CC-220 might also be
effective in the treatment of SARS-coV-2.
Methods