Perinatal mouse cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
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ABSTRACT:
PROVIDER: PRJEB64583 | ENA |
REPOSITORIES: ENA
Dataset's files
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Project description:Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection severely compromised NK cell maturation and functionality in newborns. This effect was not due to compromised virus control. Inflammatory responses to infection dysregulated the expression of major transcription factors governing NK cell fate, such as Eomes, resulting in impaired NK cell function. Most prominently, NK cells from perinatally infected mice have a diminished ability to produce IFN-γ due to the downregulation of long non-coding RNA Ifng-as1 expression. Moreover, the bone marrow's capacity to efficiently generate new NK cells is reduced, explaining the prolonged negative effects of perinatal infection on NK cells. This study demonstrates that viral infections in early life can profoundly impact NK cell biology, including long-lasting impairment in NK cell functionality.
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2024-12-22 | GSE173346 | GEO
Project description:BackgroundCongenital cytomegalovirus (CMV) infection (cCMV) is an important cause of hearing loss and cognitive impairment. Prior studies suggest that HIV-exposed children are at higher risk of acquiring cCMV. We assessed the presence, magnitude and risk factors associated with cCMV among infants born to HIV-infected women, who were not receiving antiretrovirals during pregnancy.MethodscCMV and urinary CMV load were determined in a cohort of infants born to HIV-infected women not receiving antiretrovirals during pregnancy. Neonatal urines obtained at birth were tested for CMV DNA by qualitative and reflex quantitative real-time polymerase chain reaction.ResultsUrine specimens were available for 992 (58.9%) of 1684 infants; 64 (6.5%) were CMV-positive. Mean CMV load (VL) was 470,276 copies/ml (range: < 200-2,000,000 copies/ml). Among 89 HIV-infected infants, 16 (18%) had cCMV versus 42 (4.9%) of 858 HIV-exposed, uninfected infants (P < 0.0001). cCMV was present in 23.2% of infants with in utero and 9.1% infants with intrapartum HIV infection (P < 0.0001). Rates of cCMV among HIV-infected infants were 4-fold greater (adjusted OR, 4.4; 95% CI: 2.3-8.2) and 6-fold greater among HIV in utero-infected infants (adjusted OR, 6; 95% CI: 3-12.1) compared with HIV-exposed, uninfected infants. cCMV was not associated with mode of delivery, gestational age, Apgar scores, 6-month infant mortality, maternal age, race/ethnicity, HIV viral load or CD4 count. Primary cCMV risk factors included infant HIV-infection, particularly in utero infection.ConclusionHigh rates of cCMV with high urinary CMV VL were observed in HIV-exposed infants. In utero HIV infection appears to be a major risk factor for cCMV in infants whose mothers have not received combination antiretroviral therapy in pregnancy.
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Project description:Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both of these types of immunity, currently approved vaccine adjuvants largely fail to induce significant T cell responses. However, recent work by our lab and others suggests that the mechanisms governing vaccine-elicited T cells (Tvac) may be substantially different than those governing infection-elicited T cells (Tinf). We have recently demonstrated that optimal subunit vaccine-elicited T cell responses rely on different cytokine signals (IL-27 and 15) and metabolic function (oxidative phosphorylation vs. aerobic glycolysis) leading to phenotypically and functionally different outcomes (memory vs. effector). Our goal was to investigate the transcriptional programming that promotes Tvac formation. Using a single-cell RNA-seq approach, we compared Tvac and Tinf at day 7 post-immunization or infectious challenge to determine the heterogenity of CD8 T cell responses at this peak timepoint.
2023-07-14 | GSE237416 | GEO
Project description:Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both of these types of immunity, currently approved vaccine adjuvants largely fail to induce significant T cell responses. However, recent work by our lab and others suggests that the mechanisms governing vaccine-elicited T cells (Tvac) may be substantially different than those governing infection-elicited T cells (Tinf). We have recently demonstrated that optimal subunit vaccine-elicited T cell responses rely on different cytokine signals (IL-27 and 15) and metabolic function (oxidative phosphorylation vs. aerobic glycolysis) leading to phenotypically and functionally different outcomes (memory vs. effector). Our goal was to investigate the transcriptional programming that promotes Tvac formation. Using a bulk RNAsequencing approach we compared WT Tvac at day 3 post immunization to Tvac where IL-27 or IL-15 signaling was absent, to Tinf at day 4 post infectious challenge, or to naive OT-1 T cells.
2023-07-14 | GSE237415 | GEO
Project description:Mother-to-child transmission of cytomegalovirus (CMV) and varicella zoster virus (VZV) can lead to severe birth defects and neurologic impairment of infants. Congenital CMV complicates up to 1% of all pregnancies globally. Although antiviral treatment of infants congenitally infected with CMV can ameliorate the CMV-associated hearing loss and developmental delay, interventions to prevent congenital CMV infection and the associated neurologic impairments are still being evaluated. Congenital VZV infection is rare. Active and passive immunization strategies to prevent perinatal CMV infection with similar efficacy to those established to prevent perinatal VZV infections are critically needed in pediatric health.
| S-EPMC4328139 | biostudies-other
Project description:Perinatal asphyxia remains a leading cause of neonatal mortality, and a major contributor to permanent neurological deficits. Even mild cases can result in long-term neurodevelopmental, cognitive, behavioural, and psychiatric disorders. However, the mechanisms underlying asphyxia-induced hypoxic-ischaemic brain injury remain poorly understood, limiting the development of targeted interventions during the critical early plastic period. To investigate how perinatal asphyxia-induced changes lead to neuropsychiatric deficits and associated histological and molecular alterations that progress into adulthood, we utilised a translationally relevant, non-invasive oxygen deprivation model of asphyxia in postnatal day 7 rats. We conducted comprehensive assessment of asphyxia-induced changes, integrating neurobehavioural profiling (evaluating cognitive, emotional, social, and neuromotor functions), microglial morphology analysis, neuroimaging, stress hormone measurement and whole-transcriptome sequencing techniques to elucidate the acute and long-term functional consequences. Consistent with clinical observations, the extensive functional assessment revealed distinct sex-dependent effects, including increased anxiety and impulsivity, attention deficits, and impaired inhibitory control, which were observed exclusively in males, with no apparent sensorimotor deficits. This phenotype resembling attention deficit hyperactivity disorder in adult rats was associated with a lasting increase in inhibitory bouton densities in the medial prefrontal cortex. The development of an acute inflammatory response after perinatal asphyxia marked by phenotypic transformation of microglia paralleled brain perfusion and stress hormone changes. Notably, microglial changes were mitigated by the blockade of proinflammatory interleukin-1 signalling via systemic IL-1 receptor antagonist (IL-1RA) administration in a therapeutically relevant time window. Importantly, early blockade of proinflammatory responses was able to prevent cognitive deficits in adulthood, and normalised inhibitory bouton densities. RNA sequencing analysis revealed asphyxia-induced dysregulation of molecular pathways targeting GABAergic signalling, potentially contributing to subsequent morphological and neuropsychiatric alterations. IL-1RA treatment appeared to engage distinct regulatory mechanisms, rather than merely reversing these disruptions in the acute post-asphyxia period. Collectively, these findings demonstrate that perinatal asphyxia induces marked behavioural deficits in attention and inhibitory control, paralleled by lasting inhibitory dysregulation, preceded by acute induction of microglia-driven inflammatory processes in the medial prefrontal cortex. Systemic IL-1RA administration may represent a promising therapeutic opportunity to prevent long-term cognitive impairments caused by perinatal asphyxia. Perinatal asphyxia remains a leading cause of neonatal mortality, and a major contributor to permanent neurological deficits. Even mild cases can result in long-term neurodevelopmental, cognitive, behavioural, and psychiatric disorders. However, the mechanisms underlying asphyxia-induced hypoxic-ischaemic brain injury remain poorly understood, limiting the development of targeted interventions during the critical early plastic period. To investigate how perinatal asphyxia-induced changes lead to neuropsychiatric deficits and associated histological and molecular alterations that progress into adulthood, we utilised a translationally relevant, non-invasive oxygen deprivation model of asphyxia in postnatal day 7 rats. We conducted comprehensive assessment of asphyxia-induced changes, integrating neurobehavioural profiling (evaluating cognitive, emotional, social, and neuromotor functions), microglial morphology analysis, neuroimaging, stress hormone measurement and whole-transcriptome sequencing techniques to elucidate the acute and long-term functional consequences. Consistent with clinical observations, the extensive functional assessment revealed distinct sex-dependent effects, including increased anxiety and impulsivity, attention deficits, and impaired inhibitory control, which were observed exclusively in males, with no apparent sensorimotor deficits. This phenotype resembling attention deficit hyperactivity disorder in adult rats was associated with a lasting increase in inhibitory bouton densities in the medial prefrontal cortex. The development of an acute inflammatory response after perinatal asphyxia marked by phenotypic transformation of microglia paralleled brain perfusion and stress hormone changes. Notably, microglial changes were mitigated by the blockade of proinflammatory interleukin-1 signalling via systemic IL-1 receptor antagonist (IL-1RA) administration in a therapeutically relevant time window. Importantly, early blockade of proinflammatory responses was able to prevent cognitive deficits in adulthood, and normalised inhibitory bouton densities. RNA sequencing analysis revealed asphyxia-induced dysregulation of molecular pathways targeting GABAergic signalling, potentially contributing to subsequent morphological and neuropsychiatric alterations. IL-1RA treatment appeared to engage distinct regulatory mechanisms, rather than merely reversing these disruptions in the acute post-asphyxia period. Collectively, these findings demonstrate that perinatal asphyxia induces marked behavioural deficits in attention and inhibitory control, paralleled by lasting inhibitory dysregulation, preceded by acute induction of microglia-driven inflammatory processes in the medial prefrontal cortex. Systemic IL-1RA administration may represent a promising therapeutic opportunity to prevent long-term cognitive impairments caused by perinatal asphyxia.
2025-12-30 | GSE295589 | GEO
Project description:Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in people who are immunocompromised, such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in people who are immunosuppressed have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in patients who are immunocompromised and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with noncontrolled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific CD8+ T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of CD8+ T cells could be targeted by inhibiting CD38 to reverse hyporesponsiveness in individuals who fail to control chronic viral infection.
| S-EPMC11364383 | biostudies-literature
Project description:Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.
| S-EPMC11377837 | biostudies-literature
Project description:Background & aimsA high human cytomegalovirus (HCMV) infection rate accompanied by an increased level of bile duct damage is observed in the perinatal period. The possible mechanism was investigated.MethodsA total of 1,120 HCMV-positive and 9,297 HCMV-negative children were recruited, and depending on age, their liver biochemistry profile was compared. Fetal and infant biliary epithelial cells (F-BECs and I-BECs, respectively) were infected with HCMV, and the differences in cells were revealed by proteomic analysis. Protein-protein interactions were examined by coimmunoprecipitation and mass spectrometry analyses. A murine cytomegalovirus (MCMV) infection model was established to assess treatment effects.ResultsPerinatal HCMV infection significantly increased the level of bile duct damage. Neonatal BALB/c mice inoculated with MCMV showed obvious inflammation in the portal area with an abnormal bile duct structure. Proteomics analysis showed higher CD14 expression in F-BECs than in I-BECs. CD14 siRNA administration hindered HCMV infection, and CD14-knockout mice showed lower MCMV-induced bile duct damage. HCMV infection upregulated CD55 and poly ADP-ribose polymerase-1 (PARP-1) expression in F-BECs. Coimmunoprecipitation and mass spectrometry analyses revealed formation of the CD14-CD55 complex. siRNA-mediated inhibition of CD55 expression reduced sCD14-promoted HCMV replication in F-BECs. In MCMV-infected mice, anti-mouse CD14 antibody and PARP-1 inhibitor treatment diminished cell death, ameliorated bile duct damage, and reduced mortality.ConclusionsCD14 facilitates perinatal HCMV infection in BECs via CD55, and PARP-1-mediated cell death was detected in perinatal cytomegalovirus-infected BECs. These results provide new insight into the treatment of perinatal HCMV infection with bile duct damage.Impact and implicationsPerinatal human cytomegalovirus (HCMV) infection is associated with bile duct damage, but the underlying mechanism is still unknown. We discovered that CD14 expression is increased in biliary epithelial cells during perinatal HCMV infection and facilitates viral entry through CD55. We also detected PARP-1-mediated cell death in perinatal HCMV-infected biliary epithelial cells. We showed that blocking CD14 or inhibiting PARP-1 reduced bile duct damage and mortality in a mouse model of murine cytomegalovirus infection. Our findings provide a new insight into therapeutic strategies for perinatal HCMV infection.
| S-EPMC11002872 | biostudies-literature