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《Microbes and infection / Institut Pasteur》2023,25(3):105062
With the prevalence of novel strains and drug-resistant influenza viruses, there is an urgent need to develop effective and low-toxicity anti-influenza therapeutics. Regulation of the type I interferon antiviral response is considered an attractive therapeutic strategy for viral infection. Pterostilbene, a 3,5-dimethoxy analog of resveratrol, is known for its remarkable pharmacological activity. Here, we found that pterostilbene effectively inhibited influenza A virus infection and mainly affected the late stages of viral replication. A mechanistic study showed that the antiviral activity of pterostilbene might promote the induction of antiviral type I interferon and expression of its downstream interferon-stimulated genes during viral infection. The same effect of pterostilbene was also observed in the condition of polyinosinic-polycytidylic acid (poly I:C) transfection. Further study showed that pterostilbene interacted with influenza non-structural 1 (NS1) protein, inhibited ubiquitination mediated degradation of RIG-I and activated the downstream antiviral pathway, orchestrating an antiviral state against influenza virus in the cell. Taken together, pterostilbene could be a promising anti-influenza agent for future antiviral drug exploitation and compounds with similar structures may provide new options for the development of novel inhibitors against influenza A virus (IAV). 相似文献
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Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling 总被引:4,自引:0,他引:4
Zhirnov OP Klenk HD 《Apoptosis : an international journal on programmed cell death》2007,12(8):1419-1432
PI3k-Akt and p53 pathways are known to play anti- and pro-apoptotic roles in cell death, respectively. Whether these pathways
are recruited in influenza virus infection in highly productive monkey (CV-1) and canine (MDCK) kidney cells was studied here.
Phosphorylation of Akt (Akt-pho) was found to occur only early after infection (5–9 h.p.i). Nuclear accumulation and phosphorylation
of p53 (p53-pho), and expression of its natural target p21/waf showed low constitutive levels at this period, whereas all
three parameters were markedly elevated at the late apoptotic stage (17–20 h.p.i.). Up-regulation of Akt-pho and p53-pho was
not induced by UV-inactivated virus suggesting that it required virus replication. Also, mRNAs of p53 and its natural antagonist
mdm2 were not increased throughout infection indicating that p53-pho was up-regulated by posttranslational mechanisms. However,
p53 activation did not seem to play a leading role in influenza-induced cell death: (i) infection of CV1 and MDCK cells with
recombinant NS1-deficient virus provoked accelerated apoptotic death characterized by the lack of p53 activation; (ii) mixed
apoptosis-necrosis death developed in influenza-infected human bronchial H1299 cells carrying a tetracycline-regulated p53
gene did not depend on p53 gene activation by tetracycline. Virus-induced apoptosis and signaling of Akt and p53 developed
in IFN-deficient VERO cells with similar kinetics as in IFN-competent CV1-infected cells indicating that these processes were
endocrine IFN-independent. Apoptosis in influenza-infected CV-1 and MDCK cells was Akt-dependent and was accelerated by Ly294002,
a specific inhibitor of PI3k-Akt signaling, and down-regulated by the viral protein NS1, an inducer of host Akt. The obtained
data suggest that influenza virus (i) initiates anti-apoptotic PI3k-Akt signaling at early and middle phases of infection
to protect cells from fast apoptotic death and (ii) provokes both p53-dependent and alternative p53-independent apoptotic
and/or necrotic (in some host systems) cell death at the late stage of infection.
These data have been partially presented at The 3rd Orthomyxovirus Research Conference (sponsored by ESWI and NIH). Abstr.
p. 23 entitled: “Influenza virus-specific up-regulation of Akt and Mdm2 in infected cells” by Zhirnov O.P., and Klenk H.D.,
July 28–21, 2005. Queen’s College, Cambridge, United Kingdom; and at The Annual Meeting of Virology in Munich, March 15–18
(2006)—“Influenza virus-specific up-regulation of Akt, Mdm2, and p53 in infected cells” by O. P. Zhirnov and H. D. Klenk;
Book of abstracts, p. 339 相似文献
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We present a simplified dynamical model of immune response to uncomplicated influenza A virus (IAV) infection, which focuses on the control of the infection by the innate and adaptive immunity. Innate immunity is represented by interferon-induced resistance to infection of respiratory epithelial cells and by removal of infected cells by effector cells (cytotoxic T-cells and natural killer cells). Adaptive immunity is represented by virus-specific antibodies. Similar in spirit to the recent model of Bocharov and Romanyukha [1994. Mathematical model of antiviral immune response. III. Influenza A virus infection. J. Theor. Biol. 167, 323-360], the model is constructed as a system of 10 ordinary differential equations with 27 parameters characterizing the rates of various processes contributing to the course of disease. The parameters are derived from published experimental data or estimated so as to reproduce available data about the time course of IAV infection in a na?ve host. We explore the effect of initial viral load on the severity and duration of the disease, construct a phase diagram that sheds insight into the dynamics of the disease, and perform sensitivity analysis on the model parameters to explore which ones influence the most the onset, duration and severity of infection. To account for the variability and speed of adaptation of the adaptive response to a particular virus strain, we introduce a variable that quantifies the antigenic compatibility between the virus and the antibodies currently produced by the organism. We find that for small initial viral load the disease progresses through an asymptomatic course, for intermediate value it takes a typical course with constant duration and severity of infection but variable onset, and for large initial viral load the disease becomes severe. This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load. 相似文献
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《Microbes and infection / Institut Pasteur》2021,23(8):104831
This paper reviews epigenetic mechanisms by which influenza viruses affect cellular gene activity to control their life cycles, aiming to provide new insights into the complexity of functional interactions between viral and cellular factors, as well as to introduce novel targets for therapeutic intervention and vaccine development against influenza infections. 相似文献
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Engagement of CD40 on the surface of antigen-presenting cells (APC) has been shown to substitute for T cell help in activating
APC to stimulate cytotoxic T lymphocytes (CTL). We explored whether this powerful non-specific signal could enhance the CTL
response to a self epitope from a tumor-associated antigen. We immunized mice with a lipopeptide covering the H-2Kd-restricted epitope, amino acids 232–240 of murine wild-type p53, followed by treatment with an activating anti-CD40 monoclonal
antibody. Anti-CD40 antibody, given subcutaneously or intravenously, significantly enhanced effector activity against targets
pulsed with non-lipidated 232–240 nonamer epitope peptide, as assessed both by a CTL lysis assay and an enzyme-linked immunospot
(ELISPOT) assay for interferon-γ-secreting cells. However, despite this enhancement, we could not detect activity against
targets expressing p53 endogenously by either assay. This most likely reflects the low avidity of the effectors as determined
by a titration of peptide on the target cells. The implications of this work for cancer immunotherapy based on specific responses
directed against tumor-associated antigens are discussed.
Received: 28 March 2000 / Accepted: 6 June 2000 相似文献
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Kyoji Hagiwara Atsushi Ueda Kazunori Yamada Hideo Goto Tadashi Nakata Yoko Aida 《Biochemical and biophysical research communications》2010,394(3):721-727
The nucleoprotein (NP) of the influenza virus is expressed in the early stage of infection and plays important roles in numerous steps of viral replication. NP is relatively well conserved compared with viral surface spike proteins. This study experimentally demonstrates that NP is a novel target for the development of new antiviral drugs against the influenza virus. First, artificial analogs of mycalamide A in a chemical array bound specifically with high affinity to NP. Second, the compounds inhibited multiplication of the influenza virus. Furthermore, surface plasmon resonance imaging experiments demonstrated that the binding activity of each compound to NP correlated with its antiviral activity. Finally, it was shown that these compounds bound NP within the N-terminal 110-amino acid region but their binding abilities were dramatically reduced when the N-terminal 13-amino acid tail was deleted, suggesting that the compounds might bind to this region, which mediates the nuclear transport of NP and its binding to viral RNA. These data suggest that compound binding to the N-terminal 13-amino acid tail region may inhibit viral replication by inhibiting the functions of NP. Collectively, these results strongly suggest that chemical arrays are convenient tools for the screening of viral product inhibitors. 相似文献
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Marissa L. Miller Deborah M. Brown Tadeusz A. Wysocki 《Biotechnology and bioengineering》2023,120(2):562-571
Influenza A viruses (IAV) have been the cause of several influenza pandemics in history and are a significant threat for the next global pandemic. Hospitalized influenza patients often have excess interferon production and a dysregulated immune response to the IAV infection. Obtaining a better understanding of the mechanisms of IAV infection that induce these harmful effects would help drug developers and health professionals create more effective treatments for IAV infection and improve patient outcomes. IAV stimulates viral sensors and receptors expressed by alveolar epithelial cells, like RIG-I and toll-like receptor 3 (TLR3). These two pathways coordinate with one another to induce expression of type III interferons to combat the infection. Presented here is a queuing theory-based model of these pathways that was designed to analyze the timing and amount of interferons produced in response to IAV single stranded RNA and double-stranded RNA detection. The model accurately represents biological data showing the necessary coordination of the RIG-I and TLR3 pathways for effective interferon production. This model can serve as the framework for future studies of IAV infection and identify new targets for potential treatments. 相似文献
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In order to evaluate the anti-influenza virus activity of the effective monomer from Folium Isatidis (FI) in vivo, we established mice model with viral pneumonia and divided them into 3 different dose groups, then observed their lung indexes,
pulmonary pathological changes, pulmonary virus hemagglitination titers, living time and death rates. The results showed that
the monomer could reduce the pulmonary index from 2.64 to 1.93, 1.63 and 1.40 (P<0.01) and decrease the hemagglitination titer from 1.15 to 0.84, 0.70 and 0.59 (P<0.01). In addition, different groups of FI could significantly lessen the mortality rate from 100% to 30%, 25% and 15%, and
prolong the living time from 5.1d to 6.5d, 8.4d and 8.9d respectively(P<0.01). The high dose (75 mg/kg/d) has the similar effect with 100 mg/kg/d dose of virazole(P>0.05), and more effective than 200 mg/kg/d dose of antiviral liquor (P<0.05). 相似文献
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IFIT(Interferon induced proteins with tetratricopeptide repeats)家族基因是一组较早发现的干扰素刺激基因,它在抗病毒和免疫调节中发挥了重要作用。为研究IFIT家族基因抑制A型流感病毒复制的机理,利用高通量RNA深度测序(RNA-Seq)技术发现A型流感病毒A/WSN/33(WSN)毒株感染293T细胞后,IFIT家族基因均出现明显上调。同时发现在IFIT2、IFIT3过表达后,流感病毒的复制和转录均有明显下调,并对v RNP聚合酶活性具有剂量依赖型的抑制作用。进一步研究证明在感染IFIT2、IFIT3编码蛋白与流感病毒非结构蛋白(NS1)存在细胞内共定位,证明二者存在相互作用的可能。综上所述,IFIT家族基因可以抑制A型流感病毒的复制和转录,有助于进一步阐明宿主因子对流感病毒感染的调节机制。 相似文献
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本研究旨在探究非洲猪瘟病毒(African swine fever virus, ASFV) I226R蛋白(I226R protein, pI226R)抑制cGAS-STING信号通路的作用机制。利用双荧光素酶报告系统和实时荧光定量PCR (real-time quantitative PCR, qPCR)证明pI226R显著抑制cGAS-STING通路介导的I型干扰素及干扰素刺激相关基因的产生。免疫共沉淀及激光共聚焦显微镜试验发现pI226R与cGAS蛋白相互作用。免疫印迹分析证明pI226R通过自噬-溶酶体途径促进cGAS蛋白的降解。同时,pI226R阻碍了cGAS与E3泛素连接酶三基序蛋白56 (tripartite motif protein 56, TRIM56)的结合,导致cGAS的单泛素化减弱,从而抑制了cGAS的活化和cGAS-STING通路的激活。总之,本研究证明ASFV pI226R通过拮抗cGAS进而抑制宿主的抗病毒天然免疫反应,进一步增加了对研究ASFV免疫逃逸机制的理解,为疫苗的研发提供了理论基础。 相似文献
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Xu Pang Jian-yuan Zhao Hai-yang Yu Li-yan Yu Tao Wang Yi Zhang Xiu-mei Gao Li-feng Han 《Bioorganic & medicinal chemistry letters》2018,28(9):1516-1519
A phytochemical study focusing on the secoiridoid components in the fruits of Ligustrum lucidum was carried out, which finally led to the isolation of nine secoiridoid glycosides (1–9) together with two secoiridoids (10, 11). The structures of all compounds were established mainly by NMR and MS experiments as well as the necessary chemical evidence, of which 1, 2, 4 (ligulucisides A–C), 10 and 11 (liguluciridoids A and B) were identified as new secoiridoid analogues. An in vitro antiviral bioassay indicated that 1, 4, 6, and 10 displayed the inhibitory activities against influenza A virus with the IC50 values of 16.5, 12.5, 13.1, and 18.5?μM, respectively, which were better than the positive control Ribavirin (IC50 22.6?μM).. 相似文献
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Spiro[piperidine-2,2′-adamantane] 4 is one of the most potent synthetic anti-influenza A aminoadamantanes or other cage structure amines tested so far. Based on previous results Tataridis et al. (2007) [5h] which demonstrate the boost of in vitro potency by the presence of an additional amino group, we examined whether the incorporation of a second amino group into this heterocycle would increase the anti-influenza A virus activity. The new synthetic molecules 5–7 are capable of forming two hydrogen bonds within the receptor. We identified the diamino derivatives 5 and 6, which are active against influenza A H3N2 virus although less potent than amantadine and its equipotent spiropiperidine 4. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(9):1818-1826
DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21waf1 protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21waf1 induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21waf1 protein induction. We find that neither the induction of p21waf1 mRNA nor protein half-life is sufficient to explain the low p21waf1 protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes but little protein is made suggesting these two cell lines have a reduced rate of p21waf1 mRNA translation. This represents a novel mechanism for disruption of the p53-p21waf1 pathway as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21waf1 expression may render some p53 wild type tumors sensitive to a combination of DNA damage plus checkpoint inhibition. 相似文献
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DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21waf1 protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21waf1 induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21waf1 protein induction. We find that neither the induction of p21waf1 mRNA nor protein half-life is sufficient to explain the low p21waf1 protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes but little protein is made suggesting these two cell lines have a reduced rate of p21waf1 mRNA translation. This represents a novel mechanism for disruption of the p53-p21waf1 pathway as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21waf1 expression may render some p53 wild type tumors sensitive to a combination of DNA damage plus checkpoint inhibition. 相似文献
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Oanh N. L. Le Francis Rodier Francois Fontaine Jean‐Philippe Coppe Judith Campisi James DeGregori Caroline Laverdière Victor Kokta Elie Haddad Christian M. Beauséjour 《Aging cell》2010,9(3):398-409
Exposure to IR has been shown to induce the formation of senescence markers, a phenotype that coincides with lifelong delayed repair and regeneration of irradiated tissues. We hypothesized that IR‐induced senescence markers could persist long‐term in vivo, possibly contributing to the permanent reduction in tissue functionality. Here, we show that mouse tissues exposed to a sublethal dose of IR display persistent (up to 45 weeks, the maximum time analyzed) DNA damage foci and increased p16INK4a expression, two hallmarks of cellular senescence and aging. BrdU‐labeling experiments revealed that IR‐induced damaged cells are preferentially eliminated, at least partially, in a tissue‐dependent manner. Unexpectedly, the accumulation of damaged cells was found to occur independent from the DNA damage response modulator p53, and from an intact immune system, as their levels were similar in wild‐type and Rag2?/? γC?/? mice, the latter being deficient in T, B, and NK cells. Together, our results provide compelling evidence that exposure to IR induces long‐term expression of senescence markers in vivo, an effect that may contribute to the reduced tissue functionality observed in cancer survivors. 相似文献