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Frontiers in Immunology 2021Immune cell therapeutics are increasingly applied in oncology. Especially chimeric antigen receptor (CAR) T cells are successfully used to treat several B cell...
Immune cell therapeutics are increasingly applied in oncology. Especially chimeric antigen receptor (CAR) T cells are successfully used to treat several B cell malignancies. Efforts to engineer CAR T cells for improved activity against solid tumors include co-delivery of pro-inflammatory cytokines in addition to CARs, either constitutive cytokine expression or inducible cytokine expression triggered by CAR recognition of its target antigen-so-called "T cells redirected for universal cytokine-mediated killing" (TRUCKs) or fourth-generation CARs. Here, we tested the hypothesis that TRUCK principles could be expanded to improve anticancer functions of NK cells. A comparison of the functionality of inducible promoters responsive to NFAT or NFκB in NK cells showed that, in contrast to T cells, the inclusion of NFκB-responsive elements within the inducible promoter construct was essential for CAR-inducible expression of the transgene. We demonstrated that GD2CAR-specific activation induced a tight NFκB-promoter-driven cytokine release in NK-92 and primary NK cells together with an enhanced cytotoxic capacity against GD2 target cells, also shown by increased secretion of cytolytic cytokines. The data demonstrate biologically relevant differences between T and NK cells that are important when clinically translating the TRUCK concept to NK cells for the treatment of solid malignancies.
Topics: Alpharetrovirus; Brain Neoplasms; Cell Line; Cell Movement; Coculture Techniques; Cytokines; Genetic Vectors; Glioblastoma; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; NF-kappa B; NFATC Transcription Factors
PubMed: 34804035
DOI: 10.3389/fimmu.2021.751138 -
Infection, Genetics and Evolution :... Dec 2021A small non-coding, evolutionarily conserved regulatory RNA molecule known as microRNA (miRNA) regulates various cellular activities and pathways. MicroRNAs remain...
A small non-coding, evolutionarily conserved regulatory RNA molecule known as microRNA (miRNA) regulates various cellular activities and pathways. MicroRNAs remain evolutionarily conserved in different species of same taxa. They are present in all organisms including viruses. Viral miRNAs are small, less conserved and less stable and have higher negative minimal folding free energy than miRNAs of different organisms. The size of viral precursor miRNA is approximately 60-119 nucleotides in length. The structure of the mature miRNA sequences is predicted by using higher negative MFE (ΔG) value. Rous sarcoma Virus (RSV), named after its inventor Peyton Rous, has been known for causing tumors in the chicken for which it is known as an oncogenic retrovirus. Using specific criteria we have predicted 5 potential miRNAs in RSV which targeted 8 tumor suppressor genes in Gallus gallus. This study aims to predict the potential miRNAs, secondary structures and their targets for better understanding of the regulatory network of Rous sarcoma virus miRNA in forming sarcoma.
Topics: Animals; Chickens; Genes, Tumor Suppressor; MicroRNAs; Poultry Diseases; RNA, Viral; Rous sarcoma virus; Sarcoma, Avian
PubMed: 34798320
DOI: 10.1016/j.meegid.2021.105139 -
Frontiers in Immunology 2021J subgroup avian leukosis virus (ALV-J) infection causes serious immunosuppression problems, leading to hematopoietic malignancy tumors in chicken. It has been...
J subgroup avian leukosis virus (ALV-J) infection causes serious immunosuppression problems, leading to hematopoietic malignancy tumors in chicken. It has been demonstrated that interferon-stimulated genes (ISGs) could limit ALV-J replication; nevertheless, the underlying mechanisms remain obscure. Here, we demonstrate that Long-chain Acyl-CoA synthetase 1 (ACSL1) is an interferon (IFN)-stimulated gene that specifically restricts the replication of ALV-J due to the higher IFN-I production. More importantly, ACSL1 induces primary monocyte-derived macrophages (MDMs) to pro-inflammatory phenotypic states during ALV-J infection, and ACSL1 mediates apoptosis through the PI3K/Akt signaling pathway in ALV-J-infected primary monocyte-derived macrophages (MDMs). Overall, these results provide evidence that ACSL1 contributes to the antiviral response against ALV-J.
Topics: Animals; Apoptosis; Avian Leukosis; Avian Leukosis Virus; Biomarkers; Chickens; Coenzyme A Ligases; Disease Susceptibility; Gene Expression Regulation; Host-Pathogen Interactions; Interferon Type I; Models, Biological; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Virus Replication
PubMed: 34777393
DOI: 10.3389/fimmu.2021.774323 -
Journal of Virology Jan 2022The CCCH-type zinc finger antiviral protein (ZAP) can recognize and induce the degradation of mRNAs and proteins of certain viruses, as well as exerting its antiviral...
The CCCH-type zinc finger antiviral protein (ZAP) can recognize and induce the degradation of mRNAs and proteins of certain viruses, as well as exerting its antiviral activity by activating T cells. However, the mechanism of ZAP that mediates T cell activation during virus infection remains unclear. Here, we found a potential function of ZAP that relieves immunosuppression of T cell induced by avian leukosis virus subgroup J (ALV-J) via a novel signaling pathway that involves norbin-like protein (NLP), protein kinase C delta (PKC-δ), and nuclear factor of activated T cell (NFAT). Specifically, ZAP expression activated T cells by promoting the dephosphorylation and nuclear translocation of NFAT. Furthermore, knockdown of ZAP weakened the reactivity and antiviral response of T cells. Mechanistically, ZAP reduced PKC-δ activity by upregulating and reactivating NLP by competitively binding with viral protein. Knockdown of NLP decreased the dephosphorylation of PKC-δ by ZAP expression. Moreover, we show that knockdown of PKC-δ reduced the phosphorylation levels of NFAT and enhanced its nuclear translocation. Taken together, these data revealed that ZAP relieves immunosuppression caused by ALV-J and mediates T cell activation through the NLP-PKC-δ-NFAT pathway. The evolution of the host defense system is driven synchronously in the process of resisting virus invasion. Accordingly, host innate defense factors effectively work to suppress virus replication. However, it remains unclear whether the host innate defense factors are involved in antiviral immune responses against the invasion of immunosuppressive viruses. Here, we found that CCCH-type zinc finger antiviral protein (ZAP) effectively worked in resistance to immunosuppression caused by avian leukosis virus subgroup J (ALV-J), a classic immunosuppressive virus. Evidence showed that ZAP released the phosphatase activity of NLP inhibited by ALV-J and further activated NFAT by inactivating PKC-δ. This novel molecular mechanism, i.e., ZAP regulation of the antiviral immune response by mediating the NLP-PKC-δ-NFAT pathway, has greatly enriched the understanding of the functions of host innate defense factors and provided important scientific ideas and a theoretical basis for research on immunosuppressive viruses and antiviral immunity.
Topics: Animals; Avian Leukosis Virus; Chickens; Host-Pathogen Interactions; Immune Tolerance; Lymphocyte Activation; NFATC Transcription Factors; Nerve Tissue Proteins; Phosphorylation; Protein Binding; Protein Kinase C-delta; RNA-Binding Proteins; Signal Transduction; T-Lymphocytes; Viral Proteins
PubMed: 34705559
DOI: 10.1128/JVI.01344-21 -
Viruses Sep 2021Wnt/β-catenin signaling is a highly conserved pathway related to a variety of biological processes in different cells. The regulation of replication of various viruses...
Wnt/β-catenin signaling is a highly conserved pathway related to a variety of biological processes in different cells. The regulation of replication of various viruses by Wnt/β-catenin signaling pathway has been reported. However, the interaction between the Wnt/β-catenin pathway and avian leukosis virus is unknown. In the present study, we investigated the effect of modulating the Wnt/β-catenin pathway during avian leukosis virus subgroup J (ALV-J) infection. The activation of the Wnt/β-catenin pathway by GSK-3 inhibitor increased ALV-J mRNA, viral protein expression, and virus production in CEF cells. This increase was suppressed by iCRT14, one of the specific inhibitors of the Wnt/β-catenin signaling pathway. Moreover, treatment with iCRT14 reduced virus titer and viral gene expression significantly in CEF and LMH cells in a dose-dependent manner. Inhibition Wnt/β-catenin signaling pathway by knockdown of β-catenin reduced virus proliferation in CEF cells also. Collectively, these results suggested that the status of Wnt/β-catenin signaling pathway modulated ALV-J replication. These studies extend our understanding of the role of Wnt/β-catenin signaling pathway in ALV-J replication and make a new contribution to understanding the virus-host interactions of avian leukosis virus.
Topics: Animals; Avian Leukosis; Avian Leukosis Virus; Cell Line; Chick Embryo; Chickens; China; Gene Expression; Gene Expression Regulation, Viral; Glycogen Synthase Kinase 3; Poultry Diseases; Pyridines; Pyrroles; RNA, Messenger; Thiazolidinediones; Virus Replication; Wnt Signaling Pathway
PubMed: 34696398
DOI: 10.3390/v13101968 -
Poultry Science Nov 2021As important immunosuppressive viruses, chicken infectious anemia virus (CIAV) and subgroup J avian leukosis virus (ALV-J) have caused huge economic losses to the...
As important immunosuppressive viruses, chicken infectious anemia virus (CIAV) and subgroup J avian leukosis virus (ALV-J) have caused huge economic losses to the poultry industry globally. Recently, the co-infection of CIAV and ALV-J frequently occurred in the domestic chicken flocks in China. However, the synergistic pathogenesis of CIAV and ALV-J has not been fully investigated. Here, a co-infection study was performed to further understand the potential synergistic pathogenesis of CIAV and ALV-J. In vitro study showed that CIAV could promote the replication of ALV-J in HD11 cells, but ALV-J could not increase the replication of CIAV. Chicken infection study showed both CIAV and ALV-J with synergistic effects caused significant body weight loss to the infected chickens. Although ALV-J had no effect on CIAV viral shedding and tissue load, CIAV did significantly increase ALV-J viremia, viral shedding and tissue load in the co-infection group. Moreover, both CIAV and ALV-J could significantly inhibit the humoral immunity to H9N2 influenza virus and serotype 4 fowl adenovirus (FAdV-4). All these data demonstrate the synergistic pathogenesis for the co-infection of CIAV and ALV-J, and highlight the positive effect of CIAV on the pathogenesis of ALV-J.
Topics: Animals; Avian Leukosis; Avian Leukosis Virus; Chicken anemia virus; Chickens; Influenza A Virus, H9N2 Subtype; Poultry Diseases
PubMed: 34624772
DOI: 10.1016/j.psj.2021.101468 -
Viruses Sep 2021The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles.... (Review)
Review
The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles. However, the molecular details underlying this effect have been determined only recently, with the identification of the IP6 binding site in the immature Gag lattice. IP6 also promotes formation of the mature capsid protein (CA) lattice via a second IP6 binding site, and enhances core stability, creating a favorable environment for reverse transcription. IP6 also enhances assembly of other retroviruses, from both the Lentivirus and the Alpharetrovirus genera. These findings suggest that IP6 may have a conserved function throughout the family Retroviridae. Here, we discuss the different steps in the viral life cycle that are influenced by IP6, and describe in detail how IP6 interacts with the immature and mature lattices of different retroviruses.
Topics: Binding Sites; Capsid Proteins; HIV-1; Human Immunodeficiency Virus Proteins; Mutation; Phytic Acid; Retroviridae; Retroviridae Proteins; Reverse Transcription; Rous sarcoma virus; Virus Assembly; Virus Replication; gag Gene Products, Human Immunodeficiency Virus
PubMed: 34578434
DOI: 10.3390/v13091853 -
Frontiers in Cellular and Infection... 2021Avian leukosis virus subgroup J (ALV-J) is an oncogenic retrovirus that causes immunosuppression and neoplastic diseases in poultry. Cytokine signal-transduction...
Avian leukosis virus subgroup J (ALV-J) is an oncogenic retrovirus that causes immunosuppression and neoplastic diseases in poultry. Cytokine signal-transduction inhibitor molecule 3 (SOCS3) is an important negative regulator of the JAK2/STAT3 signaling pathway and plays certain roles in ALV-J infection. It is of significance to confirm the roles of in ALV-J infection and study how this gene affects ALV-J infection. In this study, we assessed the expression of the gene and , and investigated the roles of in ALV-J infection using overexpressed or interfered assays with the in DF-1 cells. The results showed that the expression of ALV-J infected chickens was different from uninfected chickens in the spleen, thymus and cecal tonsil. Further, is mainly expressed in the nucleus as determined by immunofluorescence assay. Overexpression of in DF-1 cells promoted the replication of ALV-J virus, and the expression of interferons ( and ), inflammatory factors ( and ) along with interferon-stimulating genes (, , , and ). Conversely, interference of showed the opposite results. We also observed that SOCS3 promoted ALV-J virus replication by inhibiting JAK2/STAT3 phosphorylation. In conclusion, promotes ALV-J replication inhibiting the phosphorylation of the JAK2/STAT3 signaling pathway. These results would advance further understanding of the persistent infection and the viral immune evasion of the ALV-J virus.
Topics: Animals; Avian Leukosis; Avian Leukosis Virus; Chickens; Phosphorylation; Poultry Diseases; Virus Replication
PubMed: 34568100
DOI: 10.3389/fcimb.2021.748795 -
Veterinary Research Sep 2021Congenital avian leukosis virus subgroup J (ALV-J) infection can induce persistent immunotolerance in chicken, however, the underlying mechanism remains unclear. Here,...
Congenital avian leukosis virus subgroup J (ALV-J) infection can induce persistent immunotolerance in chicken, however, the underlying mechanism remains unclear. Here, we demonstrate that congenital ALV-J infection induces the production of high-frequency and activated CD4CD25 Tregs that maintain persistent immunotolerance. A model of congenital infection by ALV-J was established in fertilized eggs, and hatched chicks showed persistent immunotolerance characterized by persistent viremia, immune organ dysplasia, severe imbalance of the ratio of CD4/CD8 T cells in blood and immune organs, and significant decrease in CD3 T cells and Bu-1 B cells in the spleen. Concurrently, the mRNA levels of IL-2, IL-10, and IFN-γ showed significant fluctuations in immune organs. Moreover, the frequency of CD4CD25 Tregs in blood and immune organs significantly increased, and the frequency of CD4CD25 Tregs was positively correlated with changes in ALV-J load in immune organs. Interestingly, CD4CD25 Tregs increased in the marginal zone of splenic nodules in ALV-J-infected chickens and dispersed to the germinal center. In addition, the proliferation and activation of B cells in splenic nodules was inhibited, and the number of IgM and IgG cells in the marginal zone significantly decreased. We further found that the mRNA levels of TGF- β and CTLA-4 in CD4CD25 Tregs of ALV-J-infected chickens significantly increased. Together, high-frequency and activated CD4CD25 Tregs inhibited B cells functions by expressing the inhibitory cytokine TGF-β and inhibitory surface receptor CTLA-4, thereby maintaining persistent immunotolerance in congenital ALV-J-infected chickens.
Topics: Animals; Avian Leukosis; Avian Leukosis Virus; CD4-Positive T-Lymphocytes; Chick Embryo; Chickens; Immune Tolerance; Poultry Diseases; Specific Pathogen-Free Organisms; T-Lymphocytes
PubMed: 34526112
DOI: 10.1186/s13567-021-00989-9 -
Acta Biochimica Et Biophysica Sinica Oct 2021
Comparative Study
Topics: Animals; Antibodies, Monoclonal; Antibodies, Viral; Avian Leukosis; Avian Leukosis Virus; Chickens; Enzyme-Linked Immunosorbent Assay; Female; Mice, Inbred BALB C; Sensitivity and Specificity; Viral Envelope Proteins; Mice
PubMed: 34463705
DOI: 10.1093/abbs/gmab114