57 research outputs found
VARIATION OF PROTEOLYTIC CLEAVAGE SITES TOWARDS THE N-TERMINAL END OF THE S2 SUBUNIT OF THE NOVEL SARS-COV-2 OMICRON SUBLINEAGE BA.2.12.1
The prevalence of novel SARS-CoV-2 variants is also accompanied by an increased turnover
rate and additional cleavage sites at the positions necessary for priming the Spike (S) protein. Of
these priming sites, the proteolytically sensitive polybasic sequence of the activation loop at the
S1/S2 interface and the S20 location within the S2 subunit of the S protein are cleaved by furin and
TMPRSS2, which are important for the infection of the target cell. Neutrophils, migrating to the site
of infection, secrete serine proteases to fight against pathogens. The serine proteases encompass
neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG), which can hydrolyze the peptide
bond adjacent to the S1/S2 interface. SARS-CoV-2 might take the opportunity to hijack proteases
from an immune response to support viral entry to the cell. The region near S704L within the S2
subunit, a novel amino acid substitution of SARS-CoV-2 Omicron sublineage BA.2.12.1, is located
close to the S1/S2 interface. We found that NE, PR3, and CatG digested the peptide within this
region; however, the S704L amino acid substitution altered cleavage sites for PR3. In conclusion,
such an amino acid substitution modifies S2 antigen processing and might further impact the major
histocompatibility complex (MHC) binding and T cell activation
CK1δ in lymphoma: gene expression and mutation analyses and validation of CK1δ kinase activity for therapeutic application
The prognosis of lymphoid neoplasms has improved considerably during the last decades. However, treatment response for some lymphoid neoplasms is still poor, indicating the need for new therapeutic approaches. One promising new strategy is the inhibition of kinases regulating key signal transduction pathways, which are of central importance in tumorigenesis. Kinases of the CK1 family may represent an attractive drug target since CK1 expression and/or activity are associated with the pathogenesis of malignant diseases. Over the last years efforts were taken to develop highly potent and selective CK1-specific inhibitor compounds and their therapeutic potential has now to be proved in pre-clinical trials. Therefore, we analyzed expression and mutational status of CK1δ in several cell lines representing established lymphoma entities, and also measured the mRNA expression level in primary lymphoma tissue as well as in non-neoplastic blood cells. For a selection of lymphoma cell lines we furthermore determined CK1δ kinase activity and demonstrated therapeutic potential of CK1-specific inhibitors as a putative therapeutic option in the treatment of lymphoid neoplasm
Antiviral Resistance of Splenocytes in Aged Mice
We compared the susceptibility to viral infection of splenocytes, isolated from young versus old CBA mice, and evaluated the antiviral actions of lactoferrin in splenocytes infected with Encephalomyocarditis virus (EMCV). Recombinant mouse lactoferrin (rmLF) and bovine lactoferrin (bLF) were used. There were no differences in the susceptibility to EMCV infection in the studied age categories. Both types of lactoferrins were protective in young and old mice. The study confirmed the undisturbed viral resistance in old mice and the protective actions of lactoferrin in viral infection. The antiviral action of the homologous mouse lactoferrin was demonstrated for the first time
Immune phenotypes predict survival in patients with glioblastoma multiforme
Background: Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond
the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological
control in individual patients with GBM.
Methods: Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis
using flow cytometry and ELISA, respectively.
Results: Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined
marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved
survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very
short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the
relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival.
Conclusions: Defined alterations of the immune system may guide the course of disease in patients with GBM
and may be prognostically valuable for longitudinal studies or can be applied for immune intervention
Discovery and Characterization of an Endogenous CXCR4 Antagonist
CXCL12-CXCR4 signaling controls multiple physiological
processes and its dysregulation is associated
with cancers and inflammatory diseases. To
discover as-yet-unknown endogenous ligands of
CXCR4, we screened a blood-derived peptide library
for inhibitors of CXCR4-tropic HIV-1 strains.
This approach identified a 16 amino acid fragment
of serum albumin as an effective and highly specific
CXCR4 antagonist. The endogenous peptide, termed
EPI-X4, is evolutionarily conserved and generated
from the highly abundant albumin precursor by
pH-regulated proteases. EPI-X4 forms an unusual
lasso-like structure and antagonizes CXCL12-induced
tumor cell migration, mobilizes stem cells,
and suppresses inflammatory responses in mice.
Furthermore, the peptide is abundant in the urine
of patients with inflammatory kidney diseases and
may serve as a biomarker. Our results identify EPIX4
as a key regulator of CXCR4 signaling and introduce
proteolysis of an abundant precursor protein
as an alternative concept for chemokine receptor
regulation
Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients
Autoantigenic peptides resulting from self-proteins such as proinsulin are important players in the development of type 1 diabetes mellitus (T1D). Self-proteins can be processed by cathepsins (Cats) within endocytic compartments and loaded to major histocompatibility complex (MHC) class II molecules for CD4+ T cell inspection. However, the processing and presentation of proinsulin by antigen-presenting cells (APC) in humans is only partially understood. Here we demonstrate that the processing of proinsulin by B cell or myeloid dendritic cell (mDC1)-derived lysosomal cathepsins resulted in several proinsulin-derived intermediates. These intermediates were similar to those obtained using purified CatG and, to a lesser extent, CatD, S, and V in vitro. Some of these intermediates polarized T cell activation in peripheral blood mononuclear cells (PBMC) from T1D patients indicative for naturally processed T cell epitopes. Furthermore, CatG activity was found to be elevated in PBMC from T1D patients and abrogation of CatG activity resulted in functional inhibition of proinsulin-reactive T cells. Our data suggested the notion that CatG plays a critical role in proinsulin processing and is important in the activation process of diabetogenic T cells
Antiviral Resistance of Splenocytes in Aged Mice
We compared the susceptibility to viral infection of splenocytes, isolated from young versus old CBA mice, and evaluated the antiviral actions of lactoferrin in splenocytes infected with Encephalomyocarditis virus (EMCV). Recombinant mouse lactoferrin (rmLF) and bovine lactoferrin (bLF) were used. There were no differences in the susceptibility to EMCV infection in the studied age categories. Both types of lactoferrins were protective in young and old mice. The study confirmed the undisturbed viral resistance in old mice and the protective actions of lactoferrin in viral infection. The antiviral action of the homologous mouse lactoferrin was demonstrated for the first time
Regulation of MHC I Molecules in Glioblastoma Cells and the Sensitizing of NK Cells
Immunotherapy has been established as an important area in the therapy of malignant diseases. Immunogenicity sufficient for immune recognition and subsequent elimination can be bypassed by tumors through altered and/or reduced expression levels of major histocompatibility complex class I (MHC I) molecules. Natural killer (NK) cells can eliminate tumor cells in a MHC I antigen presentation-independent manner by an array of activating and inhibitory receptors, which are promising candidates for immunotherapy. Here we summarize the latest findings in recognizing and regulating MHC I molecules that affect NK cell surveillance of glioblastoma cells
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