An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19
Erin E West,
Alexandra F. Freeman,
Michail S Lionakis,
Posted 19 Jul 2020
bioRxiv DOI: 10.1101/2020.07.18.210161
Posted 19 Jul 2020
Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner. Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection. The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-γ producing CD4+ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-γ+ Th1 cells to suppressive IL-10+ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor. Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4+ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4+ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyper-inflammation in severe COVID-19. ### Competing Interest Statement The authors have declared no competing interest.
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