Abstract
Novel coronavirus disease 2019 (COVID-19) has emerged as a global pandemic with far-reaching societal impact. Here we demonstrate that Pin1 is a key cellular molecule necessary for severe ...acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagation. In this study, siRNA-mediated silencing of Pin1 expression markedly suppressed the proliferation of SARS-CoV-2 in VeroE6/TMPRSS2 cells. In addition, several recently generated Pin1 inhibitors showed strong inhibitory effects on SARS-CoV-2 proliferation, measured by both viral mRNA and protein synthesis, and alleviated the cytopathic effect (CPE) on VeroE6/TMPRSS2 cells. One compound, termed H-77, was found to block SARS-CoV-2 proliferation at an EC
50
below 5 μM regardless of whether it was added to the culture medium prior to or after SARS-CoV-2 infection. The inhibition of viral N protein mRNA synthesis by H-77 implies that the molecular mechanism underlying SARS-CoV-2 inhibition is likely to be associated with viral gene transcription or earlier steps. Another Pin1 inhibitor, all-trans retinoic acid (ATRA)—a commercially available drug used to treat acute promyelocytic leukemia (APL) and which both activates the retinoic acid receptor and inhibits the activity of Pin1—similarly reduced the proliferation of SARS-CoV-2. Taken together, the results indicate that Pin1 inhibitors could serve as potential therapeutic agents for COVID-19.
Peptidyl-prolyl isomerase (PPIase) is a unique enzyme that promotes cis-trans isomerization of a proline residue of a target protein. Peptidyl-prolyl cis-trans isomerase NIMA (never in mitosis ...A)-interacting 1 (Pin1) is a PPIase that binds to the pSer/pThr-Pro motif of target proteins and isomerizes their prolines. Pin1 has been reported to be involved in cancer development, obesity, aging, and Alzheimer’s disease and has been shown to promote the growth of several viruses including SARS-CoV-2. Pin1 enhances the efficiency of viral infection by promoting uncoating and integration of the human immunodeficiency virus. It has also been shown that Pin1 interacts with hepatitis B virus proteins and participates in viral replication. Furthermore, Pin1 promotes not only viral proliferation but also the progression of virus-induced tumorigenesis. In this review, we focus on the effects of Pin1 on the proliferation of various viruses and discuss the underlying molecular mechanisms.
Economic Burden of Hepatitis in South Korea Watson, Hugh; Minini, Pascal; Encinas, Jeffrey
Japanese Journal of Infectious Diseases,
2016, Letnik:
69, Številka:
4
Journal Article
Spleen tyrosine kinase (Syk) is associated with Fcγ receptors (FcγRs) and transmits activation signals through FcγRs in myeloid cells. Thus, application of drugs to inhibit Syk activity can affect ...the development of immune diseases mediated by autoantibodies, while unexpected systemic effects by the inhibition may be concerned because Syk has multiple physiological functions. We used tamoxifen-inducible systemic conditional Syk knockout (KO) mice to evaluate the role of Syk in the pathogenesis of autoimmune arthritis and to investigate the systemic effects of Syk deletion. In a collagen antibody-induced arthritis model, Syk KO mice were almost completely protected from disease induction and showed significantly attenuated accumulation of neutrophils and macrophages in the joints. Syk-deleted macrophages showed less IL-6 and MCP-1 production upon FcγR ligation and exhibited reduced FcγR-mediated phagocytosis in vitro. Syk-deleted macrophages produce more RANTES upon FcγR ligation, indicating a Syk-independent signaling through the FcγR. We further found that both wild-type and Syk-deleted macrophages induced neutrophil chemotaxis upon FcγR ligation in vitro, and air-pouch model demonstrated that Syk-deleted neutrophils have a potential to infiltrate into local tissues in response to collagen and anti-collagen antibodies. However, Syk-deleted neutrophils exhibited greatly decreased neutrophil extracellular traps formation and FcγR-mediated phagocytosis. Our results indicated that Syk deficiency rendered mice completely unresponsive to immune activation by anti-collagen antibodies with disabling one pathway of FcγR-mediated signaling that was crucial for arthritis induction.
SJL mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) peptide 139-151, whereas H-2 congenic B10.S mice are resistant. ...Immunodominance and susceptibility to EAE are associated with a high precursor frequency of PLP 139-151-specific T cells in the naïve repertoire of SJL mice. To understand the mechanism of EAE resistance in B10.S mice, we determined the precursor frequency of PLP 139-151-reactive T cells in both strains by using IA s/ PLP 139-151 tetramers. SJL and B10.S mice had similar frequencies of tetramer-reactive T cells in the naïve peripheral repertoire. However, in SJL mice, the majority of PLP 139-151 tetramer-positive cells were in the CD4+ CD25- population, whereas there were more tetramer-positive cells in the CD4+ CD25+ population of B10.S mice. Depletion of CD4+ CD25+ cells in vivo facilitated the expansion of PLP 139-151-reactive cells with production of T helper 1 cytokines in EAE-resistant B10.S mice. Furthermore, anti-CD25 Ab treatment before immunization resulted in EAE induction in these otherwise resistant mice. These data indicate an important role for autoantigen-specific CD4+ CD25+ cells in genetic resistance to autoimmunity.
AMP and adenosine are found in all cell types and can be released by cells or created extracellularly from the breakdown of
ATP and ADP. We have identified an orphan G protein-coupled receptor with ...homology to the P2Y family of nucleotide receptors
that can respond to both AMP and adenosine. Based on its ability to functionally bind the nucleotide AMP, we have named it
P2Y15. Upon stimulation, P2Y15 induces both Ca 2+ mobilization and cyclic AMP generation, suggesting coupling to at least two different G proteins. It is highly expressed
in mast cells and is found predominantly in the tissues of the respiratory tract and kidneys, which are known to be affected
by AMP, adenosine, and adenosine antagonists. Until now, the effects of AMP have been thought to depend on its dephosphorylation
to adenosine but we demonstrate here that P2Y15 is a bona fide AMP receptor by showing that it binds 32 PAMP. Because AMP and adenosine have bronchoconstrictive effects that can be inhibited by theophylline, we tested whether
theophylline and other adenosine receptor antagonists can block P2Y15. We found inhibition at a theophylline concentration
well within the therapeutic dose range, indicating that P2Y15 may be a clinically important target of this drug.
The T-cell Ig and mucin domain-containing (TIM) gene locus has been linked to differences in T(H)2 responsiveness and asthma susceptibility in mice. The homologous locus in human subjects harbors the ...gene for TIM-1, which encodes a receptor for hepatitis A virus and has been linked with decreased susceptibility to atopic disease in hepatitis A virus-seropositive individuals.
We investigated the effects of administering antibodies against TIM-1 in a mouse model of allergic asthma to determine whether the treatment could downregulate T(H)2 cytokines and reduce pulmonary inflammation.
BALB/c mice were sensitized and challenged with ovalbumin to induce airway inflammation. Before the ovalbumin challenge, mice were treated with anti-TIM-1 mAb or a control antibody.
Administration of anti-TIM-1 antibody to mice after ovalbumin sensitization and before ovalbumin challenge results in a significant decrease in inflammatory cells in bronchoalveolar lavage fluid compared with administration of a control antibody. The decrease is accompanied by significantly lower antigen-specific production of the T(H)2 cytokines IL-10 and IL-13 by cells from the draining lymph nodes. The T(H)1 cytokine IFN-gamma appears to be unaffected. Analysis of the lungs shows that goblet cell hyperplasia and mucus production and the expression of IL-10 are markedly decreased in anti-TIM-1-treated mice.
The results indicate that anti-TIM-1 might offer a novel approach to treating asthma.
Over the past several years, intense effort has been made to map the chromosomal locations of genes involved in the susceptibility to autoimmune diseases. The first phase of this mapping ...effort—performed in most cases by using microsatellite markers to scan the genome for loci that are linked with disease—has generated first-draft maps for numerous autoimmune diseases in humans, mice and rats, pointing to as many as 20 different loci in some diseases. The second phase is now beginning, with efforts focused on narrowing the loci sufficiently to allow the positional cloning of disease-associated alleles. From these mapping data it is clear that some of these loci overlap between various autoimmune diseases and preliminary results suggest that indeed there is a sharing of ‘autoimmunity genes’ between various autoimmune diseases.
Mapping autoimmunity genes Griffiths, Marie M; Encinas, Jeffrey A; Remmers, Elaine F ...
Current Opinion in Immunology,
12/1999, Letnik:
11, Številka:
6
Book Review, Journal Article
Recenzirano
Rat and mouse models for the major human autoimmune/inflammatory diseases are under intense genetic scrutiny. Genome-wide linkage studies reveal that each model is regulated by multiple genetic loci. ...Many of these loci colocalize to homologous genomic regions associated with several different autoimmune diseases of mice, rats and humans. Candidate genes are being identified. Polymorphic alleles associated with these chromosomal segments may represent predisposing genetic elements common to a number of human diseases with very different clinical presentations.
We cloned, expressed, and characterized in vitro and in vivo the gene encoding the rat ortholog of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a G protein-coupled ...receptor for prostaglandin D2 (PGD2). Quantitative reverse transcription-polymerase chain reaction analysis demonstrated highest CRTH2 expression in the lung, brain, ovary, and spleen. Pharmacologically, rat CRTH2 stably transfected in mouse preB lymphoma L1.2 cells behaved very similar compared with the mouse and human orthologs, showing a binding affinity for PGD2 of 11 nM, a functional calcium mobilization when exposed to agonist, and similar sensitivity to agonists and antagonists. In vivo, selective activation of CRTH2 by 13,14-dihydro-15-keto (DK)-PGD2 injection into rats led to a dose- and time-dependent increase of the number of leukocytes in the peripheral blood. Specifically, eosinophils, lymphocytes, and neutrophils were recruited with maximum effects seen 60 min after the injection of 300 microg of DK-PGD2 per rat. Pretreatment of the animals with the CRTH2/thromboxane A2 receptor antagonist, ramatroban, completely abrogated DK-PGD2-induced eosinophilia, suggesting that CRTH2 might have a physiological and/or pathophysiological role in controlling leukocyte migration.
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