The role of autophagy in innate immunity to intracellular bacterial pathogens
Bibliographic record
Abstract
Autophagy is a cytosolic degradation pathway responsible for delivering proteins and organelles to the lysosome for degradation. Recently, this pathway has been shown to be an important component of innate immunity. In this thesis, I study two intracellular pathogens with very different lifestyles and compare how they interact with autophagy. Salmonella enterica serovar Typhimurium is a vacuole-adapted pathogen that replicates in the Salmonella -containing vacuole (SCV) in host cells. During in vitro infection of epithelial cells, a population of bacteria damages the SCV and replicates in the cytosol. I show here that bacteria in damaged SCVs are targeted by autophagy. This serves to protect the cytosol from bacterial colonization and restricts bacterial replication in this cell-type. Furthermore, damage to the SCV membrane appears to act as a signal to recruit autophagy. Listeria monocytogenes is a cytosol-adapted pathogen that lyses the phagosome and replicates in the cytosol. Listeriolysin O (LLO) and bacterial phospholipases C (PLCs) form pores in the phagosomal membrane to mediate this escape. Once in the cytosol, L. monocytogenes expresses ActA to mediate actin-based motility and intercellular spread. In macrophages, a significant population of bacteria is targeted by autophagy during phagosomal escape in an LLO-dependent manner. However, once in the cytosol, L. monocytogenes is able to evade autophagy. ActA is sufficient but not necessary for autophagy evasion. Accordingly, bacterial PLCs also play a role in autophagy evasion. During infection of macrophages, we observed that a small population of L. monocytogenes replicates in Spacious Listeria -containing Phagosomes (SLAPs). LLO is essential for SLAP formation and inhibits the maturation of these compartments by forming pores in the SLAP membrane. Furthermore, we found that impaired LLO expression allows slow bacterial replication in vacuoles in an autophagy-dependent manner. Therefore, SLAPs appear to represent a 'stalemate' between bacterial virulence (LLO activity) and host innate immunity (autophagy). SLAP-like structures were observed during persistent L. monocytogenes infection of immuno-deficient mice. This work provides insights into signals that target autophagy to intracellular pathogens and mechanisms by which pathogens have evolved to evade this innate immune mechanism. Furthermore, this research suggests a possible mechanism for the establishment of persistent infection.
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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 | 0.001 | 0.000 |
| 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 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".