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Preprint WatchModerateOctober 31st, 2026

Phosphatidylserine receptors are critical for lethal infection by Crimean-Congo hemorrhagic fever virus

Berrigan, J.; Monticelli, S. R.; Ramirez, M. D.; Donovan, P. T.; Powell, T. S.; Kuehne, A. I.; Bakken, R. R.; Sulkosky, S. B.; Coyne, S. R.; Zeng, X.; Stefan, C. P.; Herbert, A. S.; Maury, W. J.; Chandran, K.; Kasikci, E.

AXL, together with TIM-1 and TIM-4, is identified as a critical phosphatidylserine receptor entry factor for Crimean-Congo haemorrhagic fever virus, with small-molecule and antibody inhibitors reducing infection in culture, single-gene knockout giving partial protection in a lethal murine challenge and double knockout giving complete protection, which the authors argue makes these receptors legitimate antiviral targets.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The two AXL programmes on file in Claidex both failed in oncology rather than in infection, which limits how much read-across applies. sitravatinib-axl-tam-post-checkpoint-nsclc-sapphire-phase3-translational-mismatch recorded a translational mismatch in which TAM-family inhibition did not reproduce its preclinical rationale in patients, and bemcentinib-axl-lung-adenocarcinoma-phase1b2-supply-termination ended before producing an efficacy answer. The relevant caution is pharmacological rather than biological. Oncology established that AXL is inhibitable and that selective AXL blockade has repeatedly failed to convert target engagement into clinical benefit, and this preprint rests on germline knockout and combined receptor loss for its strongest protection, a condition no small molecule or antibody has matched in humans. Partial protection from single-gene knockout is the result most relevant to a druggable intervention, and it was explicitly partial.

Abstract excerpt

The tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe and often fatal hemorrhagic disease for which no approved countermeasures are available. Herein, we identify the phosphatidylserine receptors (PSRs) AXL, TIM-1, and TIM-4 as critical entry host factors for CCHFV in cell lines and liver-derived primary cell cultures. Small-molecule and antibody-based PSR inhibitors greatly reduced viral infection in cell culture. Germline knockout of individual PSR genes afforded partial protection against CCHFV infection, disease, and death in a murine model of lethal viral challenge. Mice engineered to lack two PSRs were completely protected from challenge, with viremia and viral replication, pathology, and inflammation in the liver and spleen reduced to baseline. Therefore, PSRs are collectively indispensable for CCHFV infection and pathogenesis. We conclude that PSRs are not just cell entry factors but bona fide determinants of infection, dissemination, and disease by CCHFV and legitimate targets for the development of new antiviral countermeasures.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.