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Virus Research Aug 2017Prion diseases are fatal neurodegenerative disorders by which the native cellular prion protein (PrP) is misfolded into an accumulating, disease-associated isoform...
Prion diseases are fatal neurodegenerative disorders by which the native cellular prion protein (PrP) is misfolded into an accumulating, disease-associated isoform (PrP). To improve the understanding of prion pathogenesis and develop effective treatments, it is essential to elucidate factors contributing to cellular permissiveness. We previously isolated five clones from an immortalized subline of ovine microglia, two of which had demonstrated differential permissiveness to a natural isolate of sheep scrapie and distinct transcriptomic profiles. To more robustly identify factors contributing to this activity, relative permissiveness, cell proliferation, selected gene transcript level, and matrix metalloproteinase 2 (MMP2) activity were compared amongst all five clones. Differences in cell proliferation were not detected between clones; however, significant correlations were identified between relative permissiveness and genes associated with cell growth (i.e., RARRES1 and PTN), protein degradation (i.e., CTSB and SQSTM1), and heparin binding (i.e., SEPP1). MMP2 activity varied amongst clones, but did not correlate with permissiveness. These associations support the contribution of cell division and protein degradation on the permissiveness of cultured ovine microglia to PrP.
Topics: Animals; Matrix Metalloproteinase 2; Microglia; PrPSc Proteins; Scrapie; Sheep; Transcriptome
PubMed: 28754560
DOI: 10.1016/j.virusres.2017.07.016 -
Frontiers in Cellular and Infection... 2013Tsetse flies are the most important vectors of African trypanosomiasis but, surprisingly, are highly refractory to trypanosome parasite infection. In populations of wild... (Review)
Review
Tsetse flies are the most important vectors of African trypanosomiasis but, surprisingly, are highly refractory to trypanosome parasite infection. In populations of wild caught flies, it is rare to find mature salivarian and mouthpart parasite infection rates exceeding 1 and 15%, respectively. This inherent refractoriness persists throughout the lifespan of the fly, although extreme starvation and suboptimal environmental conditions can cause a reversion to the susceptible phenotype. The teneral phenomenon is a phenotype unique to newly emerged, previously unfed tsetse, and is evidenced by a profound susceptibility to trypanosome infection. This susceptibility persists for only a few days post-emergence and decreases with fly age and bloodmeal acquisition. Researchers investigating trypanosome-tsetse interactions routinely exploit this phenomenon by using young, unfed (teneral) flies to naturally boost trypanosome establishment and maturation rates. A suite of factors may contribute, at least in part, to this unusual parasite permissive phenotype. These include the physical maturity of midgut barriers, the activation of immunoresponsive tissues and their effector molecules, and the role of the microflora within the midgut of the newly emerged fly. However, at present, the molecular mechanisms that underpin the teneral phenomenon still remain unknown. This review will provide a historical overview of the teneral phenomenon and will examine immune-related factors that influence, and may help us better understand, this unusual phenotype.
Topics: Animals; Host-Parasite Interactions; Trypanosoma; Tsetse Flies; United States
PubMed: 24312903
DOI: 10.3389/fcimb.2013.00084 -
Oncotarget Feb 2019
PubMed: 30899421
DOI: 10.18632/oncotarget.26679 -
Journal of Virology Sep 2023Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies...
Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies demonstrated that human PDAC cell lines are highly variable in their permissiveness to OVs. Mouse PDAC cell lines, which are widely used for examination of the adaptive immune responses during OV and other cancer therapies, have never been examined systematically for the impact of intertumoral heterogeneity (the differences observed between tumors in different patients) on OV virus efficacy. Here, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines (C57BL6 genetic background): Panc02 (derived from chemically induced PDAC; also known as Pan02), and two cell lines originated from PDACs developed in two different KPC (Kras, Trp53, and PDX-1-Cre) mouse models. Our study (i) characterized the ability of a widely used attenuated oncolytic vesicular stomatitis virus VSV-ΔM51-GFP to infect, replicate in, and kill mouse PDAC cells; (ii) examined their innate antiviral responses; (iii) compared their permissiveness to a non-attenuated VSV-Mwt-GFP and chemotherapeutic drugs; and (iv) analyzed their karyotype and exome. Mouse PDAC cell lines showed high divergence in their permissiveness to VSV-ΔM51-GFP, which negatively correlated with their abilities to mount innate antiviral responses, while all three cell lines were highly permissive to VSV-Mwt-GFP. No correlation was found between resistance to VSV-ΔM51-GFP and chemotherapy. Also, mouse PDAC cell lines showed high divergence in their karyotype and exome. The exome analysis demonstrated that more VSV-ΔM51-GFP-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. IMPORTANCE Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies using various human PDAC cell lines demonstrated that they are highly variable in their permissiveness to OVs. In this study, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines, which are widely used for examination of the adaptive immune responses during cancer therapies. Mouse PDAC cell lines showed high divergence in their permissiveness to oncolytic vesicular stomatitis virus (VSV), which negatively correlated with their abilities to mount innate antiviral responses. Also, we discovered that more VSV-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. Our study provides essential information about three model mouse PDAC cell lines and proposes a novel platform to study OV-based therapies against different PDACs in immunocompetent mice.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Interferon Type I; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic Neoplasms; Vesicular stomatitis Indiana virus
PubMed: 37671865
DOI: 10.1128/jvi.01005-23 -
MBio Dec 2022Human immunodeficiency virus type 1 (HIV-1) can integrate viral DNA into host cell chromosomes to establish a long-term stable latent reservoir, which is a major...
Human immunodeficiency virus type 1 (HIV-1) can integrate viral DNA into host cell chromosomes to establish a long-term stable latent reservoir, which is a major obstacle to cure HIV-1 infection. The characteristics of the HIV-1 latent reservoir have not been fully understood. Here, we identified 126 upregulated plasma membrane proteins in HIV-1 latently infected cells by a label-free liquid chromatography-tandem mass spectrometry analysis. The higher levels of CD98 expression in multiple HIV-1 latently infected cell lines and primary CD4 T cells compared to uninfected cells were further confirmed by quantitative reverse transcription PCR (RT-qPCR) and flow cytometry analyses. In addition, CD98 CD4 T cells displayed hyper-permissiveness to HIV-1 infection and possessed distinct immune phenotypic profiles associated with Th17 and peripheral follicular T helper (pTFH) characteristics. Notably, the CD98 resting memory CD4 T cells harbored significantly higher cell-associated viral RNA and intact provirus than CD98 counterparts in HIV-1-infected individuals receiving combined antiretroviral therapy. Furthermore, CD98 CD4 T cells exhibited a robust proliferative capacity and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. Our study demonstrates that CD98 can be used as a novel biomarker of HIV-1 latently infected cells to indicate the effect of various strategies to reduce the viral reservoir. Identification of cellular biomarkers is the crucial challenge to eradicate the HIV-1 latent reservoir. In our study, we identified CD98 as a novel plasma membrane biomarker for HIV-1 permissiveness and latent infection. Importantly, CD98 CD4 T cells exhibited a hyper-permissiveness to HIV-1 infection and significantly contributed to the clonal expansion of the HIV-1 latent reservoir. CD98 could be targeted to develop therapeutic strategies to reduce the HIV-1 latent reservoir in further research.
Topics: Humans; Biomarkers; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Latent Infection; Permissiveness; Virus Latency; Virus Replication; Fusion Regulatory Protein-1
PubMed: 36214569
DOI: 10.1128/mbio.02496-22 -
Frontiers in Oncology 2020The tissue stroma plays a major role in tumors' natural history. Most programs for tumor progression are not activated as cell-autonomous processes but under the...
The tissue stroma plays a major role in tumors' natural history. Most programs for tumor progression are not activated as cell-autonomous processes but under the conditions of cross-talks between tumor and stroma. Adipose tissue is a major component of breast stroma. This study compares adipose tissues in tumor-bearing breasts to those in tumor-free breasts with the intention of defining a signature that could translate into markers of cancer risk. In tumor-bearing breasts, we sampled adipose tissues adjacent to, or distant from the tumor. Parameters studied included: adipocytes size and density, immune cell infiltration, vascularization, secretome and gene expression. Adipose tissues from tumor-bearing breasts, whether adjacent to or distant from the tumor, do not differ from each other by any of these parameters. By contrast, adipose tissues from tumor-bearing breasts have the capacity to secrete twice as much interleukin 8 (IL-8) than those from tumor-free breasts and differentially express a set of 137 genes of which a significant fraction belongs to inflammation, integrin and wnt signaling pathways. These observations show that adipose tissues from tumor-bearing breasts have a distinct physiological status from those from tumor-free breasts. We propose that this constitutive status contributes as a non-cell autonomous process to determine permissiveness for tumor growth.
PubMed: 32974182
DOI: 10.3389/fonc.2020.01506 -
Viruses Jan 2016Hepatitis B virus (HBV) is a small DNA virus that infects the liver. Current anti-HBV drugs efficiently suppress viral replication but do not eradicate the virus due to... (Review)
Review
Hepatitis B virus (HBV) is a small DNA virus that infects the liver. Current anti-HBV drugs efficiently suppress viral replication but do not eradicate the virus due to the persistence of its episomal DNA. Efforts to develop reliable in vitro systems to model HBV infection, an imperative tool for studying HBV biology and its interactions with the host, have been hampered by major limitations at the level of the virus, the host and infection readouts. This review summarizes major milestones in the development of in vitro systems to study HBV. Recent advances in our understanding of HBV biology, such as the discovery of the bile-acid pump sodium-taurocholate cotransporting polypeptide (NTCP) as a receptor for HBV, enabled the establishment of NTCP expressing hepatoma cell lines permissive for HBV infection. Furthermore, advanced tissue engineering techniques facilitate now the establishment of HBV infection systems based on primary human hepatocytes that maintain their phenotype and permissiveness for infection over time. The ability to differentiate inducible pluripotent stem cells into hepatocyte-like cells opens the door for studying HBV in a more isogenic background, as well. Thus, the recent advances in in vitro models for HBV infection holds promise for a better understanding of virus-host interactions and for future development of more definitive anti-viral drugs.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Hepatitis B; Hepatitis B virus; Hepatocytes; Humans
PubMed: 26784218
DOI: 10.3390/v8010021 -
JAMA Psychiatry Sep 2013The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and... (Review)
Review
The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.
Topics: Adult; Animals; Antidepressive Agents; Depressive Disorder; Humans; Nerve Net; Neuronal Plasticity; Recovery of Function
PubMed: 23842648
DOI: 10.1001/jamapsychiatry.2013.1 -
Alcoholism, Clinical and Experimental... Apr 2019Studies have shown that parents have a significant influence on emerging adult college students' drinking during the first year of college. Limited research has been...
BACKGROUND
Studies have shown that parents have a significant influence on emerging adult college students' drinking during the first year of college. Limited research has been conducted to address the question of whether parenting later in college continues to matter in a similar manner. The current study utilized a prospective design to identify associations between parental permissiveness toward alcohol use and monitoring behaviors and student drinking outcomes during the first and fourth years of college.
METHODS
Participants (N = 1,429) at 3 large public universities completed surveys during the fall semesters of their first (T1) and fourth years (T2) (84.3% retention). The study employed a saturated autoregressive cross-lag model to examine associations between parental permissiveness of college student alcohol use, parental monitoring, student drinking, and consequences at T1 and T2, controlling for peer norms, sex, and campus.
RESULTS
Examination of the association between parenting and student drinking outcomes revealed: (i) parental permissiveness was positively associated with drinking at T1 and again at T2; (ii) parental permissiveness had indirect effects on consequences via the effects on drinking at both times. Specifically, a 1-unit increase in parental permissiveness at T1 resulted in students experiencing 4 to 5 more consequences as a result of their drinking; (iii) parental permissiveness was not directly associated with monitoring at T1 or T2; and (iv) parental monitoring was significantly associated with drinking at T1 but not T2.
CONCLUSIONS
The findings provide evidence for the continued importance of parenting in the fourth year of college and parents expressing low permissiveness toward student drinking may be beneficial to reducing risky drinking even as students turn 21.
Topics: Adolescent; Alcohol Drinking in College; Female; Humans; Male; Parenting; Permissiveness; Prospective Studies; Time Factors; Young Adult
PubMed: 30748022
DOI: 10.1111/acer.13978 -
Frontiers in Immunology 2014Study of the function of epitopes of Mycobacterium tuberculosis antigens contributed significantly toward better understanding of the immunopathogenesis and to efforts... (Review)
Review
Study of the function of epitopes of Mycobacterium tuberculosis antigens contributed significantly toward better understanding of the immunopathogenesis and to efforts for improving infection and disease control. Characterization of genetically permissively presented immunodominant epitopes has implications for the evolution of the host-parasite relationship, development of immunodiagnostic tests, and subunit prophylactic vaccines. Knowledge of the determinants of cross-sensitization, relevant to other pathogenic or environmental mycobacteria and to host constituents has advanced. Epitope-defined IFNγ assay kits became established for the specific detection of infection with tubercle bacilli both in humans and cattle. The CD4 T-cell epitope repertoire was found to be more narrow in patients with active disease than in latently infected subjects. However, differential diagnosis of active TB could not be made reliably merely on the basis of epitope recognition. The mechanisms by which HLA polymorphism can influence the development of multibacillary tuberculosis (TB) need further analysis of epitopes, recognized by Th2 helper cells for B-cell responses. Future vaccine development would benefit from better definition of protective epitopes and from improved construction and formulation of subunits with enhanced immunogenicity. Epitope-defined serology, due to its operational advantages is suitable for active case finding in selected high disease incidence populations, aiming for an early detection of infectious cases and hence for reducing the transmission of infection. The existing knowledge of HLA class I binding epitopes could be the basis for the construction of T-cell receptor-like ligands for immunotherapeutic application. Continued analysis of the functions of mycobacterial epitopes, recognized by T cells and antibodies, remains a fertile avenue in TB research.
PubMed: 24715888
DOI: 10.3389/fimmu.2014.00107