scholarly journals High temporal resolution transcriptomic profiling delineates distinct patterns of interferon response following Covid-19 mRNA vaccination and SARS-CoV2 infection

2021 ◽  
Author(s):  
Darawan Rinchai ◽  
Sara Deola ◽  
Gabriele Zoppoli ◽  
Basirudeen Syed Ahamed Kabeer ◽  
Sara Ahmad Taleb ◽  
...  
Keyword(s):  
Temporal Resolution ◽  
Protective Immunity ◽  
Subsequent Development ◽  
Transcriptome Profiling ◽  
Interferon Response ◽  
High Temporal Resolution ◽  
Type I ◽  
Interferon Signature ◽  
Interferon Induction

Knowledge of the factors contributing to the development of protective immunity after vaccination with COVID-19 mRNA vaccines is fragmentary. Thus we employed high-temporal-resolution transcriptome profiling and in-depth characterization of antibody production approaches to investigate responses to COVID-19 mRNA vaccination. There were marked differences in the timing and amplitude of the responses to the priming and booster doses. Notably, two distinct interferon signatures were identified, that differed based on their temporal patterns of induction. The first signature (S1), which was preferentially induced by type I interferon, peaked at day 2 post-prime and at day 1 post-boost, and in both instances was associated with subsequent development of the antibody response. In contrast, the second interferon signature (S2) peaked at day 1 both post-prime and post-boost but was found to be potently induced only post-boost, where it coincided with a robust inflammation peak. Notably, we also observed post-prime-like (S1++,S20/+) and post-boost-like (S1++,S2++) patterns of interferon response among COVID-19 patients. A post-boost-like signature was observed in most severely ill patients at admission to the intensive care unit and was associated with a shorter hospital stay. Interestingly, severely ill patients who stayed hospitalized the longest showed a peculiar pattern of interferon induction (S1-/0,S2+), that we did not observe following the administration of mRNA vaccines. In summary, high temporal resolution profiling revealed an elaborate array of immune responses elicited by priming and booster doses of COVID-19 mRNA vaccines. Furthermore, it contributed to the identification of distinct interferon-response phenotypes underpinning vaccine immunogenicity and the course of COVID-19 disease.

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

scholarly journals Characterization of high temporal resolution prr acquisition by fast comtec card: Deadtime, PRR desaturation, temperature calibration and retrieval.

2018 ◽  
Vol 176 ◽  
pp. 01017 ◽  
Author(s):  
Giovanni Martucci ◽  
Valentin Simeonov ◽  
Ludovic Renaud ◽  
Alexander Haefele
Keyword(s):  
Water Vapor ◽  
Temporal Resolution ◽  
Dead Time ◽  
Temporal Stability ◽  
Acquisition System ◽  
High Temporal Resolution ◽  
Temperature Calibration ◽  
Raman Lidar ◽  
Meteorological Observations

RAman Lidar for Meteorological Observations (RALMO) is operated at MeteoSwiss and provides continuous measurements of water vapor and temperature since 2010. While the water vapor has been acquired by a Licel acquisition system since 2008, the temperature channels have been migrated to a Fastcom P7888 acquisition system, since August 2015. We present a characterization of this new acquisition system, namely its dead-time, desaturation, temporal stability of the Pure Rotational Raman signals and the retrieval of the PRR-temperature.

scholarly journals DDI2 protease activity controls embryonic development and inflammation via TCF11/NRF1

2020 ◽  
Author(s):  
Monika Siva ◽  
Stefanie Haberecht-Müller ◽  
Michaela Prochazkova ◽  
Jan Prochazka ◽  
Frantisek Sedlak ◽  
...  
Keyword(s):  
Stress Responses ◽  
Mammalian Cells ◽  
Type I ◽  
Interferon Signature ◽  
Knock Out ◽  
Unfolded Protein ◽  
Proteotoxic Stress ◽  
Proteasome Subunits

DDI2 is an aspartic protease that cleaves polyubiquitinated substrates. Upon proteotoxic stress, DDI2 activates the ER-bound transcription factor TCF11/NRF1 (NFE2L1), a master regulator of proteostasis maintenance in mammalian cells, and ensures the expression of rescue factors including proteasome subunits. Here we describe the consequences of DDI2 ablation both in vivo and in cells. Knock-out of DDI2 in mice resulted in embryonic lethality at E12.5 with severe developmental failure. Molecular characterization of the embryos and surrogate DDI2 knock-out cell lines showed insufficient proteasome expression with proteotoxic stress, accumulation of high molecular weight ubiquitin conjugates, and induction of the unfolded protein and integrated stress responses. We also show that DDI2 KO-induced proteotoxic stress causes the cell-autonomous innate immune system to induce a type I interferon signature. These results indicate an important role for DDI2 in the proteostasis network of cells and tissues and in the maintenance of a balanced immune response.

Transcriptome Profiling of Lenalidomide Treated Myeloma Patients Identifies an Interferon Signature Gene Response and a Novel IRF4/MYC Independent Mechanism of Resistance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 170-170
Author(s):  
Paola E. Neri ◽  
Ines Tagoug ◽  
Li Ren ◽  
Ranjan Maity ◽  
Justin Simms ◽  
...  
Keyword(s):  
Cell Line ◽  
Transcriptional Repression ◽  
Sequence Data ◽  
Transcriptome Profiling ◽  
Proteasomal Degradation ◽  
Response To Therapy ◽  
Differentially Expressed ◽  
Interferon Response ◽  
Type I

Abstract Background: Immunomodulatory (IMiDs) drugs are now recognized as modifiers of the degrons targeted by the CLR4-CRBN E3 ligase. Lenalidomide binding to CRBN promotes the proteasomal degradation to the B cell specific zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) and the transcriptional repression of IRF4 and MYC. Loss of CRBN thalidomide binding domain as well as the expression of mutants IKZF1Q146H or IKZF3Q147H confer resistance to IMiDs in vitro; however these events are rare in primary MM cells. In addition over-expression of IRF4 only partially protects MM cells from the anti-proliferative effects of IMiDs suggesting that a yet unidentified Aiolos dependent mechanism(s) regulate IMiDs sensitivity. Methods and Results: In order to identify novel mechanisms of resistance to IMiDs we profiled the transcriptome of IMiDs treated patients (sensitive and resistant), MM cell line (MM1S) exposed to lenalidomide and Aiolos silenced MM cells (OPM2). In primary samples, RNA-seq analysis was performed on paired CD138 selected cells sequentially collected from patients’ BM prior to lenalidomide treatment initiation (n=15) and at the time of acquired resistance (n=12) or ongoing response to therapy (n=3). Transcriptome sequence data was generated on the Ion Torrent Proton platform with a minimum of 70x106 reads per sample. Filtered Fastq files were mapped with the TopHat2 splice aligner against hg19. DESeq2 was used to detect differentially expressed (DE) genes. Amongst lenalidomide sensitive patients a total of 870 genes were identified as differentially expressed (FDR <0.1) between the pre- and post-lenalidomide paired samples. Functional annotation of these DE genes using DAVID revealed enrichment of genes involved in immune mediated responses (Gene-Ontology). Of interest interferon γ (IFNγ) was upregulated 3.3 fold in the post-lenalidomide sensitive cohort and 20.4% of the DE genes are type I and II interferon regulated genes (Interferome v2.01). A similar Interferon type of response was also observed in MM1S (Len-sensitive MM cell line) and post Aiolos knockdown of OPM2 cells but not in the lenalidomide resistant cohort. Notably, while several genes that are required for the induction of an interferon response (IL1α, IL1β, TBK1, NLRP3) were upregulated post-lenalidomide in the sensitive cohort, they were downregulated in resistant patients. Of particular interest, two genes that play a key role in modulating IFN response were differentially expressed in the Len resistant cohort: 1) NLRP4 a member of the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) was significantly upregulated in lenalidomide resistant patients. NLRP4 negatively regulates type I IFN signaling by targeting the kinase TBK1 for proteasomal degradation and is also recognized to suppress autophagy through Beclin1; 2) NFKBIZ (IkBζ), an atypical IkB kinase required for the induction of IFN response was significantly reduced in lenalidomide-resistant patients. Validation of this lenalidomide induced IFN response was carried out in vitro in MM cells exposed to lenalidomide 10 μM for 24 and 72 hours. A significant increase in IFN stimulated genes (ISGs) such as XAF1, DDX58, IFIT3 was observed following lenalidomide treatment. Similar changes were observed in Aiolos knockdown MM cells. Functionally, silencing of NFKBIZ (through lentiviral shRNA or transient siRNA expression) in MM1S cells resulted in 30% reduction in lenalidomide induced cell death and supressed p21 upregulation but had no effect on the downregulation Aiolos, IRF4 and MYC. Similarly stable overexpression of NLRP4 in MM cells, conferred resistance to lenalidomide. Conclusions: Through comparative transcriptome profiling of lenalidomide resistance and sensitive patients we have identified an Aiolos-dependent induction of interferon stimulated genes as a novel mechanisms of IMiDs mediated cytotoxicity and identified NLRP4 and NFKBIZ as potential mediators of IMiDs resistance. Disclosures Bahlis: Celgene: Honoraria, Research Funding.

scholarly journals Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins

2007 ◽  
Vol 81 (22) ◽  
pp. 12696-12703 ◽  
Author(s):  
Luis Martínez-Sobrido ◽  
Panagiotis Giannakas ◽  
Beatrice Cubitt ◽  
Adolfo García-Sastre ◽  
Juan Carlos de la Torre
Keyword(s):  
New World ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Lymphocytic Choriomeningitis ◽  
Interferon Response ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Induction ◽  
Tacaribe Virus ◽  
Infected Cells

ABSTRACT We have documented that the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus is an antagonist of the type I interferon response. In this study we tested the ability of NPs encoded by representative arenavirus species from both Old World and New World antigenic groups to inhibit production of interferon. We found that, with the exception of Tacaribe virus (TCRV), all NPs tested inhibited activation of beta interferon and interferon regulatory factor 3 (IRF-3)-dependent promoters, as well as the nuclear translocation of IRF-3. Consistent with this observation, TCRV-infected cells also failed to inhibit interferon production.

scholarly journals Technical Note: High temporal resolution characterization of gating response time

2016 ◽  
Vol 43 (6Part1) ◽  
pp. 2802-2806 ◽  
Author(s):  
Rodney D. Wiersma ◽  
Bradley P. McCabe ◽  
Andrew H. Belcher ◽  
Patrick J. Jensen ◽  
Brett Smith ◽  
...  
Keyword(s):  
Response Time ◽  
Temporal Resolution ◽  
Technical Note ◽  
High Temporal Resolution

scholarly journals Mapping and Characterization of Hydrological Dynamics in a Coastal Marsh Using High Temporal Resolution Sentinel-1A Images

2016 ◽  
Vol 8 (7) ◽  
pp. 570 ◽  
Author(s):  
Cécile Cazals ◽  
Sébastien Rapinel ◽  
Pierre-Louis Frison ◽  
Anne Bonis ◽  
Grégoire Mercier ◽  
...  
Keyword(s):  
Temporal Resolution ◽  
Coastal Marsh ◽  
High Temporal Resolution

scholarly journals TLR7-agonist and antineoplastic MEK1/2-inhibitor combination unlocks interferon responses from macrophages

2019 ◽  
Author(s):  
Lei Yang ◽  
Jeak Ling Ding
Keyword(s):  
Combination Therapy ◽  
Tumor Cells ◽  
Mitogen Activated Protein Kinase ◽  
Interferon Response ◽  
Type I ◽  
Model Combination ◽  
Interferon Signature ◽  
Tlr7 Agonist ◽  
Novel Strategy ◽  
Interferon Responses

AbstractType I interferons are a family of pleiotropic cytokines that exert anti-tumor actions directly on tumor cells and indirectly on the tumor immune microenvironment (TIME). Hitherto, therapeutic strategies aiming to garner the efficacies of interferon responses are still limited. Here we show a novel strategy that elicits an interferon signature response while targeting both tumor cells using antineoplastic mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) inhibitor and the TIME using toll-like receptor 7 (TLR7)-based immune adjuvant. The combination of MEK1/2 inhibitor and TLR7 agonist unlocked an interferon signature response unexpectedly in macrophages, which was otherwise tightly constrained by TLR7 agonist alone. Deficiency of interferon regulatory factor 1 (Irf1) completely abrogated the responses and prevented the reprogramming of activated macrophages, subduing them in an immunosuppressive state. In a murine melanoma model, combination therapy with TLR7 agonist and MEK1/2 inhibitor synergistically extended survival in wild-type but notIrf1-deficient mice. Specifically, we identified interferon response genes as favorable prognosis markers for cutaneous melanoma patients. Our findings demonstrate a novel strategy for combination therapy that targets both tumor cells and the immunosuppressive TIME through additive effects of monotherapies and synergistic interferon responses.

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