The host immune response of MOLF/Ei mice to salmonella typhimurium infection: studying the Ity2 and Ity3 loci
Bibliographic record
Abstract
Typhoid fever and salmonellosis, which are caused by Salmonella Typhi and typhimurium respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. Previous work in our laboratory has identified three loci (Ity, Ity2 and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. The MOLF/EI alleles at Ity and Ity2 are protective, while the MOLF/Ei allele at Ity3 confers susceptibility. We generated a novel cross combination between the highly susceptible strain, MOLF/Ei, and the resistant strain, 129S6, to better define the genetic architecture of susceptibility to infection in MOLF/Ei. We used microarrays and transcriptional profiling to examine the response of uninfected and infected Ity2 congenic mice. These analyses highlighted a role for both type-1-IFN and TRP53 signaling in the pathogenesis of Salmonella infection in the wild-derived MOLF/Ei mice. In order to further study the Ity3 locus, we established a congenic strain (B6.MOLF-Ity/Ity3) with the MOLF/Ei Ity3 donor segment on a C57BL/6J background, and a control B6.MOLF-Ity strain as well as 12 sub-congenic strains. We then studied these sub-congenic mice for survival. This approach indicated that the Ity3 locus is composed of two sub-loci that contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. The Ity3.1 sub-locus controls NADPH oxidase activity and is characterized by decreased ROS production, reduced inflammatory cytokine response and increased bacterial burden, thereby supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying this sub-locus. The Ity3.2 sub-locus is characterized by a hyper-responsive inflammatory cytokine phenotype after exposure to Salmonella.Lastly we used gene expression profiling to study the important genetic networks controlled by the Ity3 locus. This analysis indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (Selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus. Overall, this research provides support to the combined action of hormonal influences and complex genetic factors within the Ity2, Ity3 locus in the innate immune response to Salmonella infection in wild-derived MOLF/Ei mice.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".