Herpesviruses Enhance Fibrinogen Clot Lysis.
Bibliographic record
Abstract
Abstract Abstract 1153 Background: Members of the Herpesvirus family have been implicated in vascular disease. To explain the correlation on a molecular basis we have shown that the virus envelope contains anionic phospholipid derived from host cells, and proteins encoded by the host (tissue factor) as well as the viral (glycoprotein C) genomes, which initiate blood coagulation. This suggests that virus infection should be a strong independent predictor of vascular disease. Nevertheless, the clinical correlation is relatively weak, becoming more significant in combination with other risk factors. To explain this discrepancy, the current work is based on our additional report that at least one Herpesvirus (cytomegalovirus (CMV)) has host-genome-encoded annexin II on its surface. Annexin II is known to accelerate tissue plasminogen activator (tPA)-mediated activation of plasminogen to plasmin because of C-terminal lysines that interact with both plasminogen and tPA. Plasmin is the primary fibrinolytic protease, and is necessary for physiological clot dissolution. Thus, these viruses may facilitate clearance of the fibrin they generate. Hypothesis: We hypothesize that Herpesviruses enhance tPA-mediated plasmin generation and this mechanism correlates to the presence of annexin II on the virus. Methods: Purified herpes simplex virus type 1 (HSV1) and 2 (HSV2) and CMV were quantified by electron microscopy. Annexin II expression varies between cell types, therefore HSV1 was propagated in several cell lines. Virus-dependent plasmin generation was followed in the presence of purified plasminogen and tPA using a chromogenic assay. The contribution of viruses to fibrin clot lysis using purified proteins was investigated by light scattering. Plasminogen-conjugated horse radish peroxidase (plasminogen-HRP) and western blots were used to identify plasminogen-binding species and annexin II associated with the virus, respectively. The effect of plasmin-mediated signalling on virus infection was determined using cytopathic plaque assays. Results: Chromogenic experiments demonstrated that HSV1, HSV2 and CMV enhanced plasminogen activation in a dose-dependent manner by up to 5-fold, regardless of the parental cell line. Prolonged incubation confirmed the requirement for exogenous tPA. Plasminogen-HRP bound to a number of virus-associated proteins and was shown to be C-terminal lysine-dependent by complete inhibition with epsilon-aminocaproic acid (EACA). Annexin II was demonstrated to be associated with purified HSV1 cultured in different cells except when propagated in a melanoma (A7) line that did not express annexin II. An annexin II antibody inhibited binding of plasminogen-HRP to viral annexin II. HSV1, HSV2 and CMV accelerated fibrin clot lysis, which was inhibited in the presence of EACA and aprotinin, a plasmin inhibitor. However, in contrast to the chromogenic experiment for plasmin generation, each virus also exhibited a clot lysis mechanism independent of added tPA. As we have previously identified for thrombin, incubation of host cells with purified plasmin during inoculation enhanced virus infection by over 3-fold. Conclusion: Cumulatively these data demonstrate that HSV1, HSV2 and CMV accelerate tPA- mediated plasmin generation in the absence of fibrin and identify annexin II as one of several plasminogen binding partners. These viruses furthermore enhance the rate of fibrin clot lysis. However, in the presence of fibrin, purified HSV1, HSV2 and CMV are capable of facilitating clot dissolution in the absence of exogenous tPA. The molecular basis for this novel mechanism is not yet known, but requires plasminogen activation. The finding that purified plasmin enhances infection suggests these viruses may have evolved to initiate plasmin generation. Hence, the virus-mediated activation of fibrinolysis may compensate for its ability to trigger coagulation and attenuate potential contributions as an independent predictor of vascular disease. Disclosures: No relevant conflicts of interest to declare.
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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) | 0.004 | 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".