Dataset Information

Gene signatures of SARS-CoV/SARS-CoV-2-infected ferret lungs in short- and long-term models.

ABSTRACT: Coronaviruses (CoVs) consist of six strains, and the severe acute respiratory syndrome coronavirus (SARS-CoV), newly found coronavirus (SARS-CoV-2) has rapidly spread leading to a global outbreak. The ferret (Mustela putorius furo) serves as a useful animal model for studying SARS-CoV/SARS-CoV-2 infection and developing therapeutic strategies. A holistic approach for distinguishing differences in gene signatures during disease progression is lacking. The present study discovered gene expression profiles of short-term (3 days) and long-term (14 days) ferret models after SARS-CoV/SARS-CoV-2 infection using a bioinformatics approach. Through Gene Ontology (GO) and MetaCore analyses, we found that the development of stemness signaling was related to short-term SARS-CoV/SARS-CoV-2 infection. In contrast, pathways involving extracellular matrix and immune responses were associated with long-term SARS-CoV/SARS-CoV-2 infection. Some highly expressed genes in both short- and long-term models played a crucial role in the progression of SARS-CoV/SARS-CoV-2 infection, including DPP4, BMP2, NFIA, AXIN2, DAAM1, ZNF608, ME1, MGLL, LGR4, ABHD6, and ACADM. Meanwhile, we revealed that metabolic, glucocorticoid, and reactive oxygen species-associated networks were enriched in both short- and long-term infection models. The present study showed alterations in gene expressions from short-term to long-term SARS-CoV/SARS-CoV-2 infection. The current result provides an explanation of the pathophysiology for post-infectious sequelae and potential targets for treatment.

SUBMITTER: Liu HL

PROVIDER: S-EPMC7832673 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Gene signatures of SARS-CoV/SARS-CoV-2-infected ferret lungs in short- and long-term models.

Liu Hsin-Liang HL Yeh I-Jeng IJ Phan Nam Nhut NN Wu Yen-Hung YH Yen Meng-Chi MC Hung Jui-Hsiang JH Chiao Chung-Chieh CC Chen Chien-Fu CF Sun Zhengda Z Jiang Jia-Zhen JZ Hsu Hui-Ping HP Wang Chih-Yang CY Lai Ming-Derg MD

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 20200629

Coronaviruses (CoVs) consist of six strains, and the severe acute respiratory syndrome coronavirus (SARS-CoV), newly found coronavirus (SARS-CoV-2) has rapidly spread leading to a global outbreak. The ferret (Mustela putorius furo) serves as a useful animal model for studying SARS-CoV/SARS-CoV-2 infection and developing therapeutic strategies. A holistic approach for distinguishing differences in gene signatures during disease progression is lacking. The present study discovered gene expression ...[more]

PMID: 32615317

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Project description:ImportanceShort-term and long-term persistent postacute sequelae of COVID-19 (PASC) have not been systematically evaluated. The incidence and evolution of PASC are dependent on time from infection, organ systems and tissue affected, vaccination status, variant of the virus, and geographic region.ObjectiveTo estimate organ system-specific frequency and evolution of PASC.Evidence reviewPubMed (MEDLINE), Scopus, the World Health Organization Global Literature on Coronavirus Disease, and CoronaCentral databases were searched from December 2019 through March 2021. A total of 2100 studies were identified from databases and through cited references. Studies providing data on PASC in children and adults were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for abstracting data were followed and performed independently by 2 reviewers. Quality was assessed using the Newcastle-Ottawa Scale for cohort studies. The main outcome was frequency of PASC diagnosed by (1) laboratory investigation, (2) radiologic pathology, and (3) clinical signs and symptoms. PASC were classified by organ system, ie, neurologic; cardiovascular; respiratory; digestive; dermatologic; and ear, nose, and throat as well as mental health, constitutional symptoms, and functional mobility.FindingsFrom a total of 2100 studies identified, 57 studies with 250 351 survivors of COVID-19 met inclusion criteria. The mean (SD) age of survivors was 54.4 (8.9) years, 140 196 (56%) were male, and 197 777 (79%) were hospitalized during acute COVID-19. High-income countries contributed 45 studies (79%). The median (IQR) proportion of COVID-19 survivors experiencing at least 1 PASC was 54.0% (45.0%-69.0%; 13 studies) at 1 month (short-term), 55.0% (34.8%-65.5%; 38 studies) at 2 to 5 months (intermediate-term), and 54.0% (31.0%-67.0%; 9 studies) at 6 or more months (long-term). Most prevalent pulmonary sequelae, neurologic disorders, mental health disorders, functional mobility impairments, and general and constitutional symptoms were chest imaging abnormality (median [IQR], 62.2% [45.8%-76.5%]), difficulty concentrating (median [IQR], 23.8% [20.4%-25.9%]), generalized anxiety disorder (median [IQR], 29.6% [14.0%-44.0%]), general functional impairments (median [IQR], 44.0% [23.4%-62.6%]), and fatigue or muscle weakness (median [IQR], 37.5% [25.4%-54.5%]), respectively. Other frequently reported symptoms included cardiac, dermatologic, digestive, and ear, nose, and throat disorders.Conclusions and relevanceIn this systematic review, more than half of COVID-19 survivors experienced PASC 6 months after recovery. The most common PASC involved functional mobility impairments, pulmonary abnormalities, and mental health disorders. These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low- and middle-income countries.

Project description:Coronavirus disease 19 (COVID-19) is the clinical manifestation of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. A hallmark of COVID-19 is a lung inflammation characterized by an abundant leukocyte infiltrate, elevated levels of cytokines/chemokines, lipid mediators of inflammation (LMI) and microthrombotic events. Animal models are useful for understanding the pathophysiological events leading to COVID-19. One such animal model is the K18-ACE2 transgenic mice. Despite their importance in inflammation, the study of LMI in lung of SARS-CoV-2 infected K18-ACE2 mice has yet to be studied to our knowledge. Using tandem mass spectrometry, the lung lipidome at different time points of infection was analyzed. Significantly increased LMI included N-oleoyl-serine, N-linoleoyl-glycine, N-oleoyl-alanine, 1/2-linoleoyl-glycerol, 1/2-docosahexaenoyl-glycerol and 12-hydroxy-eicosapenatenoic acid. The levels of prostaglandin (PG) E1, PGF2α, stearoyl-ethanolamide and linoleoyl-ethanolamide were found to be significantly reduced relative to mock-infected mice. Other LMI were present at similar levels (or undetected) in both uninfected and infected mouse lungs. In parallel to LMI measures, transcriptomic and cytokine/chemokine profiling were performed. Viral replication was robust with maximal lung viral loads detected on days 2-3 post-infection. Lung histology revealed leukocyte infiltration starting on day 3 post-infection, which correlated with the presence of high concentrations of several chemokines/cytokines. At early times post-infection, the plasma of infected mice contained highly elevated concentration of D-dimers suggestive of blood clot formation/dissolution. In support, the presence of blood clots in the lung vasculature was observed during infection. RNA-Seq analysis of lung tissues indicate that SARS-CoV-2 infection results in the progressive modulation of several hundred genes, including several inflammatory mediators and genes related to the interferons. Analysis of the lung lipidome indicated modest, yet significant modulation of a minority of lipids. In summary, our study suggests that SARS-CoV-2 infection in humans and mice share common features, such as elevated levels of chemokines in lungs, leukocyte infiltration and increased levels of circulating D-dimers. However, the K18-ACE2 mouse model highlight major differences in terms of LMI being produced in response to SARS-CoV-2 infection. The potential reasons and impact of these differences on the pathology and therapeutic strategies to be employed to treat severe COVID-19 are discussed.

Dataset Information

Gene signatures of SARS-CoV/SARS-CoV-2-infected ferret lungs in short- and long-term models.

Publications

Gene signatures of SARS-CoV/SARS-CoV-2-infected ferret lungs in short- and long-term models.

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