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Revealing differential type I and type II IFN responses in different immune cells in various human diseases by a new IFNs transcriptomic atlas

ABSTRACT: Interferons (IFNs) are key cytokines mediating broad immunological responses in diverse processes including host defense, autoimmune diseases, and cancer. To gain single cell resolution in response to different IFNs in different human immune cells, we generated a new single-cell transcriptomic dataset in various human immune cell subsets by stimulating with IFN-α, IFN-β, IFN-γ, and IFN-λ1. We not only found classical IFN stimulated genes (ISGs) highly elevated across multiple immune cell subsets, but each immune cell subset also displayed unique gene sets in response to IFN-α or IFN-γ stimulation. Furthermore, expression fold changes of many ISGs shared between IFN-α and IFN-γ were different, which prompted us to utilize those unique features to generate a new scoring method. To obtain a comprehensive view of type I & II IFN responses from many different human diseases, we applied our tool to several published scRNAseq datasets from patients with known elevated IFN responses. We also applied this to a new cohort of newly diagnosed multiple myeloma (NDMM) patients and ran a cross-sectional and a longitudinal analysis to explore IFN responses in NDMM compared to healthy and NDMM after induction therapies, with or without daratumumab. We found higher circulating protein levels of IFN-α2A, IFN-β, and IFN-γ, and higher type I and type II IFN scores across all circulating immune cells in NDMM. Induction therapies only decreased type I IFN responses, especially in CD14 monocytes, and circulating IFN-α. Both known ISGs and novel cell-type specific ISGs from our ex vivo dataset could be recapitulated in in vivo NDMM. Our work provides insights into immune cell-type specific responses to IFNs and a new level of clarity to dissect different IFN responses from human diseases. With our cloud-based explorers, this new tool can be easily used by many others to further expand human IFN research.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306664 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:To investigate the early host response triggered by three different strains of Trypanosoma cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes (ISGs) was observed in excised skin 24 hours post-infection where the level of ISG induction was parasite strain-dependent with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFNÎ³-producing cells or infection of IFNÎ³-deficient mice had minimal impact on the IFN response generated in T. cruzi infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi the site of inoculation and their role in shaping the early transcriptional response to this pathogen. We used microarrays to detail the local host transcriptional response to intradermal T. cruzi infection in WT mice and mice depleted of NK cells, or deficient in IFN-gamma or type I IFN responses. Additionally we compared the local host-transcriptional response generated to infection with 3 different strains of Trypanosoma cruzi (Y, Brazil, and G). Experiment Overall Design: Mice were infected by intradermal injection of 10^6 T. cruzi trypomastigotes in 100uL of saline split between 2 adjacent sites on the shaved side flank. Control mice were injected with an equal volume of saline. 24 hours post-injection approximately 75mm^2 of skin immediately surrounding the injection site was excised and RNA was isolated from the tissue. Balb/c mice were used for most experiments and IFN-gamma KO mice were on the Balb/c background. WT 129 mice were also used as IFNAR-/- mice were on the 129 background. In total 33 arrays were performed. 7 WT (Balb/c) control, 3 Y strain infected, 3 Brazil strain infected, 3 G strain infected, 2 IFN-gamma KO control, 2 IFN-gamma KO infected, 1 NK cell depleted control, 1 NK cell depleted infected, 3 WT (129) control, 3 WT (129) infected, 3 IFNAR KO control, 3 IFNAR KO infected

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Revealing differential type I and type II IFN responses in different immune cells in various human diseases by a new IFNs transcriptomic atlas

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