NOD2 mediates innate and adaptive immunity to «Mycobacterium avium paratuberculosis»
Bibliographic record
Abstract
Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of paratuberculosis, a chronic granulomatous enteritis of ruminants. MAP has been specifically and significantly associated with Crohn's disease (CD), a human enteritis with similarities to paratuberculosis. While these observations do not attest to causality of disease, they have potentiated efforts to investigate whether CD-susceptibility genes play a role in MAP infection. Specifically, our interests lie in the gene NOD2. NOD2 is part of the NOD-like receptor family and is involved in innate recognition of muramyl dipeptide (MDP), a component of bacterial peptidoglycan. Interestingly, CD-associated polymorphisms abrogate this response. In addition, NOD2 appears to be especially sensitive to mycobacterial MDP; thus we hypothesized that NOD2 would play a role in control of MAP infection. Using Nod2-/- mice as models of human NOD2 deficiency, we tested ex vivo and in vivo bacteriological, immunological and pathological phenotypes in response to MAP infection. Stimulation of peritoneal Nod2-/- macrophages revealed impaired innate recognition of MAP, a phenotype not seen when using Escherichia coli. Furthermore, we consistently observed higher burdens of MAP (~0.3 log) in Nod2-/- macrophages cell culture at 5 days post-infection; E. coli intracellular growth was NOD2-independent. Four weeks following intraperitoneal MAP infection, NOD2 disruption led to weakened adaptive immune responses towards infection as evidenced by diminished MAP-specific IFN-γ producing cells. Moreover, Nod2-/- splenocytes provided no anti-mycobacterial benefit in MAP-infected macrophage co-culture, as opposed to Nod2+/+ splenocytes which were directly responsible for a ~0.5 log reduction in MAP burden. During long-term investigations, we observed mesenteric adenitis, but no gut pathology following a 1 year MAP-infection in Nod2+/+ and Nod2-/- and a 6 month infection in Cybb-/- mice, despite isolation of organisms from mesenteric lymph nodes. In contrast, Irf-1-/- mice showed impaired elimination of MAP. Taken together, NOD2 is involved in control of intracellular growth of MAP and disruption leads to impaired innate and adaptive immune responses towards MAP infection. The subtle nature of this pathogen indicates that Nod2-/- and Cybb-/- are unlikely to serve as tractable murine models of paratuberculosis. However, Irf-1 disruption did lead to enhanced persistence of MAP.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".