Gene Expression
Nebulas
Gene Expression NebulasSummary: SARS-CoV-2 has spread globally and caused the COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 are in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected mice. Whereas Fc effector functions are fully dispensable when mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact but not LALA-PG loss of Fc effector function variant mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and enhanced tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Our study demonstrates that therapeutic neutralizing mAbs require Fc effector functions to reduce SARS-CoV-2 infection and modulate protective immune responses.
Overall Design: RNA sequencing analysis was performed with the lung homogenates of naive K18-hACE2 mice or mice infected with SARS-CoV-2 infection at 8 dpi. At 1 (D+1) or 2 (D+2) dpi, mice were given a single 200 ug dose of COV2-2050 or COV2-2050 LALA-PG via an intraperitoneal injection. Note: data for 4 of 6 naive samples were uploaded previously under GSE154104 and labeled as D0 group.
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| Treatment Protocol: | Eight-week-old mice of both sexes were administered 2.5 x 10^4 PFU of SARS-CoV-2 via intranasal administration. |
| Extract Protocol: | Total RNAs were extracted with the MagMax mirVana Total RNA isolation kit (Thermo Scientific) on the Kingfisher Flex extraction robot (Thermo Scientific). cDNA libraries were constructed from 10 ng of total RNA from lung tissues of mice. Library construction was performed using 100 ng of cDNA undergoing end repair, A tailing, ligation of universal TruSeq adapters and amplification of 8 cycles to incorporate unique dual index sequences. |
| Library Construction Protocol: | Libraries were sequenced on the NovaSeq 6000 (Illumina, San Diego, CA) targeting 40 million read pairs and extending 150 cycles with paired end reads. |
| Molecule Type: | total RNA |
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| Library Layout: | PAIRED |
| Library Strand: | - |
| Platform: | ILLUMINA |
| Instrument Model: | Illumina NovaSeq 6000 |
| Strand-Specific: | unspecific |
| Data Resource | GEN Sample ID | GEN Dataset ID | Project ID | BioProject ID | Sample ID | Sample Name | BioSample ID | Sample Accession | Experiment Accession | Release Date | Submission Date | Update Date | Species | Race | Ethnicity | Age | Age Unit | Gender | Source Name | Tissue | Cell Type | Cell Subtype | Cell Line | Disease | Disease State | Development Stage | Mutation | Phenotype | Case Detail | Control Detail | Growth Protocol | Treatment Protocol | Extract Protocol | Library Construction Protocol | Molecule Type | Library Layout | Strand-Specific | Library Strand | Spike-In | Strategy | Platform | Instrument Model | Cell Number | Reads Number | Gbases | AvgSpotLen1 | AvgSpotLen2 | Uniq Mapping Rate | Multiple Mapping Rate | Coverage Rate |
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