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Preprint WatchModerateSeptember 10th, 2026

Interleukin-1 receptor antagonist is a conserved factor for exacerbating tuberculosis susceptibility

Lee, O. V.; Pathak, E.; Hernandez-Bazan, S.; Ji, D. X.; Rosa, B. A.; Jaye, D. L.; Suliman, S.; Mitreva, M.; Gabay, C.; Vance, R. E.; Kotov, D. I.

Interleukin-1 signalling promotes pulmonary control of Mycobacterium tuberculosis by amplifying TNF production in uninfected bystander cells, and IL-1 receptor antagonist expressed by Spp1+ macrophages limits that control.

Moderate contradiction

1 prior failure

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

A version 4 revision of this preprint, posted to bioRxiv on 9 September 2026, reports that enhancing interleukin-1 signalling by deleting IL-1 receptor antagonist improves control of Mycobacterium tuberculosis across three susceptible mouse models, and attributes that control to amplified TNF production by uninfected bystander cells. The Claidex graph holds one recorded TNF failure, inb03-soluble-tnf-covid19-ards-futility, in which selective neutralisation of soluble TNF in COVID-19 acute respiratory distress syndrome was stopped for futility at Phase 2/3. The two point in opposite directions on the same node. The preprint treats TNF amplification as protective in an infectious lung setting, while the failed programme treated soluble TNF as the pathogenic species in an infectious lung setting. The indications differ and the preprint is animal work, so this is a directional flag on TNF modulation in pulmonary infection rather than a contradiction of the trial result. Programmes proposing to block soluble TNF in infection-driven lung injury should account for the possibility that bystander TNF is contributing to pathogen control.

Abstract excerpt

Mycobacterium tuberculosis (Mtb) causes 1.25 million deaths a year; however, tuberculosis (TB) pathogenesis remains poorly understood. Here we find that gene signatures from three different Mtb-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice, non-human primates, and humans, but largely absent from B6 mice, was Mtb-induced Spp1+ macrophage differentiation. Spp1+ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). Here we report that enhancement of IL-1 signaling via deletion of IL-1Ra promoted bacterial control across three susceptible mouse models. We found that IL-1 signaling promotes pulmonary control of Mtb infection through amplifying TNF production by uninfected bystander cells. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved mechanism limiting Mtb control in mice, non-human primates, and humans.

Matching Claidex post-mortems

1 of 1 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.