Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination.
Ontology highlight
ABSTRACT:
SUBMITTER: Sacher T
PROVIDER: S-EPMC3219709 | biostudies-other | 2011 Nov
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Recent advances in fluorescence microscopy have opened up new possibilities to investigate chromosomal and nuclear 3D organization on the nanoscale. We here discuss their potential for elucidating topographical details of the nuclear lamina. Single molecule localization microscopy (SMLM) in combination with immunostainings of lamina proteins readily reveals tube-like invaginations with a diameter of 100-500 nm. Although these invaginations have been established as a frequent and general feature of interphase nuclei across different cell types, their formation mechanism and function have remained largely elusive. We critically review the current state of research, propose possible connections to lamina associated domains (LADs), and revisit the discussion about the potential role of these invaginations for accelerating mRNA nuclear export. Illustrative studies using 3D super-resolution imaging are shown and will be instrumental to decipher the physiological role of these nanoscale invaginations.
| S-EPMC5703262 | biostudies-literature
Project description:UnlabelledThe UL128 complex of human cytomegalovirus (CMV) is a major determinant of viral entry into epithelial and endothelial cells and a target for vaccine development. The UL/b' region of rhesus CMV contains several open reading frames, including orthologs of the UL128 complex. We recently showed that the coding content of the rhesus CMV (RhCMV) UL/b' region predicts acute endothelial tropism and long-term shedding in vivo in the rhesus macaque model of CMV infection. The laboratory-passaged RhCMV 180.92 strain has a truncated UL/b' region but an intact UL128 complex. To investigate whether the presence of the UL128 complex alone was sufficient to confer endothelial and epithelial tropism in vivo, we investigated tissue dissemination and viral excretion following experimental RhCMV 180.92 inoculation of RhCMV-seronegative rhesus macaques. We show the presence of at least two virus variants in the RhCMV 180.92 infectious virus stock. A rare variant noted for a nontruncated wild-type-virus-like UL/b' region, rapidly emerged during in vivo replication and showed high-level replication in blood and tissues and excretion in urine and saliva, features similar to those previously reported in naturally occurring wild-type RhCMV infection. In contrast, the predominant truncated version of RhCMV 180.92 showed significantly lower plasma DNAemia and limited tissue dissemination and viral shedding. These data demonstrate that the truncated RhCMV 180.92 variant is attenuated in vivo and suggest that additional UL/b' genes, besides the UL128 complex, are required for optimal in vivo CMV replication and dissemination.ImportanceAn effective vaccine against human CMV infection will need to target genes that are essential for virus propagation and transmission. The human CMV UL128 complex represents one such candidate antigen since it is essential for endothelial and epithelial cell tropism, and is a target for neutralizing antibodies in CMV-infected individuals. In this study, we used the rhesus macaque animal model of CMV infection to investigate the in vivo function of the UL128 complex. Using experimental infection of rhesus macaques with a rhesus CMV virus variant that contained an intact UL128 complex but was missing several other genes, we show that the presence of the UL128 complex alone is not sufficient for widespread tissue dissemination and virus excretion. These data highlight the importance of in vivo studies in evaluating human CMV gene function and suggest that additional UL/b' genes are required for optimal CMV dissemination and transmission.
| S-EPMC4136270 | biostudies-literature
Project description:As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3'-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.
| S-EPMC8308470 | biostudies-literature
Project description:Chronic myeloid leukemia stem cells (CML LSCs) are a rare and quiescent population that are resistant to tyrosine kinase inhibitors (TKI). When TKI therapy is discontinued in CML patients in deep, sustained and apparently stable molecular remission, these cells in approximately half of the cases restart to grow, resuming the leukemic process. The elimination of these TKI resistant leukemic stem cells is therefore an essential step in increasing the percentage of those patients who can reach a successful long-term treatment free remission (TFR). The understanding of the biology of the LSCs and the identification of the differences, phenotypic and/or metabolic, that could eventually allow them to be distinguished from the normal hematopoietic stem cells (HSCs) are therefore important steps in designing strategies to target LSCs in a rather selective way, sparing the normal counterparts.
| S-EPMC8708315 | biostudies-literature
Project description:BackgroundPassive dissemination of information in healthcare refers to the publication or mailing of newly established guidelines or recommendations. It is one of the least costly knowledge translation activities. This approach is generally considered to be ineffective or to result in only small changes in practice. Recent research, however, suggests that passive dissemination could, under certain conditions, result in modifications of practice, similar to more active dissemination approaches. The objective of our study was to uncover the conditions associated with the change in primary care practice, namely Family Medicine Groups (FMGs) in Quebec (Canada), following the passive dissemination of recommendations for the diagnosis and management of Alzheimer's disease and related dementia (AD).MethodsWe used a three-step, innovative, convergent mixed methods design based on a multiple case study in eight FMGs. Two studies were conducted in parallel: (1) a before and after retrospective chart review and a cluster analysis of FMGs performed on two clinical performance indicators-the rate of AD diagnosis and the quality of follow-up care; (2) a qualitative descriptive study using interviews and focus groups with FMG clinicians and healthcare managers. The results were integrated using joint displays.ResultsAfter the passive dissemination of the recommendations, some FMGs started to implement the recommendations while other FMGs did not change their practice with respect to the AD diagnosis rate and quality of follow-up care. Three interrelated conditions were identified for the successful passive dissemination of clinical recommendations: (1) FMG clinicians with a moderate to high baseline expertise and confidence, which was linked to their existing collaboration with hospital-based specialists in dementia and their motivation; (2) the presence of a self-identified champion (individual champion or collective championship) in the FMGs taking the lead, motivating the clinical staff or organizing training; (3) the availability of sufficient clinical staff enabled these two conditions to have an impact on the implementation of recommendations through passive dissemination.ConclusionsPassive dissemination of clinical recommendations, a low-cost knowledge translation approach, may lead to practice change under some specific conditions. More active dissemination efforts may only be needed in sites where these conditions are absent.
| S-EPMC6192363 | biostudies-literature
Project description:Human cytomegalovirus (HCMV) is a ubiquitous pathogen that establishes a life-long infection affecting up to 80% of the US population. HCMV periodically reactivates leading to enhanced morbidity and mortality in immunosuppressed patients causing a range of complications including organ transplant failure and cognitive disorders in neonates. Therapeutic options for HCMV are limited to a handful of antivirals that target late stages of the virus life cycle and efficacy is often challenged by the emergence of mutations that confer resistance. In addition, these antiviral therapies may have adverse reactions including neutropenia in newborns and an increase in adverse cardiac events in HSCT patients. These findings highlight the need to develop novel therapeutics that target different steps of the viral life cycle. To this end, we screened a small molecule library against ion transporters to identify new antivirals against the early steps of virus infection. We identified valspodar, a 2nd-generation ABC transporter inhibitor, that limits HCMV infection as demonstrated by the decrease in IE2 expression of virus infected cells. Cells treated with increasing concentrations of valspodar over a 9-day period show minimal cytotoxicity. Importantly, valspodar limits HCMV plaque numbers in comparison to DMSO controls demonstrating its ability to inhibit viral dissemination. Collectively, valspodar represents a potential new anti-HCMV therapeutic that limits virus infection by likely targeting a host factor. Further, the data suggest that specific ABC transporters may participate in the HCMV life-cycle.
| S-EPMC9157689 | biostudies-literature
Project description:A series of fluorescent anion transporters consisting of a urea or thiourea group linked to a naphthalimide fluorophore have been synthesised and their anion transport properties studied. The compounds possess similar anion transport properties to (thio)urea-based anionophores that have previously been reported. Fluorescence studies in cells show all anionophores cross the plasma membrane and localise within the interior of cells. The most lipophilic, aromatic substituted transporters localise homogeneously throughout the cell and are toxic towards cancer cells with the highly fluorinated compound 6 being the most effective. The least lipophilic, alkyl substituted transporters localise in specific vesicles and are non-toxic to cells. This work provides new insight to the actions of anionophores in cells and may be useful in the design of novel antineoplastic agents.
| S-EPMC6018715 | biostudies-literature
Project description:Murine cytomegalovirus encodes a secreted, pro-inflammatory chemokine-like protein, MCK-2, that recruits leukocytes and facilitates viral dissemination. We have shown that MCK-2-enhanced recruitment of myelomonocytic leukocytes with an immature phenotype occurs early during infection and is associated with efficient viral dissemination. Expression of MCK-2 drives the mobilization of a population of leukocytes from bone marrow that express myeloid marker Mac-1 (CD11b), intermediate levels of Gr-1 (Ly6 G/C), platelet-endothelial-cell adhesion molecule-1 (PECAM-1, CD31), together with heterogeneous levels of stem-cell antigen-1 (Sca-1, Ly-6 A /E). Recombinant MCK-2 mediates recruitment of this population even in the absence of viral infection. Recruitment of this cell population and viral dissemination via the bloodstream to salivary glands proceeds normally in mice that lack CCR2 and MCP-1 (CCL2), suggesting that recruitment of macrophages is not a requisite component of pathogenesis. Thus, a systemic impact of MCK-2 enhances the normal host response and causes a marked increase in myelomonocytic recruitment with an immature phenotype to initial sites of infection. Mobilization influences levels of virus dissemination via the bloodstream to salivary glands and is dependent on a myelomonocytic cell type other than mature macrophages.
| S-EPMC1895360 | biostudies-literature
Project description:Among innate cells, natural killer (NK) cells play a crucial role in the defense against cytomegalovirus (CMV). In some individuals, CMV infection induces the expansion of NKG2C+ NK cells that persist after control of the infection. We have previously shown that KIR2DL+ NK cells, in contrast to NKG2C+ NK cells, contribute to controlling CMV infection using a CMV-infected monocyte-derived dendritic cell (MDDC) model. However, the nature of CMV-infected cells contributing to the expansion of the NKG2C+ NK cell subset remains unclear. To gain more insight into this question, we investigated the contribution of NKG2C+ NK cell activation by CMV-infected primary human aortic endothelial cells (EC) isolated from kidney transplant donors, which constitutively express the human leukocyte antigen (HLA)-E molecule. Here, we show that, although classic HLA class I expression was drastically downregulated, nonclassic HLA-E expression was maintained in CMV-infected EC. By comparing HLA expression patterns in CMV-infected EC, fibroblasts and MDDC, we demonstrate a cell-dependent modulation of HLA-E expression by CMV infection. NKG2C+ NK cell degranulation was significantly triggered by CMV-infected EC regardless of the nature of the HLA-E allele product. EC, predominantly present in vessels, may constitute a privileged site for CMV infection that drives a 'memory' NKG2C+ NK cell subset.
| S-EPMC6738823 | biostudies-other
Project description:Molecular assessment of colorectal cancer (CRC) is receiving growing attention, beyond RAS and BRAF, because of its influence on prognosis and prediction in cancer treatment. PTEN (phosphatase and tensin homologue), a tumor suppressor, regulating cell division and apoptosis, has been explored, and significant evidence suggests a role in cetuximab and panitumumab resistance linked to the epidermal growth factor receptor (EGFR) signal transduction pathway. Factors influencing PTEN activity should be analyzed to develop strategies to maximize the tumor suppressor role and to improve tumor response to cancer treatment. Therefore, an in-depth knowledge of the PI3K-Akt pathway-one of the major cancer survival pathways-and the role of PTEN-a major brake of this pathway-is essential in the era of precision medicine. The purpose of this literature review is to summarize the role of PTEN as a predictive factor and possible therapeutic target in CRC, focusing on ongoing studies and the possible implications in clinical practice.
| S-EPMC6896095 | biostudies-literature