Differential time-restricted sensitivity of enveloped viruses to Sec61 translocon blockade
Bibliographic record
Abstract
Abstract The morphogenesis of enveloped viruses relies on the trafficking of transmembrane proteins through the secretory pathway to sites of virus envelopment. The first step in this pathway, their translocation into the endoplasmic reticulum, is therefore an attractive target for broad-spectrum intervention. Here, we tested if blockade of the Sec61 translocon by the Mycobacterium ulcerans exotoxin mycolactone, a potent inhibitor of Sec61, could block the production of virus glycoproteins and subsequent production of infectious virus from a range of human enveloped viruses: the DNA virus herpes simplex virus 1 (HSV1), and the RNA viruses, respiratory syncytial virus (RSV), influenza A virus (IAV), SARS coronavirus 2 (SARS CoV2) and Zika virus (ZIKV). In line with known translocation mechanisms, mycolactone blocked in vitro translocation and ectopic expression of type I transmembrane proteins but not type III, multipass or cytosolic proteins. Translocation of the type II protein RSV G was also blocked and although ectopically expressed G protein was detected, it was not glycosylated. Pretreatment of cells with mycolactone also blocked the synthesis of type I transmembrane proteins in infected cells and either the synthesis or glycosylation of type II transmembrane proteins, and the production of progeny from all viruses tested, while having no effect on virus entry or downstream synthesis of cytosolic proteins. While mycolactone treatment of HSV1 infected cells at various times after infection resulted in the immediate inhibition of virus production at the point of addition, IAV, RSV and ZIKV became resistant to the action of mycolactone surprisingly early in infection, and before virus glycoprotein synthesis was even detectable or virus production had begun. We therefore conclude that although inhibition of the translocation of virus transmembrane proteins through the Sec61 translocon can in principle block virus production, the morphogenesis of many enveloped RNA viruses requires only limited amounts of envelope proteins for successful propagation, providing novel insight into the biology of these viruses. Author Summary Many circulating human pathogens are enveloped viruses that all use the cellular secretory pathway to target their envelope proteins to cellular sites of virus particle assembly. The potential to target this pathway could therefore offer a novel broad-spectrum therapy for existing, emerging and as yet unknown human pathogens. Here we have targeted the initial step in this pathway using a highly potent Sec61 inhibitor, mycolactone, to carry out the first comprehensive assessment of translocation disruption on a range of enveloped human viruses from different virus families, including herpes simplex virus, influenza A virus and SARS-CoV2. Our results have shown that Sec61 inhibition blocks the onward trafficking of many virus envelope proteins that are essential to produce infectious virus at assembly sites. However, unexpectedly, we found that several of the viruses were resistant to the effects of this toxin when it was added early in infection, indicating that the synthesis of these essential virus proteins occurs earlier in infection than previously recognised. Hence, while this approach may not be suitable as a broad intervention strategy, it has revealed new information on virus biology and provides us with a novel tool for exploring a wide range of enveloped viruses.
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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 | 0.000 |
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".