Biology subjects

Pfeifer, C. G.

Publications and source records attributed to Pfeifer, C. G..

5 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

Phagocytosis in macrophages is regulated by the ATP-binding cassette family gene ABCF1

Phagocytosis is a conserved biological mechanism that is integral to tissue remodeling, clearance of apoptotic cells, and immune defense in animals. Additionally, it serves as a pivotal means of sustenance for diverse unicellular eukaryotes. In the context of mammals, this crucial role is fulfilled by specific cell types such as macrophages, monocytes, dendritic cells, and neutrophils. It is orchestrated by an array of receptors, kinases, cytoskeletal elements, and enzymes, working collaboratively to enable the recognition, engulfment, and internalization of particles. Despite its profound significance, the intricate mechanisms underpinning the regulation of this phenomenon remains enigmatic. In this study, we present compelling evidence indicating the involvement of ABCF1, a member of the ATP-binding cassette family, in the Fc{gamma}RIIA phagocytic pathway. ABCF1s contribution lies in facilitating downstream signal activation through interactions with Src family members and SYK, pivotal players in this cascade. Additionally, our findings highlight ABCF1s essentiality in the biosynthesis of various SFKs (Src family kinases) and MAPKs (mitogen-activated protein kinases). These molecules collectively oversee the orchestration of phagocytic cup formation, a pivotal step governing the engulfment process within macrophages. Consequently, the regulation of ABCF1 presents a potential avenue for modulating phagocytosis, allowing for the precise modulation of this fundamental process to either enhance or attenuate according to the specific physiological demands.

immunology↗

bioRxiv2023

Complete Synthesis and Stereochemical Assignment of Novel Curcuphenol Analogues Possessing Anti-Metastatic Cancer Biological Activity

For eons, turmeric and curcumin have been used as culinary spices and as traditional medicines and as vogue dietary supplements for a growing list of disorders, including arthritis, digestive disorders, respiratory infections, allergies, liver disease, depression and cancer. The activities of these spices are commonly attributed to curcuminoids; however, the medical applications of this class of compounds has been limited due to the low water solubility, chemical instability, acid lability, poor absorption, rapid catabolism by enzymes of the diverse curcuminoids contained in turmeric and curcumin extracts. Furthermore, identifying the bio-active curcuminoids with unique molecular entities responsible for specific medicinal benefit is at its infancy. To overcome these many issues and substantially advance this area of inquiry, we created a water-soluble achiral curcuphenol analogue and a water-soluble racemic analogue that have enhanced chemical characteristics and biological performance, and we subsequently demonstrated their ability to reverse the immune-escape phenotype, a process that enables tumours to hide from host immune responses and thereby provides tumours a significant growth advantage to metastatic tumours. The discovery that curcuphenols can reverse tumour immune-escape mechanisms and thereby reduce tumour growth, provides a rationale for the development of advanced dissecting nutraceuticals and bioceuticals for unique chemical entities as therapeutic building blocks to synthesize analogues with optimal chemical characteristics capable of harnessing the power of the immune system to extinguish metastatic cancers and beyond.

biochemistry↗

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↗

bioRxiv2019

Mutation of an L-Type Calcium Channel Gene Leads to a Novel Human Primary Cellular Immunodeficiency

Human primary immunodeficiencies are inherited diseases that can provide valuable insight into the immune system. Calcium (Ca2+) is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and Cav channels. Here we describe three Cav1.4-deficient siblings presenting with X-linked incomplete congenital stationary night blindness as well as an immune phenotype characterized by several recurrent infections. Complete exome sequencing demonstrated that the patients share only a single pathogenic allele; a R625X (p.Arg625Ter) point mutation that leads to a premature stop codon in the CACNA1F gene encoding the L-type Ca2+ channel Cav1.4. The subjects uniformly exhibited an expansion of central and effector memory T lymphocytes, and evidence of T lymphocytes exhaustion with corresponding upregulation of inhibitory receptors. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Finally, the T lymphocytes from patients and CACNA1F knockdown Jurkat T lymphocytes exhibited a reduced Ca2+ flux, compared to controls. This is the first example where the mutation of any Cav channel causes a primary immunodeficiency in humans and establishes the physiological importance of Cav channels in the human immune system.

immunology↗