Advances in related research about the development of glioma and its relationship with human cytomegalovirus infection

Suppression of human trophoblast syncytialization by human cytomegalovirus infection.

Human Cytomegalovirus Selectively Suppresses the Megakaryo/Thrombopoiesis of PDGFR+ and αvβ3+ Megakaryocytes Via the TPO/c-Mpl Pathway after Allo-HSCT

Objective: To investigate the interaction between human cytomegalovirus infection and PAX9 gene polymorphisms in low birth weight (LBW) infants.Methods: Nested-PCR was used to detect human cytomegalovirus (HCMV) infection and restriction fragment length polymorphism PCR (RFLP-PCR) was then used to detect polymorphisms at rs2073244 and rs4904210 on the PAX9 gene in 65 HCMV-positive infant cases and 65 HCMV-negative infant controls. Cases and controls were compared for differences in the rates of LBW using the χ2 test. Genetic and environmental interactions were assessed by comparing rates of LBW between the cases and controls in stratified analyses and logistic regressions.Results: The study confirmed that HCMV infection is significantly associated with LBW (OR = 5.519, χ2 = 20.924, p < 0.05) and suggested that some PAX9 polymorphisms may promote the induction of LBW by HCMV infection. The AG and GG genotypes at rs2073244 and the CC genotype at rs4904210, with interaction coefficients greater than unity suggest that they may strengthen the association between HCMV infection and LBW.Conclusions: Congenital HCMV infection can cause LBW and some PAX9 polymorphisms can increase the risk of LBW in HCMV-infected infants. The results may provide new clues into the relationship among HCMV infection, PAX9 polymorphisms and LBW as well as a foundation for additional molecular epidemiological and biochemical research in the future.

BackgroundViral infections are known to induce the occurrence and pathogenesis of systemic lupus erythematosus (SLE). Previous studies have indicated a possible relationship between SLE and human cytomegalovirus (HCMV) infection and have attributed HCMV to be associated with various autoantibodies; however, these studies were constrained by variations in sample size and potential selection bias. Therefore, in the present study, we aimed to elucidate the relationship between HCMV and autoantibodies in patients with SLE by integrating clinical data and genetic susceptibility.MethodsUsing various statistical methods, we conducted a retrospective analysis of the spectrum of SLE autoantibodies and HCMV infections among patients hospitalized at our center over the past 10 years. Machine learning modeling was used to predict active HCMV infections based on the antinuclear (ANA) spectrum. Moreover, Mendelian randomization (MR) was used to investigate the causal relationship between SLE and HCMV infection.ResultsIn the HCMV group, the levels of ANA, anti-dsDNA, anti-histone antibody (AHA), and anti-nucleosome antibody (ANuA) were significantly increased (P < 0.001) and were linked to the presence of CMV-pp65-antigen-positive polymorphonuclear leukocytes (P < 0.001). A weak correlation was observed between the titers of anti-CMV IgM and ANA (P < 0.001). The ANA spectrum demonstrated a strong predictive performance for active HCMV infection based on principal component analysis (Adonis and ANOSIM P < 0.001) as well as support vector machine and extreme gradient boosting modeling. MR analyses of inverse-variance weighted, weighted mean, MR-Egger, and weighted mode revealed that patients with SLE were at a higher risk of developing HCMV infection (P < 0.05). However, HCMV infection did not have a causal effect on SLE (P > 0.05).ConclusionThe ANA spectrum in patients with SLE can be used to predict HCMV infection status. Due to the inherent susceptibility of patients with SLE to HCMV infection, we propose for the first time that if a patient with SLE exhibits high serum titers of ANA, anti-dsDNA, ANuA, and AHA, caution should be exercised for HCMV infection, which can contribute to the clinical assessment of SLE and improve patient prognosis.

Human cytomegalovirus infection of cells of hematopoietic origin: HCMV-induced immunosuppression, immune evasion, and latency

Objective To observe the changes in the expression of pro-inflammatory cytokines IL-1β over time in THP-1 derived macrophages after human cytomegalovirus (HCMV) infection. Methods The model of HCMV infection in THP-1 derived macrophages was constructed, then HCMV infected group, the mock-infected control group, LPS + ATP group and poly (dA : dT) control group were established. ELISA analysis was performed to measure the levels of IL-1β in culture supernatant of THP-1 derived macrophages at 1 hour, 3 hours, 6 hours, 12 hours, 24 hours and 48 hours after infected with HCMV. Real-time PCR and western blot were performed to measure the expression levels of IL-1β gene and protein, respectively. Results The gene expression of pro-inflammatory cytokines IL-1β in HCMV infected group is 7.77 times to the mock-infected control group at 6 hours after HCMV infected THP-1 derived macrophages. IL-1β in supernatant of THP-1-derived macrophages increased significantly at 1 hour after HCMV infection, was continuously rising at 3 hours and 6 hours subsequently, and reached at peak at 12 hours and maintained till 48 hours. The protein expression of IL-1β in HCMV infected group was significantly higher than the mock-infected control group and poly (dA : dT) control group at 6 hours after HCMV infected THP-1 derived macrophages, while no significant difference between the LPS + ATP control group. Conclusions The expression of IL-1β is induced by HCMV infected THP-1 derived macrophages, and continue to increase over time. Key words: Human cytomegalovirus; THP-1 derived macrophages; Interleukine-1 beta

First-Line Therapy with Donor Derived HCMV-Specific T Cells Reduce Persistent HCMV Infection after Allogenic Stem Cell Transplantation

PDGFR-Mediated Cytomegalovirus Infection of Megakaryocytes Induces Thrombocytopenia Via Demethylation of AML1 and IEX-1 in the TPO/c-Mpl Signaling Pathway Following Allo-HSCT

Congenital human cytomegalovirus (HCMV) infection is a major cause of abnormalities and disorders in the central nervous system (CNS) and/or the peripheral nervous system (PNS). However, the complete pathogenesis of neural differentiation disorders caused by HCMV infection remains to be fully elucidated. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells (MSCs) with a high proliferation and neurogenic differentiation capacity. Since SHEDs originate from the neural crest of the early embryonic ectoderm, SHEDs were hypothesized to serve as a promising cell line for investigating the pathogenesis of neural differentiation disorders in the PNS caused by congenital HCMV infection. In this work, SHEDs were demonstrated to be fully permissive to HCMV infection and the virus was able to complete its life cycle in SHEDs. Under neurogenic inductive conditions, HCMV infection of SHEDs caused an abnormal neural morphology. The expression of stem/neural cell markers was also disturbed by HCMV infection. The impairment of neural differentiation was mainly due to a reduction of intracellular cholesterol levels caused by HCMV infection. Sterol regulatory element binding protein-2 (SREBP2) is a critical transcription regulator that guides cholesterol synthesis. HCMV infection was shown to hinder the migration of SREBP2 into nucleus and resulted in perinuclear aggregations of SREBP2 during neural differentiation. Our findings provide new insights into the prevention and treatment of nervous system diseases caused by congenital HCMV infection.

Human cytomegalovirus (HCMV) is a leading cause of birth defects in humans. These birth defects include microcephaly, sensorineural hearing loss, vision loss, and cognitive impairment. The process by which the developing fetus incurs these neurological defects is poorly understood. To elucidate some of these mechanisms, we have utilized HCMV-infected induced pluripotent stem cells (iPSCs) to generate in vitro brain organoids, modeling the first trimester of fetal brain development. Early during culturing, brain organoids generate neural rosettes. These structures are believed to model neural tube formation. Rosette formation was analyzed in HCMV-infected and mock-infected brain organoids at 17, 24, and 31 days postinfection. Histological analysis revealed fewer neural rosettes in HCMV-infected compared to mock-infected organoids. HCMV-infected organoid rosettes incurred multiple structural deficits, including increased lumen area, decreased ventricular zone depth, and decreased cell count. Immunofluorescent (IF) analysis found that nidogen-1 (NID1) protein expression in the basement membrane surrounding neural rosettes was greatly reduced by virus infection. IF analysis also identified a similar downregulation of laminin in basement membranes of HCMV-infected organoid rosettes. Knockdown of NID1 alone in brain organoids impaired their development, leading to the production of rosettes with increased lumen area, decreased structural integrity, and reduced laminin localization in the basement membrane, paralleling observations in HCMV-infected organoids. Our data strongly suggest that HCMV-induced downregulation of NID1 impairs neural rosette formation and integrity, likely contributing to many of HCMV's most severe birth defects. IMPORTANCE HCMV infection in pregnant women continues to be the leading cause of virus-induced neurologic birth defects. The mechanism through which congenital HCMV (cCMV) infection induces pathological changes to the developing fetal central nervous system (CNS) remains unclear. Our lab previously reproduced identified clinical defects in HCMV-infected infants using a three dimensional (3D) brain organoid model. In this new study, we have striven to discover very early HCMV-induced changes in developing brain organoids. We investigated the development of neural tube-like structures, neural rosettes. HCMV-infected rosettes displayed multiple structural abnormalities and cell loss. HCMV-infected rosettes displayed reduced expression of the key basement membrane protein, NID1. We previously found NID1 to be specifically targeted in HCMV-infected fibroblasts and endothelial cells. Brain organoids generated from NID1 knockdown iPSCs recapitulated the structural defects observed in HCMV-infected rosettes. Findings in this study revealed HCMV infection induced early and dramatic structural changes in 3D brain organoids. We believe our results suggest a major role for infection-induced NID1 downregulation in HCMV-induced CNS birth defects.

Comparing Costs Associated to Letermovir Prophylaxis Vs Ganciclovir Pre-Emptive Therapy in HCMV-Seropositive Patients Who Undergone to Hemopoietic Stem Cells Transplantation

Human cytomegalovirus infection inhibits the differentiation of human hippocampus neural precursor cells into astrocytes

Congenital human cytomegalovirus (HCMV) infection is a common cause of deafness and neurological disabilities. Many aspects of this prenatal infection, including which cell types are infected and how infection proceeds, are poorly understood. Transcription of HCMV immediate-early (IE) genes is required for expression of all other HCMV genes and is dependent on host cell transcription factors. Cell type-specific differences in levels of IE transcription are believed to underlie differences in infection permissivity. However, DNA transfection experiments have paradoxically suggested that the HCMV major IE enhancer/promoter is a broadly active transcriptional element with little cell type specificity. In contrast, we show here that expression of a lacZ gene driven by the HCMV major IE enhancer/promoter -524 to +13 segment is restricted in transgenic mouse embryos to sites that correlate with known sites of congenital HCMV infection in human fetuses. This finding suggests that the IE enhancer/promoter is a major determinant of HCMV infection sites in humans and that transcription factors responsible for its regulation are cell type-specifically conserved between humans and mice. The lacZ expression patterns of these transgenic embryos yield insight into congenital HCMV pathogenesis by providing a spatiotemporal map of the sets of vascular, neural, and epithelial cells that are likely targets of infection. These transgenic mice may constitute a useful model system for investigating IE enhancer/promoter regulation in vivo and for identifying factors that modulate active and latent HCMV infections in humans.

Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs) and induces cell cycle arrest, which in turn modifies the cellular environment to favor virus replication. Previous observations found that HCMV infection reduces miR-21 expression in neural progenitor/stem cells (NPCs). Here, we show that infection of NPCs and U-251MG cells represses miR-21 while increasing the levels of Cdc25a, a cell cycle regulator and known target of miR-21. These opposing responses to infection prompted an investigation of the relationship between miR-21, Cdc25a, and viral replication. Overexpression of miR-21 in NPCs and U-251MG cells inhibited viral gene expression, genome replication, and production of infectious progeny, while shRNA-knockdown of miR-21 in U-251MG cells increased viral gene expression. In contrast, overexpression of Cdc25a in U-251MG cells increased viral gene expression and production of infectious progeny and overcame the inhibitory effects of miR-21 overexpression. Three viral gene products-IE1, pp71, and UL26-were shown to inhibit miR-21 expression at the transcriptional level. These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS. Human cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.

Cytomegalovirus Infection in Bone Marrow-Derived Mesenchymal Stem Cells: Implications for Functions and Exploration of Relevant Mechanisms