In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age

Lieberman, Nicole A P; Peddu, Vikas; Xie, Hong; Shrestha, Lasata; Huang, Meei Li; Mears, Megan; Cajimat, Maria N.B.; Bente, Dennis A.; Shi, Pei Yong; Bovier, Francesca T.; Roychoudhury, Pavitra; Jerome, Keith R.; Moscona, Anne; Porotto, Matteo; Greninger, Alexander L.

doi:10.1371/journal.pbio.3000849

Cited by 248 publications

(301 citation statements)

References 64 publications

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“…as previously reported 18,19 ; however, a few other non-immune related pathways were enriched in female patients, including down-regulation of mitochondrial respiratory responses and regulation of cholesterol biosynthesis (Figure 4 G-I). The younger male group presented the downregulation of various immune responses such as humoral immune response, acute inflammatory response, and Fc-gamma signaling pathways ( Figure 4G), while the older male group had no enriched pathways.…”

Section: Sex Stratified Analysis Of Host Responses To Sars-cov-2supporting

confidence: 82%

Sex differences in viral entry protein expression and host transcript responses to SARS-CoV-2

Sun

Shankar

et al. 2020

Preprint

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Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the gene expression of viral entry proteins ACE2 and TMPRSS2, and host transcriptional responses to SARS-CoV-2 through large-scale analysis of genomic and clinical data. We first compiled 220,000 human gene expression profiles from three databases and completed the meta-information through machine learning and manual annotation. Large scale analysis of these profiles indicated that male samples show higher expression levels of ACE2 and TMPRSS2 than female samples, especially in the older group (>60 years) and in the kidney. Subsequent analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present distinct expression changes. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients. Together, this study suggests biological differences in the kidney between sexes may contribute to sex disparity in COVID-19.

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Section: Sex Stratified Analysis Of Host Responses To Sars-cov-2supporting

confidence: 82%

Sex differences in viral entry protein expression and host transcript responses to SARS-CoV-2

Sun

Shankar

et al. 2020

Preprint

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“…Finally, we analyzed RNA-Seq data obtained from the BALF of 430 SARS-CoV-2–infected people and 54 controls ( 32 ). Consistent with previous findings, PARP9 was up-regulated nearly 4-fold whereas PARP12 and PARP14 were up-regulated more that 2-fold ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2 D were obtained from GSE152075. Briefly, samples were obtained from nasopharyngeal swabs of from 430 male and female individuals with SARS-CoV-2 infection and 54 controls ( 32 ). NHBE ( Fig.…”

Section: Methodsmentioning

confidence: 99%

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Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Heer

Sanderson

Voth

et al. 2020

Journal of Biological Chemistry

138

117

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Poly-ADP-ribose polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using nicotinamide adenine dinucleotide (NAD) as the source of ADPR. While the well-known poly-ADP-ribosylating (PARylating) PARPs primarily function in the DNA damage response, many non-canonical mono-ADP-ribosylating (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust upregulation of several PARPs following infection with Murine Hepatitis Virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly upregulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM and NR dramatically decrease the replication of an MHV virus that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD, and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.

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“…As reported, DNAJB 1 has been shown to be down-regulated during the infection of influenza A virus ( Batra et al, 2016 ), but not SARS-CoV-2. Specifically, CXCL9 , as a core regulator for immune responses against viral infection, has been reported to be significantly up-regulated during SARS-CoV-2 infection ( Lieberman et al, 2020 ). Therefore, a lower expression level, which is indicated by this rule, may help us distinguish other infections from SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Identifying Transcriptomic Signatures and Rules for SARS-CoV-2 Infection

Zhang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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The world-wide Coronavirus Disease 2019 (COVID-19) pandemic was triggered by the widespread of a new strain of coronavirus named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Multiple studies on the pathogenesis of SARS-CoV-2 have been conducted immediately after the spread of the disease. However, the molecular pathogenesis of the virus and related diseases has still not been fully revealed. In this study, we attempted to identify new transcriptomic signatures as candidate diagnostic models for clinical testing or as therapeutic targets for vaccine design. Using the recently reported transcriptomics data of upper airway tissue with acute respiratory illnesses, we integrated multiple machine learning methods to identify effective qualitative biomarkers and quantitative rules for the distinction of SARS-CoV-2 infection from other infectious diseases. The transcriptomics data was first analyzed by Boruta so that important features were selected, which were further evaluated by the minimum redundancy maximum relevance method. A feature list was produced. This list was fed into the incremental feature selection, incorporating some classification algorithms, to extract qualitative biomarker genes and construct quantitative rules. Also, an efficient classifier was built to identify patients infected with SARS-COV-2. The findings reported in this study may help in revealing the potential pathogenic mechanisms of COVID-19 and finding new targets for vaccine design.

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In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age

Cited by 248 publications

References 64 publications

Sex differences in viral entry protein expression and host transcript responses to SARS-CoV-2

Sex differences in viral entry protein expression and host transcript responses to SARS-CoV-2

Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Identifying Transcriptomic Signatures and Rules for SARS-CoV-2 Infection

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