Mouse genetic models of cardiovirulent coxsackievirus B3 infection
Bibliographic record
Abstract
Coxsackievirus B3 (CVB3) is a relatively common cause of infection. Infection by coxsackieviruses is typically mild and resolves quickly without lasting complications. In a subset of individuals, coxsackievirus infection can be severe, leading to permanent damage of vital organs or even death. The mouse presents an ideal model to study natural variation in response CVB3 infection as human isolates of CVB3 productively infect the mouse, and lead to similar pathologies as found in humans. Inbred strains of mice respond differently to CVB3 infection, therefore the genetic background of the host can determine susceptibility to CVB3 infection. We hypothesize that interrogation of genetically determined susceptibility to CVB3 infection will help to identify genes whose direct involvement in control of CVB3 was previously unsuspected. To characterize the contribution of host genetics to coxsackievirus, we screened a panel of recombinant congenic strains (RCS) generated from susceptible A/J and C57BL/6 progenitors. While most C57BL/6 background (BcA) strains were more susceptible than C57BL/6, BcA86 in particular was particularly susceptible to early lethality and hepatic necrosis. A segregating [BcA86xC57BL/10]F2 mapping cross led to the identification of a locus on distal chromosome 13 controlling liver damage during coxsackieviral hepatitis. Previously through the analysis of a segregating we detected the Vms1 (viral myocarditis susceptibility) locus on distal chromosome 3. Vms1 controls viral replication, inflammation and necrosis within the heart during CVB3 infection. We have further refined this locus in additional mapping crosses and congenic lines of mice. We have also determined that Vms1 controls viral replication before inflammation becomes evident within the heart. The cardiac specific kinase Tnni3k is a candidate gene for Vms1. We found that overexpression of TNNI3K greatly enhanced necrosis and inflammation in the heart following CVB3 infection. Furthermore, we found increased viral replication and gene expression and changes within isolated cardiomyocytes, indicating TNNI3K is implicated in a heart specific immune pathway. Altogether, our results provide new functional insight into the host determinants of pathogenesis following infection with coxsackievirus B3.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".