scholarly journals Cell-Penetrating Mx1 Enhances Anti-Viral Resistance against Mucosal Influenza Viral Infection

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 109 ◽  
Author(s):  
Hi Jung ◽  
Ji Oh ◽  
Heung Lee
Keyword(s):  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Cell Penetrating Peptides ◽  
Viral Rna ◽  
Type I ◽  
Cell Penetrating ◽  
Influenza Viral Infection

Dynamin-like GTPase myxovirus resistance protein 1 (Mx1) is an intracellular anti-viral protein following the activation of type I and type III interferon signaling. Mx1 inhibits viral replication by blocking the transcription of viral RNA, and a deficiency in this protein enhances susceptibility to influenza infection. Thus, Mx1 could be another efficient target of anti-influenza therapy. To test our hypothesis, we fused poly-arginine cell-penetrating peptides to the C terminus of Mx1 (Mx1-9R) and examined the anti-viral activity of Mx1-9R in vitro and in vivo. Madin-Darby Canine Kidney epithelial cells internalized the Mx1-9R within 12 h. Pre-exposure Mx1-9R treatment inhibited viral replication and viral RNA expression in infected cells. Further, intranasal administration of Mx1-9R improved the survival of mice infected with the PR8 influenza viral strain. These data support the consideration of Mx1-9R as a novel therapeutic agent against mucosal influenza virus infection.

scholarly journals Modelling The Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics

2021 ◽  
Author(s):  
Ke Li ◽  
Pengxing Cao ◽  
James M. McCaw
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Host Immune Response ◽  
Viral Control ◽  
Macrophage Populations ◽  
Influenza Viral Infection

AbstractMUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we utilize available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.

scholarly journals Modelling the Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 850
Author(s):  
Ke Li ◽  
Pengxing Cao ◽  
James M. McCaw
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Host Immune Response ◽  
Viral Control ◽  
Macrophage Populations ◽  
Influenza Viral Infection

MUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we use available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.

scholarly journals Transcriptional role of p53 in interferon-mediated antiviral immunity

2008 ◽  
Vol 205 (8) ◽  
pp. 1929-1938 ◽  
Author(s):  
César Muñoz-Fontela ◽  
Salvador Macip ◽  
Luis Martínez-Sobrido ◽  
Lauren Brown ◽  
Joseph Ashour ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Viral Replication ◽  
Viral Infections ◽  
Suppressor Gene ◽  
Central Component ◽  
Type I ◽  
Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

scholarly journals STAT2-Dependent Immune Responses Ensure Host Survival despite the Presence of a Potent Viral Antagonist

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Vu Thuy Khanh Le-Trilling ◽  
Kerstin Wohlgemuth ◽  
Meike U. Rückborn ◽  
Andreja Jagnjic ◽  
Fabienne Maaßen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Mutual Influence ◽  
Type I ◽  
Mcmv Infection ◽  
General Importance ◽  
Interferon Antagonism ◽  
Deficient Mice

ABSTRACTA pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, the host and pathogens are situated in a continuous arms race which shapes host evolution toward optimized immune responses and the pathogens toward enhanced immune-evasive properties. Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2, which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lackingM27and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pairin vitroandin vivo. In contrast to wild-type (wt) MCMV, ΔM27 mutant MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication. Despite this effective and relevant STAT2 antagonism, wt and STAT2-deficient mice exhibited fundamentally different susceptibilities to MCMV infections. MCMV replication was increased in all assessed organs (e.g., liver, spleen, lungs, and salivary glands) of STAT2-deficient mice, resulting in mortality during the first week after infection. Taken together, the results of our study reveal the importance of cytomegaloviral interferon antagonism for viral replication as well as a pivotal role of the remaining STAT2 activity for host survival. This mutual influence establishes a stable evolutionary standoff situation with fatal consequences when the equilibrium is disturbed.IMPORTANCEThe host limits viral replication by the use of interferons (IFNs), which signal via STAT proteins. Several viruses evolved antagonists targeting STATs to antagonize IFNs (e.g., cytomegaloviruses, Zika virus, dengue virus, and several paramyxoviruses). We analyzed infections caused by MCMV expressing or lacking the STAT2 antagonist pM27 in STAT2-deficient and control mice to evaluate its importance for the host and the virusin vitroandin vivo. The inability to counteract STAT2 directly translates into exaggerated IFN susceptibilityin vitroand pronounced attenuationin vivo. Thus, the antiviral activity mediated by IFNs via STAT2-dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination. Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Our findings highlight a remarkably delicate balance between host and virus.

scholarly journals Cell-Penetrating Peptide Modified PEG-PLA Micelles for Efficient PTX Delivery

2020 ◽  
Vol 21 (5) ◽  
pp. 1856
Author(s):  
Qi Shuai ◽  
Yue Cai ◽  
Guangkuo Zhao ◽  
Xuanrong Sun
Keyword(s):  
Cell Penetrating Peptides ◽  
Mice Model ◽  
Block Polymer ◽  
Chemotherapy Drugs ◽  
Tumor Tissues ◽  
Cell Penetrating ◽  
20 Nm ◽  
Targeting Effect

On account of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, amphiphilic block copolymer-based micelles have been widely utilized for chemotherapy drug delivery. In order to further improve the antitumor ability and to also reduce undesired side effects of drugs, cell-penetrating peptides have been used to functionalize the surface of polymer micelles endowed with the ability to target tumor tissues. Herein, we first synthesized functional polyethylene glycol-polylactic acid (PEG-PLA) tethered with maleimide at the PEG section of the block polymer, which was further conjugated with a specific peptide, the transactivating transcriptional activator (TAT), with an approved capacity of aiding translocation across the plasma membrane. Then, TAT-conjugated, paclitaxel-loaded nanoparticles were self-assembled into stable nanoparticles with a favorable size of 20 nm, and displayed a significantly increased cytotoxicity, due to their enhanced accumulation via peptide-mediated cellular association in human breast cancer cells (MCF-7) in vitro. But when further used in vivo, TAT-NP-PTX showed an acceleration of the drug’s plasma clearance rate compared with NP-PTX, and therefore weakened its antitumor activities in the mice model, because of its positive charge, its elimination by the endoplasmic reticulum system more quickly, and its targeting effect on normal cells leading towards being more toxic. So further modification of TAT-NP-PTX to shield TAT peptide’s positive charges may be a hot topic to overcome the present dilemma.

scholarly journals The anticancer efficacy of paclitaxel liposomes modified with low-toxicity hydrophobic cell-penetrating peptides in breast cancer: an in vitro and in vivo evaluation

RSC Advances ◽  
2018 ◽  
Vol 8 (43) ◽  
pp. 24084-24093 ◽  
Author(s):  
Qi Zhang ◽  
Jing Wang ◽  
Hao Zhang ◽  
Dan Liu ◽  
Linlin Ming ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Delivery ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
In Vivo Evaluation ◽  
Anticancer Efficacy ◽  
Cell Penetrating ◽  
Low Toxicity

Hydrophobic cell penetrating peptide PFVYLI-modified liposomes have been developed for the targeted delivery of PTX into tumors.

scholarly journals Type I and Type II Interferons Inhibit the Translation of Murine Norovirus Proteins

2009 ◽  
Vol 83 (11) ◽  
pp. 5683-5692 ◽  
Author(s):  
Harish Changotra ◽  
Yali Jia ◽  
Tara N. Moore ◽  
Guangliang Liu ◽  
Shannon M. Kahan ◽  
...  
Keyword(s):  
Viral Replication ◽  
Small Animal ◽  
Type I ◽  
Type Ii ◽  
Murine Norovirus ◽  
Human Noroviruses ◽  
Interferon Responses ◽  
Replication Intermediates

ABSTRACT Human noroviruses are responsible for more than 95% of nonbacterial epidemic gastroenteritis worldwide. Both onset and resolution of disease symptoms are rapid, suggesting that components of the innate immune response are critical in norovirus control. While the study of the human noroviruses has been hampered by the lack of small animal and tissue culture systems, our recent discovery of a murine norovirus (MNV) and its in vitro propagation have allowed us to begin addressing norovirus replication strategies and immune responses to norovirus infection. We have previously demonstrated that interferon responses are critical to control MNV-1 infection in vivo and to directly inhibit viral replication in vitro. We now extend these studies to define the molecular basis for interferon-mediated inhibition. Viral replication intermediates were not detected in permissive cells pretreated with type I interferon after either infection or transfection of virion-associated RNA, demonstrating a very early block to virion production that is after virus entry and uncoating. A similar absence of viral replication intermediates was observed in infected primary macrophages and dendritic cells pretreated with type I IFN. This was not due to degradation of incoming genomes in interferon-pretreated cells since similar levels of genomes were present in untreated and pretreated cells through 6 h of infection, and these genomes retained their integrity. Surprisingly, this block to the translation of viral proteins was not dependent on the well-characterized interferon-induced antiviral molecule PKR. Similar results were observed in cells pretreated with type II interferon, except that the inhibition of viral translation was dependent on PKR. Thus, both type I and type II interferon signaling inhibit norovirus translation in permissive myeloid cells, but they display distinct dependence on PKR for this inhibition.

In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides

Peptides ◽  
2017 ◽  
Vol 87 ◽  
pp. 50-63 ◽  
Author(s):  
Azam Bolhassani ◽  
Behnaz Sadat Jafarzade ◽  
Golnaz Mardani
Keyword(s):  
Therapeutic Proteins ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating ◽  
In Vivo Delivery

scholarly journals TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

2020 ◽  
Vol 11 (12) ◽  
pp. 894-914
Author(s):  
Nan Sun ◽  
Li Jiang ◽  
Miaomiao Ye ◽  
Yihan Wang ◽  
Guangwen Wang ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Type I ◽  
Subsequent Formation ◽  
Antiviral Immune Response ◽  
Signaling Complex ◽  
Deficient Mice

AbstractTripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-I-mediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63- or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.

Applications of cell-penetrating peptides in regulation of gene expression

2007 ◽  
Vol 35 (4) ◽  
pp. 770-774 ◽  
Author(s):  
P. Järver ◽  
K. Langel ◽  
S. El-Andaloussi ◽  
Ü. Langel
Keyword(s):  
Gene Expression ◽  
Lipid Bilayers ◽  
Regulation Of Gene Expression ◽  
Cell Penetrating Peptides ◽  
Remarkable Feature ◽  
Cell Penetrating ◽  
Plasmid Delivery ◽  
Interfering Rna

CPPs (cell-penetrating peptides) can be defined as short peptides that are able to efficiently penetrate cellular lipid bilayers. Because of this remarkable feature, they are excellent candidates regarding alterations in gene expression. CPPs have been utilized in in vivo and in vitro experiments as delivery vectors for different bioactive cargoes. This review focuses on the experiments performed in recent years where CPPs have been used as vectors for multiple effectors of gene expression such as oligonucleotides for antisense, siRNA (small interfering RNA) and decoy dsDNA (double-stranded DNA) applications, and as transfection agents for plasmid delivery.

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