Author response: Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection
Bibliographic record
Abstract
The immune system protects an individual from invading bacteria, viruses and parasites, as well as malfunctioning or cancerous host cells. However, some people inherit genetic defects that cause part of the immune system to be missing or to not work properly. This is called a genetic immunodeficiency, and puts individuals at a higher risk of infection and disease. The symptoms of immunodeficiencies can vary substantially between individuals, even when they have defects in the same gene. For example, only some of the individuals who have defects in both of their copies of a gene called HOIL-1—which has been linked to several roles in the body's immune response—are reported to suffer from an altered susceptibility to bacterial infections and chronic (persistent) inflammation. Gaining a clear understanding of the possible factors that influence such variations in the symptoms of genetic immune deficiencies could help to speed up their diagnosis, as well as helping to develop more effective treatments. MacDuff et al. studied mice that had mutations in both copies of the mouse equivalent of the HOIL-1 gene. These mice, when raised in a clean barrier facility that reduces their exposure to viruses, were severely immunodeficient and died when infected by certain bacteria and parasites, including Listeria monocytogenes. However, they were able to tolerate infections with a herpesvirus or the bacterium that causes tuberculosis. The immunodeficiency to L. monocytogenes was linked to problems producing protective molecules called cytokines, which form a crucial part of the immune response. Unexpectedly, MacDuff et al. found that a chronic herpesvirus infection substantially protected these very immunodeficient animals from infection with Listeria monocytogenes, and the mice were able to efficiently produce protective cytokines. Mice with two other distinct genetic deficiencies that affect their immune system were also better able to survive otherwise lethal bacterial infections if they had a long-term herpesvirus infection. Macduff et al. suggest that the chronic herpesvirus infection stimulates the immune system, and so allows it to compensate for the lack of cytokine production associated with various immunodeficiencies, including those caused by mutations in the HOIL-1 gene. This suggests that the presence of viruses or other long-term infections may be responsible for some of the variability seen in the symptoms of different individuals with the same genetic immunodeficiency. This is an important concept since essentially all humans have life-long chronic infections from various herpesviruses, as well as other viruses that form the human virome.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.003 | 0.003 |
| Insufficient payload (model declined to judge) | 0.354 | 0.168 |
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".