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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 27, 2022 |
| Title |
Maximal interferon induction in the absence of influenza NS1 is infrequent owing to requirements for replication and export |
| Organisms |
Homo sapiens; Canis lupus familiaris; Influenza A virus (A/WSN/1933(H1N1)) |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Influenza A virus exhibits high rates of replicative failure due to a variety of genetic defects. As such, most viral particles cannot complete the life cycle. However, despite this failure, this virus is incredibly successful in the suppression of innate immune detection and the production of interferons, succeeding at remaining undetected in >99% of cells in tissue-culture models of infection. As the same variation that leads to replication failure can, by chance, inactivate the major innate immune antagonist in influenza A virus, NS1, what features prevent these events from triggering massive amounts of interferon production? By studying how genetic and phenotypic variation in a viral population lacking NS1 correlates with interferon production, we have built a model of the "worst-case" failure from an improved understanding of the steps at which NS1 acts in the viral lifecycle to prevent triggering of an innate immune response. In doing so, we find that NS1 prevents the detection of de novo innate immune ligands, and protects against both defective viral genomes, bearing large deletions, and viral products exported from the nucleus. Taken together, the highest level of stimulation we observe ( 97% of infected cells), requires a high level of replication in the presence of defective viral genomes with NS1 and NS1 alone from the NS segment bearing an inactivating mutation. This is incredibly unlikely to occur within the standard variation found within a viral population, and would generally require direct, artificial, intervention to achieve at an appreciable rate. Thus from our study, we procure at least a partial explanation for the seeming contradiction between high rates of replicative failure and the rarity of the interferon response to influenza infection.
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| Overall design |
A549 cells infected with either wild-type, or NS1stop, influenza A virus were processed, mixed with canine cells, fixed with methanol, and analyzed by scRNAseq. Additionally, viral populations bearing a large number of defective particles were used to infect interferon lambda reporter A549 cells, sorted on interferon production, and vRNA was sequenced to look for variation that co-enriches with interferon induction
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| Contributor(s) |
Russell AB |
| Citation(s) |
37068114 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R35 GM147031 |
Understanding evasion of cell intrinsic innate immunity in viral populations with high rates of replicative failure |
THE REGENTS OF THE UNIV. OF CALIF., UNIV. OF CALIF., SAN DIEGO |
Alistair B Russell |
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| Submission date |
Oct 17, 2022 |
| Last update date |
Apr 18, 2023 |
| Contact name |
Alistair Brian Russell |
| E-mail(s) |
a5russell@ucsd.edu
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| Organization name |
University of California, San Diego
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| Department |
Biological Sciences
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| Lab |
Russell
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| Street address |
9500 Gilman Dr,
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| City |
San Diego |
| State/province |
CA |
| ZIP/Postal code |
92161 |
| Country |
USA |
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| Platforms (2) |
| GPL25643 |
Illumina HiSeq 2500 (Canis lupus familiaris; Homo sapiens; Influenza A virus (A/WSN/1933(H1N1))) |
| GPL32752 |
Illumina NovaSeq 6000 (Influenza A virus (A/WSN/1933(H1N1))) |
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| Samples (14)
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| GSM6647283 |
High-defective virus population 1, interferon enriched, replicate 2 |
| GSM6647284 |
High-defective virus population 1, interferon enriched, replicate 3 |
| GSM6647285 |
High-defective virus population 1, interferon depleted, replicate 1 |
| GSM6647286 |
High-defective virus population 1, interferon depleted, replicate 2 |
| GSM6647287 |
High-defective virus population 1, interferon depleted, replicate 3 |
| GSM6647288 |
High-defective virus population 2, interferon enriched, replicate 1 |
| GSM6647289 |
High-defective virus population 2, interferon enriched, replicate 2 |
| GSM6647290 |
High-defective virus population 2, interferon enriched, replicate 3 |
| GSM6647291 |
High-defective virus population 2, interferon depleted, replicate 1 |
| GSM6647292 |
High-defective virus population 2, interferon depleted, replicate 2 |
| GSM6647293 |
High-defective virus population 2, interferon depleted, replicate 3 |
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| Relations |
| BioProject |
PRJNA891279 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE215914_RAW.tar |
87.4 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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