COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm?

Rizzo, Paola; Sega, Francesco Vieceli Dalla; Fortini, Francesca; Marracino, Luisa; Rapezzi, Claudio; Ferrari, Roberto

doi:10.1007/s00395-020-0791-5

Cited by 182 publications

(192 citation statements)

References 55 publications

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“…Receptors Reflecting their well-documented roles in the response to CoV infection 18-21 , we observed appreciable significant intersections between CoV HCTs and those of the [22][23][24][25][26] . The Notch 9 receptor HCT intersection points to a possible mechanistic basis for the potential of Notch pathway modulation in the treatment of SARS2 27 . The strong HCT intersection between CoV infection and xenobiotic receptors (q-values: SARS1, 1e-30; SARS2, 1e-44; MERS, 5e-32; Fig.…”

Section: To Illuminate Human Signaling Pathways Orchestrating the Tramentioning

confidence: 99%

Consensus transcriptional regulatory networks of coronavirus-infected human cells

Ochsner

Pillich

McKenna

2020

Preprint

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15Identifying transcriptional responses that are most consistently associated with 16 experimental coronavirus (CoV) infection can help illuminate human cellular signaling 17 pathways impacted by CoV infection. Here, we distilled over 3,000,000 data points from 18 publically archived CoV infection transcriptomic datasets into consensus regulatory 19 signatures, or consensomes, that rank genes based on their transcriptional 20 responsiveness to infection of human cells by MERS, SARS-CoV-1 and SARS-CoV-2 21 subtypes. We computed overlap between genes with elevated rankings in the CoV 22 consensomes against those from transcriptomic and ChIP-Seq consensomes for nearly 23 880 cellular signaling pathway nodes. Validating the CoV infection consensomes, we 24 identified robust overlap between their highly ranked genes and high confidence targets 25 of signaling pathway nodes with known roles in CoV infection. We then developed a 26 series of use cases that illustrate the utility of the CoV consensomes for hypothesis 27 generation around mechanistic aspects of the cellular response to CoV infection. We 28 make the CoV infection consensomes and their universe of underlying data points freely 29 accessible through the Signaling Pathways Project web knowledgebase. 30 31 65 points in a series of use cases illuminates previously uncharacterized intersections 66 between CoV infection and human cellular signaling pathways. The CoV infection 67 consensome and its underlying datasets provide researchers with a unique and freely 68 accessible framework within which to generate and pressure test hypotheses around 69 human cellular signaling pathways impacted by CoV infection.70 71 72 73 5 Results 74Generation of the CoV consensomes 75 We first set out to generate a set of consensomes ranking human genes based on the 76 frequency of their significant differential expression in response to infection by MERS, 77 SARS1 and SARS2 CoVs. To do this we searched the Gene Expression Omnibus 78 (GEO) and ArrayExpress databases to identify datasets involving infection of human 79 cells by these species. From this initial collection of datasets, we next carried out a 80 three step quality control check as previously described (Ochsner et al., 2019), yielding 81 a total of 3,041,047 million data points in 111 experiments from 25 independent CoV 82 infection transcriptomic datasets (Supplementary information, Section 1). Using these 83 curated datasets, we next generated consensomes for each CoV species, as well as 84 one ranking genes across all CoV infection experiments (ALL CoV). As a reference 85 consensome for a virus whose transcriptional impact on human cells has been studied 86 in depth, we also generated a consensome for human influenza A virus (IAV) infection. 87The Supplementary information files contain the full human ALL CoV (Section 2), MERS 88 (Section 3), SARS1 (Section 4), SARS2 (Section 5) and IAV (Section 6) infection 89 transcriptomic consensomes. To assist researchers in inferring transcriptional regulation 90 of sig...

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Section: To Illuminate Human Signaling Pathways Orchestrating the Tramentioning

confidence: 99%

Consensus transcriptional regulatory networks of coronavirus-infected human cells

Ochsner

Pillich

McKenna

2020

Preprint

View full text Add to dashboard Cite

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“…Immunomodulatory therapies under active investigation for COVID-19 include corticosteroids, anti-cytokine therapies (including monoclonal antibodies), convalescent plasma, intravenous immune globulin (IVIG) therapy, and inhibitors of specific inflammatory pathways, including Notch signaling [1,38]. All treatments await validation in large-scale randomized controlled trials.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series

et al. 2020

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There are no definitive therapies for patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Therefore, new therapeutic strategies are needed to improve clinical outcomes, particularly in patients with severe disease. This case series explores the safety and effectiveness of intravenous allogeneic cardiosphere-derived cells (CDCs), formulated as CAP-1002, in critically ill patients with confirmed coronavirus disease 2019 . Adverse reactions to CAP-1002, clinical status on the World Health Organization (WHO) ordinal scale, and changes in pro-inflammatory biomarkers and leukocyte counts were analyzed. All patients (n = 6; age range 19-75 years, 1 female) required ventilatory support (invasive mechanical ventilation, n = 5) with PaO 2 /FiO 2 ranging from 69 to 198. No adverse events related to CAP-1002 administration were observed. Four patients (67%) were weaned from respiratory support and discharged from the hospital. One patient remains mechanically ventilated as of April 28th, 2020; all survive. A contemporaneous control group of critically ill COVID-19 patients (n = 34) at our institution showed 18% overall mortality at a similar stage of hospitalization. Ferritin was elevated in all patients at baseline (range of all patients 605.43-2991.52 ng/ml) and decreased in 5/6 patients (range of all patients 252.89-1029.90 ng/ml). Absolute lymphocyte counts were low in 5/6 patients at baseline (range 0.26-0.82 × 10 3 / µl) but had increased in three of these five patients at last follow-up (range 0.23-1.02 × 10 3 /µl). In this series of six critically ill COVID-19 patients, intravenous infusion of CAP-1002 was well tolerated and associated with resolution of critical illness in 4 patients. This series demonstrates the apparent safety of CAP-1002 in COVID-19. While this initial experience is promising, efficacy will need to be further assessed in a randomized controlled trial.

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“…There is also a well-documented relationship between Notch signaling and viral infections. For example, Human Papilloma Virus and Simian Virus 40 can highjack the cellular machinery, including components of Notch signaling, and these events re associated with cancer progression(73). Most studies thus far have only followed SARS-CoV-2 infected macaque for up to two weeks, and it was initially thought that this virus causes acute infection.…”

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confidence: 99%

IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection

Rosa

Ahmed

Singh

et al. 2020

Preprint

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The novel virus SARS-CoV-2 has infected more than 14 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Limited information on the underlying immune mechanisms that drive disease or protection during COVID-19 severely hamper development of therapeutics and vaccines. Thus, the establishment of relevant animal models that mimic the pathobiology of the disease is urgent. Rhesus macaques infected with SARS-CoV-2 exhibit disease pathobiology similar to human COVID-19, thus serving as a relevant animal model. In the current study, we have characterized the transcriptional signatures induced in the lungs of juvenile and old rhesus macaques following SARS-CoV-2 infection. We show that genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. We demonstrate that Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. In contrast, pathways involving VEGF are downregulated in lungs of old infected macaques. Using samples from humans with SARS-CoV-2 infection and COVID-19, we validate a subset of our findings. Finally, neutrophil degranulation, innate immune system and IFN gamma signaling pathways are upregulated in both tuberculosis and COVID-19, two pulmonary diseases where neutrophils are associated with increased severity. Together, our transcriptomic studies have delineated disease pathways to improve our understanding of the immunopathogenesis of COVID-19 to facilitate the design of new therapeutics for COVID-19.

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COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm?

Cited by 182 publications

References 55 publications

Consensus transcriptional regulatory networks of coronavirus-infected human cells

Consensus transcriptional regulatory networks of coronavirus-infected human cells

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series

IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection

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