PT  - JOURNAL ARTICLE
AU  - Reuben McGregor
AU  - Daniel Chauss
AU  - Tilo Freiwald
AU  - Bingyu Yan
AU  - Luopin Wang
AU  - Estefania Nova-Lamperti
AU  - Zonghao Zhang
AU  - Heather Teague
AU  - Erin E West
AU  - Jack Bibby
AU  - Audrey Kelly
AU  - Amna Malik
AU  - Alexandra F Freeman
AU  - Daniella Schwartz
AU  - Didier Portilla
AU  - Susan John
AU  - Paul Lavender
AU  - Michail S Lionakis
AU  - Nehal N Mehta
AU  - Claudia Kemper
AU  - Nichola Cooper
AU  - Giovanna Lombardi
AU  - Arian Laurence
AU  - Majid Kazemian
AU  - Behdad Afzali
TI  - An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19
AID  - 10.1101/2020.07.18.210161
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.18.210161
4099  - http://biorxiv.org/content/early/2020/07/19/2020.07.18.210161.short
4100  - http://biorxiv.org/content/early/2020/07/19/2020.07.18.210161.full
AB  - Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner1,2. Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection4. 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 superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor5–7. 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 hyperinflammation in severe COVID-19.Competing Interest StatementThe authors have declared no competing interest.