An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19.
Reuben McGregorDaniel ChaussTilo FreiwaldBingyu YanLuopin WangEstefanía Nova-LampetiZonghao ZhangHeather TeagueErin E WestJack A BibbyAudrey KellyAmna MalikAlexandra F FreemanDaniella Muallem SchwartzDidier PortillaSusan JohnPaul LavenderMichail S LionakisNehal N MehtaClaudia KemperNichola CooperGiovanna LombardiArian Dominic John LaurenceMajid KazemianBehdad AfzaliPublished in: bioRxiv : the preprint server for biology (2020)
Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner 1,2 . Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis 3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection 4 . 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 factor 5-7 . 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.
Keyphrases
- sars cov
- induced apoptosis
- immune response
- respiratory syndrome coronavirus
- coronavirus disease
- transcription factor
- dendritic cells
- cell cycle arrest
- genome wide
- poor prognosis
- drug induced
- oxidative stress
- endoplasmic reticulum stress
- dna methylation
- single cell
- early onset
- binding protein
- signaling pathway
- cell death
- stem cells
- regulatory t cells
- artificial intelligence
- machine learning
- cell proliferation
- weight gain
- smooth muscle
- bone marrow
- toll like receptor
- electronic health record
- data analysis
- candida albicans