Host transcriptional response to SARS‐CoV‐2 infection in COVID‐19 patients – Wiley

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CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Equal contribution of authors.
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Equal contribution of authors.
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Equal contribution of authors.
Department of Medicine, Gandhi Hospital, Hyderabad, India
Department of Medicine, Gandhi Hospital, Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Corresponding Author
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Correspondence
Divya Tej Sowpati, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Uppal Road, Hyderabad 500007, India.
Email: [email protected]
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Equal contribution of authors.
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Equal contribution of authors.
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Equal contribution of authors.
Department of Medicine, Gandhi Hospital, Hyderabad, India
Department of Medicine, Gandhi Hospital, Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Corresponding Author
CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India
Correspondence
Divya Tej Sowpati, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Uppal Road, Hyderabad 500007, India.
Email: [email protected]
Funding information:
This work is supported by the CSIR grant MLP0128.
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Dear Editor,
COVID-19 has an extremely variable prognosis, ranging from asymptomatic and mildly affected individuals to severe disease and death. We have investigated the transcriptional changes in 36 COVID-19 positive Indian patients hospitalized during the first surge (Figure 1A, Table S1, and Supplementary Methods) against 5 COVID-19 negative samples. RNA was isolated from naso/oropharyngeal swabs for paired end sequencing using the Illumina Nova-seq 6000. We identified 251 upregulated (220 protein coding) and 9068 downregulated (3252 protein coding) differentially expressed genes (DEGs) (adjusted p-value < 0.05 and absolute log2 fold change > 1) (Figure 1B, Tables S2 and S3). Seven patients were critical and required intensive care unit (ICU) intervention, while 23 were discharged from COVID-19 ward (W), although no significant differences could be seen in their transcriptional profiles (Figure 1C). The overall transcriptional reduction, irrespective of disease severity (Figure 1C), is well correlated with the phenomenon of fading host cell functionality and prominent viral protein synthesis, and may be associated with interference in host cellular processes and responses.1 The results indicate a diverse transcriptomic profile in response to SARS-CoV-2, in line with the variable prognosis seen in many COVID-19 patients. However, we find robust activation of the innate immune response concomitant with a reduction in the gene expression profiles associated with cardiac, muscular, and neurological processes, as well as peripheral neurosensory markers.
Immune response genes were highly upregulated (Figure 2A and Table S4), with prominent clusters of genes associated with multiple viral infections (Figure 2B and Table S5) marking the activation of infection clearance pathways. Meta-analysis of published datasets identified a signature of 19 upregulated genes (Table S6), linking Type I interferon (IFN) signaling, host defense, and innate immune responses in SARS-CoV-2 infection (Figure 2C). Prominent nodes include well-documented IFN-stimulated genes (ISGs), IFIT paralogs that restrict viral translation, IFIH1 and ISG15 that drive innate immune response upon sensing viral RNA, as well as proviral factors XAF1 and MX1, and DExD/H-Box Helicase antiviral factors that promote RIG-I like receptor-mediated signaling. STAT1 binding to ISGs mediates the IFN-triggered host response and its dysfunction has been associated with hyperactivation of inflammatory pathways in individuals with acute COVID-19 pathophysiology. IFN-mediated activation of the JAK-STAT signaling pathway may play a role in inducing necroptosis (Figure 2B), and is implicated in Acute Respiratory Distress Syndrome (ARDS) development and protection from severe COVID-19 along with OAS1.2, 3 Though not a part of this network, all the MHC class 1 and some MHC class 2 genes (HLA-A,B,C,E,F, and HLA-DQB1, DR-B1, DR-B5), involved in T-cell mediated cell death and the antibody-mediated adaptive immune response, were also upregulated along with RFX5, that binds to MHC-II promoters. However, many of the proinflammatory markers remained unchanged, suggesting an absence of hyperinflammation and a better disease prognosis in these patients.
Downregulated protein coding genes were associated with processes related to neurotransmission and cardiac and muscular contraction (Figure 2A and Table S7). Multiple cardiomyopathy pathways appear to be affected (Figure 2B and Table S8), either as a direct result of the infection or as a downstream consequence of the immune response activation, that may shed light on adverse clinical outcomes. RAS and cAMP signaling pathways, CACNs related to cellular calcium signaling, and key cardiac proteins, such as troponin and tropomyosin, which together with calcium ions are required for proper cardiac muscle contraction, were also downregulated (Figure 2B). These results suggest myocardial issues and highlight the importance of continued follow-up in COVID-19 patients.4 Pancreatic and insulin secretory systems-related genes were also downregulated, in agreement with recent work showing that the insulin requirement for patients with diabetes mellitus increases at the peak of COVID-19 illness.5
Interestingly, there was a strong enrichment for “olfactory transduction” and “taste transduction” pathways among downregulated genes (Figure 2B), including 105 olfactory receptor genes. Over the last year, olfactory dysfunction has emerged as a key symptom of COVID-19 and the loss of smell and taste is likely a consequence of the observed impairment of neurosensory perception pathways.6 Genes associated with drug addiction and neuroactive ligand-receptor pathways also lost their expression pattern. Protein–protein interaction analysis showed two strong networks of genes from the family of gamma-aminobutyric acid type A (GABA) receptors (Figure 2D), important for normal neurological functioning, and the GRIN genes which are part of the N-methyl-D-aspartate receptors family involved in memory, learning, and synaptic development. Reduction in GABA and alterations in GABA receptor levels are associated with stress-induced anxiety and depression, increasingly recognized in COVID-19 patients. The effect on GABAergic interneurons in the olfactory bulb, connecting sensory neurons in the olfactory epithelium, might increase the potential for neurological complications observed in COVID-19 patients.7 Further studies are underway to delineate the implications for neuronal infectivity via the olfactory and respiratory tracts and the nasopharyngeal compartment,6 which are predominantly epithelial cells.
A large proportion of the DEGs included relatively low expression lncRNAs (Figure 3A), including some known to have functional roles during viral infection. For example, ZBTB11-AS1, an antisense lncRNA to ZBTB11, regulating neutrophil development8 was upregulated along with the cognate gene. HEIH, associated with recurrence in hepatitis C virus-related hepatocellular carcinoma and IGF2-AS, associated with HepC viral replication9, 10 were also significantly misregulated. However, the role of many lncRNAs is unspecified. We identified 720 differentially expressed protein coding genes nearest to the misregulated lncRNAs, most of which were found to overlap the cognate gene or its promoter on the antisense strand (Figure 3B) and potentially mediated many developmentally regulated processes (Figure 3C and Table S9).
In conclusion, we have documented significantly misregulated genes and associated pathways during SARS-CoV-2 infection in Indian patients (summarized in Figure 4). Our results highlight a commonly upregulated network of innate immune response genes and absence of hyperinflammatory markers. A majority of the genes being downregulated suggest host shutdown and large-scale systemic effects spanning not just lung and respiratory complications but also cardiac, endocrine, and neurological issues. The downregulation of a large proportion of sensory receptors, including olfactory and taste receptors, and associated pathways stands out as a major correlate of SARS-CoV-2 infection. Such studies can help compare host responses in the current and subsequent waves of the pandemic across the globe and identify targets for monitoring and planning therapeutic approaches.
The authors declare no conflict of interest.
Raw data and the RNA-seq count data can be accessed from Gene Expression Omnibus (GEO) database (accession number GSE166530).
Table S1 : Sample metadata.
Table S2 : Differential expression analysis result from DESeq2 when COVID-19 positive samples were compared with control.
Table S3 : Biotype composition table for differentially expressed genes.
Table S4 : GO enrichment table for the protein coding genes that were upregulated in COVID-19 samples.
Table S5 : KEGG enrichment table for the protein coding genes that were upregulated in COVID-19 samples.
Table S6 : List of genes identified from meta analysis of existing transcriptomic datasets for COVID-19 samples.
Table S7 : GO enrichment table for the protein coding genes that were downregulated in COVID-19 samples.
Table S8 : KEGG enrichment table for the protein coding genes that were downregulated in COVID-19 samples.
Table S9 : GO enrichment analysis of the differentially expressed protein-coding genes nearest to differentially expressed lncRNAs.
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Volume11, Issue9
September 2021
e534
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