Biology subjects

Kari, S.

Publications and source records attributed to Kari, S..

3 recordsLinked to original sources

bioRxiv2024

An ATP-Binding Cassette Transporter Gene Links Innate and Adaptive Immune Responses

Positive-strand RNA viruses and DNA viruses generate double-stranded RNA (dsRNA) during their replication processes and innate immune responses against viral infections are orchestrated by numerous interferon-stimulating genes, yet the detailed coordination of downstream signaling of anti-viral immune responses is not fully understood. Recent studies suggest 2-5- Oligoadenylate Synthetase 1 (OAS1) may have a protective role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections; however, the mechanism regulating OAS1 remains uninvestigated. Our aim is to understand the regulation of OAS1 and its modulation of RNaseL activity, as this has significant implications for responses to RNA viruses, including Vesicular stomatitis virus (VSV) and SARS-CoV-2. We explore the hypothesis that ABCF1 an ATP-binding cassette family member protein, a key regulator of innate immune responses and macrophage polarization and cytokine storm, play a role in regulating the antiviral responses and downstream dsRNA signaling revealed by measuring responses to the synthetic dsRNA analog termed poly (I:C). We utilize ABCF1 haplo-insufficient mice to discover that ABCF1 modulates the amplitude and frequency of VSV-specific Cytolytic T lymphocyte in anti-viral immune responses and suggests that innate immune responses underpin this process. To understand this mechanism, we describe that ABCF1 interacts with 2-5-oligoadenylate synthetase 1 (OAS1) which in turn modulates essential proteins that leads to the modulation of RNaseL activity via ABCE1. Furthermore, we find that ABCF1 also influences the production of interferon- (IFN-) and interferon-{beta} (IFN-{beta}) in bone marrow-derived macrophages. Overall,, we unexpectedly discovered that ABCF1 acts as a crucial link between innate and adaptive immunity, regulating the development of adaptive Cytolytic T lymphocyte responses and interacting with OAS1, a key regulator of innate immune responses against viral infections. Exploring pharmacological agents that target ABCE1 or ABCF1 may lead to the discovery of novel modalities for countering SARS CoV-2 and other viruses where OAS1 is a crucial innate immune response gene.

immunology↗

bioRxiv2023

CITE-seq reveals inhibition of NF-kB pathway in B cells from vitamin D-treated multiple sclerosis patients

Vitamin D deficiency is a recognized risk factor for multiple sclerosis (MS) and has been associated with disease activity and progression. Vitamin D treatment has emerged as potentially protective, despite conflicting results from randomized controlled trials. Here, we used single-cell RNA-sequencing (scRNA-seq) combined with barcoded antibodies targeting surface markers (CITE-seq) to uncover candidate genes and pathways regulated in PBMC subpopulations from MS patients receiving high-dose vitamin D (n=5) or placebo (n=5). Best candidates were combined with genes involved in immune function and vitamin D metabolism for validation in a new cohort (n=8 in each group) by high-throughput quantitative polymerase chain reaction (HT-qPCR) in FACS-sorted naive CD4, Th1, Th17, Treg, naive CD8, memory and naive B cells, and MAIT cells. CITE-seq revealed no significant changes in the proportions of these subpopulations in response to vitamin D treatment. Out of the 92 candidate genes identified by CITE-seq, we validated differential expression of five genes (UXT, SNRPN, SUB1, GNLY and KLF6) using HT-qPCR. Furthermore, CITE-seq uncovered vitamin D-induced regulation of several pathways in naive and memory B cells, including MAPK, TLR and interleukin pathways, that may contribute to counteract Epstein-Barr virus (EBV)-induced resistance to apoptosis, notably through inhibition of the NF-{kappa}B pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/559400v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1ad28c1org.highwire.dtl.DTLVardef@14ed135org.highwire.dtl.DTLVardef@188fea1org.highwire.dtl.DTLVardef@105353c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2022

A Binary RNA and DNA Self-Amplifying Platform for Next Generation Vaccines and Therapeutics

Conventional mRNA-based vaccines were instrumental in lowering the burden of the pandemic on healthcare systems and in reducing mortality. However, such first-generation vaccines have significant weaknesses. Here, we describe a high-performance binary recombinant vectoral platform offering the flexibility to be used as a self-amplifying mRNA or a self-amplifying DNA. Both formats drive long-lasting expression and actuate robust antibody responses against SAR-CoV-2 spike, and neither format require encapsulation with lipid nanoparticles (LNP) in the generation immune responses. The platform combines the power of conventional mRNA with the low-dosage of self-amplifying vectors together with the simplicity, rapid creation, ease of storage, and convenience of distribution of plasmid DNA vectors. This platform promises to pave the way for more effective, less expensive, and truly democratized vaccines and therapeutics. One-Sentence SummaryGemini: a versatile platform that improves on existing vaccine formats in terms of effectiveness, manufacturing, distribution, and cost.

immunology↗