Mouse chemical mutagenesis to identify new immune mechanisms against cytomegalovirus and herpes simplex virus 1
Bibliographic record
Abstract
Herpes simplex virus 1 (HSV-1) and cytomegalovirus (CMV) are ubiquitous and very prevalent pathogens.Infections with these agents result in a variety of clinical syndromes, ranging from asymptomatic to severe infection, with high mortality rates and significant long-term morbidity, particularly in vulnerable in immunocompromised or immature populations.The use of inbred mouse strains that accurately replicate disease and exhibit natural genetic variation in susceptibility has been particularly useful to understand fundamental mechanisms of virus disease pathogenesis.Further, random chemical mutagenesis with N-Ethyl-N-Nitrosourea (ENU) is a powerful tool to identify new mutations on genes and pathways critical to immunity.We have developed an ENU mutagenesis platform followed by a high-throughput infection pipeline allowing us to screen a high number of mice for susceptibility to either CMV or to HSV-1 infection.We generated and tested more than 264 pedigrees, for a total of 4200 animals for gained susceptibility to infection.Doing so, we found 6 families exhibiting susceptibility to HSV-1 and 1 to CMV.We selected one pedigree susceptible to HSV-1 for further analysis.We found a non-synonymous mutation in the linker domain (LD) of STAT5A (W484G).CD8+ T cells and NK cell responses were affected in STAT5A W484G mice, as their numbers were reduced following infection with HSV-1, as were the antigen experienced CD44+ CD8+ T cells.After stimulation with IL-2, which is mediated in part by STAT5A, NK cells did not increase the expression of IL-2Rβ as much as wild type mice, while the expression of IL-2Rα on CD4 and CD8 T cells was abrogated.These results show that STAT5A is important to the T cell and NK cell immune responses to HSV-1 and CMV infection and a single point mutation in its LD is sufficient to compromise STAT5A function.We also analysed a pedigree susceptible to CMV and identified a critical mutation on the uncharacterized GTPase GNL1.NK cells, which play a non-redundant role in CMV resistance, were drastically reduced in mutant animals, causing viral susceptibility.NK cells also exhibited an increase in caspase 3 activity accompanied with a dysfunctional cell cycle progression after IL2 and IL15 stimulation, two cytokines critical for NK cell GNL1 deficiency affects the integrity of the main immune organs ...................................The absence of GNL1 leads to a NK deficiency .......
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".