The CRAC channel inhibitor Auxora interrupts inflammatory circuits between alveolar macrophages and T cells in patients with viral pneumonia
Casalino-Matsuda, S. M.; Guggilla, V.; Gao, C. A.; Demeulenaere, K. E.; Cusick, L. P.; Fenske, S. W.; Yu, Z.; Lu, Z.; Swaminathan, S.; Grant, R. A.; Schleck, M. J.; Prakriya, M.; Hebbar, S.; Stauderman, K.; Donnelly, H. K.; Pickens, C.; Morales-Nebreda, L.; The NU SCRIPT Study Investigators, ; Wunderink, R. G.; Misharin, A. V.; Singer, B. D.; Budinger, G. S.
Show abstract
Viral pneumonia is perpetuated by inflammatory circuits between activated T cells and monocyte-derived alveolar macrophages (MoAM). T cells and macrophages express ORAI1 and STIM1, which form calcium release-activated calcium (CRAC) channels that allow extracellular calcium entry in response to endoplasmic reticulum calcium store depletion. In a randomized, placebo-controlled, multicenter phase 2 trial (CARDEA), Auxora, a CRAC channel inhibitor, reduced all-cause 30-day mortality by 56% in patients with severe SARS-CoV-2 pneumonia. Here, we report a multi-omics analysis of serially collected alveolar samples from unvaccinated patients with severe SARS-CoV-2 pneumonia treated with Auxora versus placebo. We found reductions in plasma levels of the monocyte- and T cell-chemokines, CCL8 and PDGF-AA. Using peripheral blood mononuclear cells (PBMC) from healthy volunteers, we show that Auxora directly targets T cells to inhibit the transcription of CCL8 and PDGFA in monocyte-derived macrophages, supporting a mechanism for its effects and a potential intermediate biomarker of efficacy.
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