COVID-19 patients exhibit unique transcriptional signatures indicative of disease severity

Daamen, Andrea R.; Bachali, Prathyusha; Bonham, Catherine A.; Somerville, Lindsay; Sturek, Jeffrey M.; Grammer, Amrie C.; Kadl, Alexandra; Lipsky, Peter E.

doi:10.3389/fimmu.2022.989556

Cited by 8 publications

(10 citation statements)

References 69 publications

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“…They also compared the timing of sampling with disease outcome and although gene expression trajectories change over two time points taken, they found that the signatures were still significantly dysregulated between severe versus moderate COVID-19 and between those who died and those who survived. A smaller study conducted in the ICU setting in those with severe disease (n= 31) also found enrichment of IFN and neutrophil gene signatures ( 49 ). Interestingly, they also found no significant differences in viral loads between the COVID-19 patient groups despite their clear differences in clinical features and gene expression profiles.…”

Section: Discussionmentioning

confidence: 98%

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

et al. 2023

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BackgroundDysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease.MethodsWe analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-β), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays.ResultsWe identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19.ConclusionsThis study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals.

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Section: Discussionmentioning

confidence: 98%

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

et al. 2023

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“…In a mouse-adapted SARS-CoV virus (MA15) study, it was observed that gonadectomized female mice had a gradual weight loss and a higher death rate than the control group. In a different experiment, the treatment of female mice with ICI-182, 780 (Faslodex; an estrogen receptor antagonist) made the group more vulnerable to MA15 infection in contrast to the female mice that were given estrogen agonists [ 55 ]. Our analysis also provided the data that ACE2 can enhance estrogen regulation in females during COVID-19 and thus counteract SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Immune Factors Drive Expression of SARS-CoV-2 Receptor Genes Amid Sexual Disparity

Vashisht

Ahluwalia

Mondal

et al. 2023

Viruses

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The emergence of COVID-19 has led to significant morbidity and mortality, with around seven million deaths worldwide as of February 2023. There are several risk factors such as age and sex that are associated with the development of severe symptoms due to COVID-19. There have been limited studies that have explored the role of sex differences in SARS-CoV-2 infection. As a result, there is an urgent need to identify molecular features associated with sex and COVID-19 pathogenesis to develop more effective interventions to combat the ongoing pandemic. To address this gap, we explored sex-specific molecular factors in both mouse and human datasets. The host immune targets such as TLR7, IRF7, IRF5, and IL6, which are involved in the immune response against viral infections, and the sex-specific targets such as AR and ESSR were taken to investigate any possible link with the SARS-CoV-2 host receptors ACE2 and TMPRSS2. For the mouse analysis, a single-cell RNA sequencing dataset was used, while bulk RNA-Seq datasets were used to analyze the human clinical data. Additional databases such as the Database of Transcription Start Sites (DBTS), STRING-DB, and the Swiss Regulon Portal were used for further analysis. We identified a 6-gene signature that showed differential expression in males and females. Additionally, this gene signature showed potential prognostic utility by differentiating ICU patients from non-ICU patients due to COVID-19. Our study highlights the importance of assessing sex differences in SARS-CoV-2 infection, which can assist in the optimal treatment and better vaccination strategies.

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“…The R/Bioconductor software package GSVA 32 was used as a nonparametric, unsupervised method to estimate enrichment of immune cell and pathway gene sets in RNAseq data as previously described. 12,33,34 Gene sets used as input for GSVA can be found in Supplementary Table 2. Based on previous literature and preliminary studies, we identified C57BL/6 N and C3H/HeJ mice as resistant and susceptible models, respectively, to mouse hepatitis virus 1 (MHV-1).…”

Section: Gene Set Variation Analysis (Gsva)mentioning

confidence: 99%

Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities

Rai,

Marano,

Kang

et al. 2024

Journal of Medical Virology

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Obesity has been identified as an independent risk factor for severe outcomes in humans with coronavirus disease 2019 (COVID‐19) and other infectious diseases. Here, we established a mouse model of COVID‐19 using the murine betacoronavirus, mouse hepatitis virus 1 (MHV‐1). C57BL/6 and C3H/HeJ mice exposed to MHV‐1 developed mild and severe disease, respectively. Obese C57BL/6 mice developed clinical manifestations similar to those of lean controls. In contrast, all obese C3H/HeJ mice succumbed by 8 days postinfection, compared to a 50% mortality rate in lean controls. Notably, both lean and obese C3H/HeJ mice exposed to MHV‐1 developed lung lesions consistent with severe human COVID‐19, with marked evidence of diffuse alveolar damage (DAD). To identify early predictive biomarkers of worsened disease outcomes in obese C3H/HeJ mice, we sequenced RNA from whole blood 2 days postinfection and assessed changes in gene and pathway expression. Many pathways uniquely altered in obese C3H/HeJ mice postinfection aligned with those found in humans with severe COVID‐19. Furthermore, we observed altered gene expression related to the unfolded protein response and lipid metabolism in infected obese mice compared to their lean counterparts, suggesting a role in the severity of disease outcomes. This study presents a novel model for studying COVID‐19 and elucidating the mechanisms underlying severe disease outcomes in obese and other hosts.

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COVID-19 patients exhibit unique transcriptional signatures indicative of disease severity

Cited by 8 publications

References 69 publications

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

Immune Factors Drive Expression of SARS-CoV-2 Receptor Genes Amid Sexual Disparity

Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities

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