Sublethal Enteroviral Infection Exacerbates Disease Progression in an ALS Mouse Model
Bibliographic record
Abstract
Abstract Background: Amyotrophic lateral sclerosis (ALS) is a fatalneurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors.Infection with enteroviruses, including poliovirus and coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALSdue to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathologicalphenotypes closely resembleALS. However, a causal relationship has not yet been affirmed.Methods:Wild-type C57BL/6J and SOD1G85R ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute and/or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting atweek 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression.Results: We found that sublethal infection (mimicking chronic infection) of SOD1G85R ALS mice with CVB3 resulted inearly onset and progressive motor dysfunction, andshortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1G85R mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeksPI).Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TDP-43 pathology and neuronal damage) in the CNS of both SOD1G85R and C57BL/6J mice. Finally, wediscovered that early (day 1) but not late (day 15) administration of ribavirincould rescue ALS-like neuropathology and symptoms induced by CVB3 infection.Conclusions: Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".