A systems biology approach identifies candidate drugs to reduce mortality in severely ill patients with COVID-19

Fava, Vinicius M.; Bourgey, Mathieu; Nawarathna, Pubudu M.; Orlova, Marianna; Cassart, Pauline; Vinh, Donald C.; Cheng, Matthew P.; Bourque, Guillaume; Schurr, Erwin; Langlais, David

doi:10.1126/sciadv.abm2510

Cited by 15 publications

(17 citation statements)

References 131 publications

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“…A recent study based on single cell omics data confirmed that T cell populations rather than B cell populations are significantly reduced in critically ill COVID‐19 patients. 44 , 45 …”

Section: Resultsmentioning

confidence: 99%

Uncovering common pathobiological processes between COVID‐19 and pulmonary arterial hypertension by integrating Omics data

Wang

Loscalzo

2023

Pulm. circ.

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Coronavirus disease 2019 (COVID‐19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which led to the current pandemic. Many factors, including age and comorbidities, influence the severity and mortality of COVID‐19. SARS‐CoV‐2 infection can cause pulmonary vascular dysfunction. The COVID‐19 case‐fatality rate in patients with pulmonary arterial hypertension (PAH) is higher in comparison with the general population. In this study, we aimed to identify pathobiological processes common to COVID‐19 and PAH by utilizing the human protein–protein interactome and whole‐genome transcription data from peripheral blood mononuclear cells (PBMCs) and from lung tissue. We found that there are significantly more interactions between SARS‐CoV‐2 targets and PAH disease proteins than expected by chance, suggesting that the PAH disease module is in the neighborhood of SARS‐CoV‐2 targets in the human interactome. In addition, SARS‐CoV‐2 infection‐induced changes in gene expression significantly overlap with PAH‐induced gene expression changes in both tissues, indicating SARS‐CoV‐2 and PAH may share common transcriptional regulators. We identified many upregulated genes and downregulated genes common to COVID‐19 and PAH. Interestingly, we observed different co‐regulation patterns and dysfunctional signaling pathways in PBMCs versus lung tissue. Endophenotype enrichment analysis revealed that genes regulating fibrosis, inflammation, hypoxia, oxidative stress, immune response, and thromboembolism are significantly enriched in the COVID‐19‐PAH co‐expression modules. We examined the network proximity of the targets of repositioned drugs for COVID‐19 to the co‐expression modules in PBMCs and lung tissue, and identified 42 drugs that can be potentially used for COVID‐19 patients with PAH as a comorbidity. The uncovered common pathobiological pathways are crucial for discovering therapeutic targets and designing tailored treatments for COVID‐19 patients who also have PAH.

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“…A recent study based on single cell omics data confirmed that T cell populations rather than B cell populations are significantly reduced in critically ill COVID‐19 patients. 44 , 45 …”

Section: Resultsmentioning

confidence: 99%

Uncovering common pathobiological processes between COVID‐19 and pulmonary arterial hypertension by integrating Omics data

Wang

Loscalzo

2023

Pulm. circ.

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“…Values were expressed as medians. N sample = MOD (10) and SEV (16) for each endpoint (A or B), CTRL (6). Yellow asterisks = Infected A versus controls A; Red asterisks = Infected B versus Infected A; Blue asterisks = Infected B versus controls A. E and F : Bar charts depicting intracellular protein levels of CCL3 (Panel E) and IL-1B (Panel F).…”

Section: Resultsmentioning

confidence: 99%

“…Epigenetic changes in host cells during COVID-19 have already been described and are associated with the regulation of the SARS-CoV-2 cycle ( 25, 26 ), the disease severity ( 17, 26 ) or the prognosis for critically ill patients ( 16, 26 ). However, to the best of our knowledge, this is the first work to demonstrate that pharmacological modulation of the leukocyte epigenetic marks favorably regulates central components of hyperinflammation in moderate and severe forms of the disease.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic marks

Cassiano

Silva

Oliveira³

et al. 2022

Preprint

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COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, raising the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic marks in leukocytes favorably regulates central components of COVID-19 physiopathology.

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“…Here we proposed examples by adapting designs applied to study the host response to infections, detect somatic mutations in cancers and evaluate embryonic development. 20 , 21 , 22 , 23 …”

Section: How To Test the Hypothesismentioning

confidence: 99%

Experimental approaches to assess melanocytes mosaicism in segmental vitiligo

Dellatorre¹,

Fava

Mira

et al. 2023

Anais Brasileiros de Dermatologia

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A systems biology approach identifies candidate drugs to reduce mortality in severely ill patients with COVID-19

Cited by 15 publications

References 131 publications

Uncovering common pathobiological processes between COVID‐19 and pulmonary arterial hypertension by integrating Omics data

Uncovering common pathobiological processes between COVID‐19 and pulmonary arterial hypertension by integrating Omics data

Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic marks

Experimental approaches to assess melanocytes mosaicism in segmental vitiligo

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