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Series GSE205429 Query DataSets for GSE205429
Status Public on Nov 16, 2022
Title Modulation of type-I interferon responses reduces SARS-CoV-2 replication and inflammation in rhesus macaques
Organism Macaca mulatta
Experiment type Expression profiling by high throughput sequencing
Summary Inflammation following SARS-CoV-2 infection is a hallmark of COVID-19 and predictive of morbidity and death. However, the inflammatory pathways contributing to host-defense vs immune-mediated pathology have not been fully elucidated. This duality is clearly seen with type-I interferons (IFN-I) which are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to site of infection, a key feature of severe COVID-19. Here, we modulated IFN-I signaling in rhesus macaques (Macaca mulatta) prior to and during acute SARS-CoV-2 infection (day -1 through day 2 post infection) using a mutated IFNα2 (IFN-modulator; IFNmod) which blocks binding to IFNAR2 and signaling of endogenous IFN-I. IFNmod treatment resulted in a highly significant and consistent reduction in SARS-CoV-2 viral load in BAL, lung, and hilar LN (>3-log difference) and upper airways (nasal swabs). IFNmod also potently reduced inflammatory cytokines and chemokines in BAL, expansion of inflammatory monocytes (CD14+CD16+), and lung pathogenesis. Furthermore, Siglec-1 expression, which has been shown to enhance SARS-CoV-2 infection, was rapidly downregulated in the lung and on monocytes of IFNmod-treated SARS-CoV-2 infected RMs. Notably, while RNAseq analysis showed that IFNmod induced a modest upregulation of antiviral IFN-stimulated genes (ISGs) in uninfected RMs, it resulted in a robust reduction in pathways associated with both antiviral and inflammatory ISGs in SARS-CoV-2-infected RMs. In conclusion, IFNmod treatment provides sufficient levels of type I IFN signaling that inhibit viral replication while also limiting hyperinflammation. IFN-I plays a vital role in regulating SARS-CoV-2 replication, but uncontrolled IFN signaling has a detrimental impact on inflammation and pathogenesis. A better understanding of the role of IFN-I pathways is essential for designing therapies targeting these pathways and aimed at limiting COVID-19 pathogenesis.
 
Overall design Uninfected Rhesus Macaque Study (n=4): Four uninfected rhesus macaques (RMs) were treated with a four-day course of IFNmod (1mg/day, intramuscularly) to assess the effects of IFNmod in the absence of experimental infection. Brochoalveolar lavage (BAL) fluid was collected prior to treatment initiation (pre-treatment baseline (BL)), 1 day post treatment initiation, and 3 days post treatment initiation. Blood was collected at BL and at days 1, 2, and 3 post treatment initiation.; SARS-CoV-2-infected Rhesus Macaque Study (n=18). 18 RMs were infected with SARS-CoV-2 (USA-WA/2020 strain) intratracheally and intranasally. To investigate the role of type I IFN in SARS-CoV-2 pathogenesis, 9 of these RMs received a four-day course of IFNmod (1mg/day, intramuscularly) beginning 1 day prior to infection (day-1) and ending on day 2 post infection while the remaining 9 control animals were untreated. Animals were necropsied at 2 days post infection (dpi), 4dpi, or 7dpi. Brochoalveolar lavage (BAL) fluid was collected before treatment was initiated and animals were infected (baseline (BL)), 2 days post infection (dpi), and, depending on necropsy date, at 4dpi and 7dpi. Blood was collected at BL and at days 1, 2, 4, 5 and 7dpi also depending on necropsy date.
 
Contributor(s) Paiardini M, Hoang TN, Viox EG, Upadhyay AA, Pino M, Boddapati AK, Nchioua R, Hirschenberger M, Gagne M, Strongin Z, Harper JL, Nguyen K, Tharp GK, Pellegrini KL, Karunakaran KA, Bosinger SE
Citation(s) 36324810, 37506197
Submission date Jun 03, 2022
Last update date Mar 20, 2024
Contact name Gregory K Tharp
E-mail(s) gktharp@emory.edu
Phone 404-727-7797
Organization name Yerkes National Primate Research Center
Department Developmental and Cognitive Neuroscience
Lab Genomics Core
Street address 954 Gatewood Dr
City Atlanta
State/province GA
ZIP/Postal code 30329-4208
Country USA
 
Platforms (1)
GPL27943 Illumina NovaSeq 6000 (Macaca mulatta)
Samples (240)
GSM6212269 p21094-s001_RMs8-PBMC-Day-7-2021-03-08
GSM6212270 p21094-s002_RMs8-PBMC-Day0-2021-03-15
GSM6212271 p21094-s003_RMs8-PBMC-Day1-2021-03-16
Relations
BioProject PRJNA845212

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE205429_COVTen_Raw_Counts.csv.gz 5.9 Mb (ftp)(http) CSV
GSE205429_p21061-s011_RRc17-RGo9_D2_S3.filtered_feature_bc_matrix.h5 51.4 Mb (ftp)(http) H5
GSE205429_p21061-s012_RCk17-RRj11_D2_S4.filtered_feature_bc_matrix.h5 24.3 Mb (ftp)(http) H5
GSE205429_p21061-s013_RRc17-RGo9_D4_S5.filtered_feature_bc_matrix.h5 24.4 Mb (ftp)(http) H5
GSE205429_p21061-s014_RCk17-RRj11_D4_S6.filtered_feature_bc_matrix.h5 28.9 Mb (ftp)(http) H5
GSE205429_p21061-s015_RGo9-RRj11_D7_S7.filtered_feature_bc_matrix.h5 55.1 Mb (ftp)(http) H5
GSE205429_p21061-s016_LG92-LC10_BL_S8.filtered_feature_bc_matrix.h5 29.7 Mb (ftp)(http) H5
GSE205429_p21061-s017_RNi17-RZs14_BL_S9.filtered_feature_bc_matrix.h5 35.9 Mb (ftp)(http) H5
GSE205429_p21061-s018_LG92-LC10_D2_S10.filtered_feature_bc_matrix.h5 27.9 Mb (ftp)(http) H5
GSE205429_p21061-s019_RNi17-RZs14_D2_S11.filtered_feature_bc_matrix.h5 30.5 Mb (ftp)(http) H5
GSE205429_p21061-s020_LG92-LC10_D4_S12.filtered_feature_bc_matrix.h5 25.5 Mb (ftp)(http) H5
GSE205429_p21061-s021_RNi17-RZs14_D4_S13.filtered_feature_bc_matrix.h5 20.3 Mb (ftp)(http) H5
GSE205429_p21061-s024_LC10-RZs14_D7_S16.filtered_feature_bc_matrix.h5 32.9 Mb (ftp)(http) H5
GSE205429_p21061-s025_LC10_D7_Lung_GEX_S17.filtered_feature_bc_matrix.h5 26.9 Mb (ftp)(http) H5
GSE205429_p21061-s026_RZs14_D7_Lung_GEX_S18.filtered_feature_bc_matrix.h5 37.3 Mb (ftp)(http) H5
GSE205429_p21061_s001_RMs8-GR1_BL_S9.filtered_feature_bc_matrix.h5 24.3 Mb (ftp)(http) H5
GSE205429_p21061_s002_CD68-GR1_BL_S10.filtered_feature_bc_matrix.h5 10.9 Mb (ftp)(http) H5
GSE205429_p21061_s003_RMj8-KV31_BL_S11.filtered_feature_bc_matrix.h5 20.3 Mb (ftp)(http) H5
GSE205429_p21061_s004_RMs8-CD68_D2_S12.filtered_feature_bc_matrix.h5 21.1 Mb (ftp)(http) H5
GSE205429_p21061_s005_RMj8-KV31_D2_S13.filtered_feature_bc_matrix.h5 26.6 Mb (ftp)(http) H5
GSE205429_p21061_s006_RMs8-CD68_D4_S6.filtered_feature_bc_matrix.h5 21.4 Mb (ftp)(http) H5
GSE205429_p21061_s007_RMj8-KV31_D4_S7.filtered_feature_bc_matrix.h5 21.4 Mb (ftp)(http) H5
GSE205429_p21061_s008_KV31-CD68_D7_S8.filtered_feature_bc_matrix.h5 44.1 Mb (ftp)(http) H5
GSE205429_p21061_s009_RRc17-RGo9_BL_S1.filtered_feature_bc_matrix.h5 29.8 Mb (ftp)(http) H5
GSE205429_p21061_s010_RCk17-RRj11_BL_S2.filtered_feature_bc_matrix.h5 32.3 Mb (ftp)(http) H5
GSE205429_p21206-s013_Lung_LD22_day2_GEX_S35.filtered_feature_bc_matrix.h5 14.5 Mb (ftp)(http) H5
GSE205429_p21206-s014_Lung_KV30_day2_GEX_S36.filtered_feature_bc_matrix.h5 18.8 Mb (ftp)(http) H5
GSE205429_p21206-s021_Lung_Red8_GEX.filtered_feature_bc_matrix.h5 21.5 Mb (ftp)(http) H5
GSE205429_p21206-s022_Lung_Raz8_GEX_S8.filtered_feature_bc_matrix.h5 21.9 Mb (ftp)(http) H5
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