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The disease progression in severe COVID-19 is characterized by an initial phase of increased viraemia followed by a second phase of increased systemic inflammation where high levels of inflammatory molecules correlate with the risk of death due to infection. Infection with SARS-CoV-2 triggers overactivation of pro-inflammatory cytokines such as interleukin 6, interleukin 1 beta, and tumor necrosis factor alpha, as well as chemokines such as patterned chemokine ligand CXC (CXCL) 8, 9 and 10 and CC motif chemokine ligand 2.
“So far, in preclinical models of SARS-CoV-2, there are no therapies – antiviral, antibody or plasma – that reduce the burden of SARS-CoV-2 disease when they are given more than a day after infection. Senior author Ivan Marazzi, PhD, associate professor of microbiology at Icahn School of Medicine at Mount Sinai, said in a statement. “It’s a huge problem because people with severe COVID-19 and hospitalized often don’t show symptoms until several days after infection.
Although the pathophysiology of SARS-CoV-2 infection is not fully understood, exaggerated immune system responses associated with increased expression of pro-inflammatory molecules can lead to inflammation, possible tissue damage, tissue failure. organs and death in COVID-19 patients. Therefore, reducing the extent of induction of gene expression during infection may be the key to therapy to treat infections that cause hyperinflammation.
A global group of researchers led by a team from Mount Sinai suspected that host-directed epigenetic therapies that address chemical changes that influence gene expression could be used to treat COVID-19.
Although little is known about how epigenetic changes and genome structure are affected by infection, the authors have previously shown that chromatin factors play a key role in controlling the induction of inflammatory gene expression programs. Thus, targeting the activities of these proteins could lead to the deletion of several genes during infection.
The researchers first sought to define the effect of viral infection on altering host chromatin and how these affect gene expression. To do this, they performed Hi-C analysis, a chromosome conformation capture technique, to characterize the structural changes in chromatin during SARS-CoV-2 infection.
The team’s data suggests that infection with SARS-CoV-2 causes global and local changes in chromatin, leading to specific gene expression programs in infected cells. Specifically, chromatin immunoprecipitation (ChIP) sequencing showed that the acetylation of histone 3 lysine 27 (K27ac), an epigenetic mark found in active regulatory regions (promoters and enhancers) undergoes significant changes (acquired and lost) during infection.
The researchers suggested that this dynamic restructuring of the genome’s compartmentalization of regulatory regions controls inflammatory responses via gene transcription.
“We found that the infection causes significant changes in the 3D connections between inflammatory genes and the ‘molecular switching’ regions that control their expression,” noted co-author Mikhail Spivakov, PhD, head of the Functional group. Gene Control at the Medical Research Council. (MRC) London Institute of Medical Sciences. “This may partly explain why inhibition of topoisomerase, a protein that helps to remodel DNA, helps dampen the hyper-inflammatory response of cells.”
“The point is that a multitude of inflammatory genes and signaling pathways are deregulated during a SARS-CoV-2 infection,” explained lead author Jessica Sook Yuin Ho, PhD, postdoctoral researcher at Icahn Mount Sinai.
Next, to test whether chromatin factors can thwart SARS-CoV-2 infection, the team focused on the host enzyme topoisomerase 1 (TOP1), which is required to fully transactivate genes induced by infection and controls the development of inflammatory gene programs in many viruses and bacterial infections.
In animal studies, topotecan (TPT), a TOP1 inhibitor approved by the United States Food and Drug Administration, was able to reduce the expression of inflammatory genes in cells infected with the SARS-CoV-2 virus. In hamster models, TPT suppressed the expression of inflammatory genes in the lungs.
“We have demonstrated that TOP1 inhibitors are able to broadly or systemically suppress inflammatory gene expression in animal models, regardless of gene or pathway of activation,” Ho explained.
When TPT was administered to mice four to five days after infection, treatment significantly improved morbidity and mortality outcomes compared to the control.
“We have found that TOP1 inhibitors given a few days after infection can further limit the expression of hyper-inflammatory genes in the lungs of infected animals and improve the outcome of infection,” said Marazzi.
The safety and efficacy of this TOP1 inhibitor treatment strategy in humans will soon be evaluated in global clinical studies.
“The results of our work suggest that the reuse of the TOP1 inhibitor could be a valuable overall strategy to treat severe cases of COVID-19,” Marazzi said. “The fact that TPT is already approved by the FDA and its derivatives are inexpensive, with generic formulations existing around the world is particularly appealing. This makes these drugs easily accessible and available for immediate use in developing countries. and developed around the world. “
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