Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality

Budhraja, Anshul; Basu, Anubhav; Gheware, Atish; Abhilash, Dasari; Rajagopala, Seesandra V.; Pakala, Suman B.; Sumit, Madhuresh; Goel, Ayush; Arulselvi, S; Mathur, Purva; Nambirajan, Aruna; Kumar, Sachin; Gupta, Ritu; Wig, Naveet; Trikha, Anjan; Guleria, Randeep; Sarkar, Chitra; Gupta, Ishaan; Jain, Deepali

doi:10.1242/dmm.049572

Cited by 18 publications

(24 citation statements)

References 109 publications

(143 reference statements)

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“…Whole-transcriptome sequencing of postmortem lung tissue from COVID-19 patients reveals two distinct molecular signatures: Lung damage caused by a massive metabolic reprogramming due to the upregulation of the unfolded protein response, steroid biosynthesis, and complement activation; and secondarily, ‘cytokine release syndrome’ (CRS) represented by the upregulation of cytokines such as IL-1 and CCL19, but absence of complement activation ( Budhraja et al, 2022 ). Although most patients cleared the viral infection, they succumbed to acute dysbiosis overrepresented by Staphylococcus cohnii in ‘classical’ patients and Pasteurella multocida in CRS patients ( Budhraja et al, 2022 ).…”

Section: Molecular Mechanisms Of Respiratory Pascmentioning

confidence: 99%

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Sherif

Gómez

Connors

et al. 2023

eLife

102

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COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

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Section: Molecular Mechanisms Of Respiratory Pascmentioning

confidence: 99%

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Sherif

Gómez

Connors

et al. 2023

eLife

102

View full text Add to dashboard Cite

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“…28 We also retrieved the RNA-seq whole transcriptomes of lung biopsies from 31 deceased COVID-19 patients and 10 healthy individuals (GSE183533). 29 An R package, EdgeR, was used to identify differentially expressed genes in COVID-19. 30 A gene is said to be significantly differentially expressed if the corresponding false discovery rate (FDR) is less than 0.05 and the fold change is greater than 2.…”

Section: Gene Expression Data Of Covid-19 and Pahmentioning

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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“…The advantage of such large-scale data is that we can rapidly utilize them to repurpose existing drugs in urgent situations. For example, several approved drugs have been proposed as candidates for clinical intervention to combat rapidly emerging diseases such as COVID-19 through in silico screening using CMap data ( 114 , 115 ). Accordingly, the establishment of a well-organized drug-related database (e.g., drug-induced transcriptome data) for standardized herbs or herbal medicines should pave the way for advancement of herbal medicine research.…”

Section: Closing Remarksmentioning

confidence: 99%

Systems pharmacology approaches in herbal medicine research: a brief review

Lee¹,

Shin²,

Park³

et al. 2022

BMB Rep

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Herbal medicine, a multi-component treatment, has been extensively practiced for treating various symptoms and diseases. However, its molecular mechanism of action on the human body is unknown, which impedes the development and application of herbal medicine. To address this, recent studies are increasingly adopting systems pharmacology, which interprets pharmacological effects of drugs from consequences of the interaction networks that drugs might have. Most conventional network-based approaches collect associations of herb-compound, compound-target, and target-disease from individual databases, respectively, and construct an integrated network of herb-compound-target-disease to study the complex mechanisms underlying herbal treatment. More recently, rapid advances in highthroughput omics technology have led numerous studies to exploring gene expression profiles induced by herbal treatments to elicit information on direct associations between herbs and genes at the genome-wide scale. In this review, we summarize key databases and computational methods utilized in systems pharmacology for studying herbal medicine. We also highlight recent studies that identify modes of action or novel indications of herbal medicine by harnessing drug-induced transcriptome data. [

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Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality

Cited by 18 publications

References 109 publications

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

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

Systems pharmacology approaches in herbal medicine research: a brief review

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