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PROVIDER: PRJNA1235228 | ENA |
REPOSITORIES: ENA
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Project description:<p><b>Public health importance</b>: Babies born preterm, approximately 1 out of every 9 live births in the United States, have significant respiratory morbidity over the first two years of life, exacerbated by respiratory viral infections. Many (<50%) return to pediatricians, emergency rooms and pulmonologists with symptoms of respiratory dysfunction (SRD): intermittent or chronic wheezing, poor growth and an excess of upper and lower respiratory tract infections (LRTI). SRD correlate inversely with gestational age and weight at birth and is more common in those with chronic lung disease of prematurity, yet its incidence and severity varies widely among both the prematurely born and those born at term. There is evidence from clinical studies and animal models that risks of LRTI and recurrent wheezing is influenced by gut and respiratory flora and by T cell responses to infection. Information gained from this study will be used to identify characteristics, risk factors and potential mechanisms for early and persistent lung disease in children born at term and born preterm.</p> <p>This Clinical Research Study will investigate the relationships between sequential respiratory viral infections, patterns of intestinal and respiratory bacterial colonization, and adaptive cellular immune phenotypes which are associated with increased susceptibility to respiratory infections and long term respiratory morbidity in preterm and full term infants. We hypothesize that the timing and acquisition of specific viral infections and bacterial species are directly related to respiratory morbidity in the first year of life as defined by SRD and by measures of pulmonary function. We hypothesize that cellular and molecular immuno-maturity are altered due to factors presented by premature birth in such a way as to promote chronic inflammatory and cytotoxic damage to the lung, with subsequent enhanced, damaging responses to infectious agents and environmental irritants. Our preliminary studies demonstrate both feasibility and expertise in mutiparameter immunophenotyping of small volume peripheral blood samples obtained from premature infants including gene expression arrays of flow cytometry sorted cells. We will use new technologies for known viral identification, as well as high-throughput metagenome sequencing of RNA and DNA virus like particles (VLP) to be used for viral discovery in infant respiratory sample and use of high-throughput pyrosequencing (454T) of bacterial 16S rRNA to determine shifts in bacterial community structure, occurring in pre-term (PT) as compared to full term (FT) infants, over the first year of life. Finally, we present statistical approaches to stratify disease risk predictors using multivariate logistic regression modeling approaches. We propose to evaluate T cell phenotypic and functional profiles relative to viral and predominant bacterial exposures according to highly complementary, but independent, Specific Objectives.</p> <p><b>Objective 1</b>: To determine if viral respiratory infections and patterns of respiratory and gut bacterial community structure (microbiome) in prematurely born babies predict the rate and degree of immunologic maturation, and pulmonary dysfunction, measured from birth to 36 weeks corrected gestational age (CGA).</p> <p><b>Objective 2</b>: To determine the relationship between respiratory viral infections and disease severity up to one year CGA, and the lymphocyte (Lc) phenotypes documented at term gestation (birth for term infants and 36 wks/NICU discharge in preterm infants) and at one year CGA. Three secondary outcomes of this objective will be to a) relate the quantity, type and severity of viral infections with pulmonary function at one and three years of life, b) relate the viral community structure to severity of viral infections and c) to seek evidence of modulation of viral susceptibility by bacterial respiratory and gut community structure (microbiome). The relationship of colonization with known and non-identified bacterial species in both the respiratory tract and the gut will be evaluated. </p>
| phs001347 | dbGaP
Project description:Viruses often establish persistent infections by interrupting immune cell responses. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phsophate, which is known to regulate versatile cellular processes, including immune responses. However, little is known about the role of SphK2 in the immune response to viral infections. Here, we demonstrate that during lymphocytic choriomeningitis virus (LCMV) clone 13 infection, a virus known to establish a persistent infection in mice, SphK2 functions to limit CD4+ T cell responses, which aids in the establishment of virus-induced immunosuppression and viral persistence. The infection of SphK2-deficient (Sphk2-/-) mice with LCMV resulted in kidney disease and ultimately mortality. Following infection, Sphk2-/- mice were shown to have increased LCMV-specific CD4+ and CD8+ T cell responses. With the use of LCMV epitope-specific TCR transgenic mouse lines in adoptive transfer studies, SphK2 was shown to have intrinsic negative function in CD4+ T cells, but not CD8+ T cells. Furthermore, Sphk2-/- CD4+ T cells were able to promote endogenous, virus-specific CD8+ T cell responses more efficiently than Sphk2+/+ CD4+ T cells. Our results suggest that SphK2 is a novel regulator of the immune response during LCMV clone 13 infection and targeting SphK2 may provide a promising immunotherapeutic strategy for the control of persistent viral infections. This study incorporated the use of RNA sequencing to determine what pathways SphK2 was involved in to affect CD4+ T cell activity and proliferation. Sphk2+/+ or Sphk2-/- LCMV epitope-recognizing tg CD4+ T cells were transferred into C57BL/6 mice and recovered 7 days following LCMV Cl 13 infection. RNA sequencing revealed several pathways upregulated in Sphk2-/- CD4+ T cells relating to cell cycle progression, regulation of transcription, and regulation of nucleic acid binding.
2020-10-29 | GSE155030 | GEO
Project description:Sepsis survivors exhibit long-term endothelial dysfunction, increasing susceptibility to secondary infections such as pneumonia. To investigate the epigenetic and transcriptional basis of endothelial inflammatory memory, we employed transcriptomic profiling of primary endothelial cells exposed to inflammatory stimuli in a two-hit model. This study reveals persistent transcriptional reprogramming following IL-6 exposure and identifies a primed endothelial state that amplifies responses to secondary challenges.
2025-11-06 | GSE298902 | GEO
Project description:The group B Coxsackieviruses can establish persistent infections in human cells, and these infections have been linked to chronic diseases including type 1 diabetes. Still, only little is known about persistent Coxsackievirus B infection induced changes in human pancreas. We have established persistent Coxsackievirus B1 infections in human pancreatic duct cell line using two different virus strains, and studied infection-induced changes in protein secretion using mass spectrometry-based proteomics. Persistent Coxsackievirus B1 infections caused broad changes in protein secretion, for example changes regulated secretory pathway. Strikingly, many changes differed between the virus strains, including extensive shut down of antiviral immune responses by one of the viruses. Our results provide novel information about persistent Coxsackievirus B infection induced changes in human pancreas and about the potential heterogeneity in the outcomes of the infections.
2019-08-06 | PXD012154 | Pride
Project description:T cell exhaustion is a well-defined process diminishing the efficacy of the CD8 response in persistent viremia. What is less understood is whether early differences in T cell regulation already predetermine the fate of the T cell response and infection outcome. Its dichotomous outcome that is unique among human viral infections makes hepatitis C virus infection uniquely suited to compare transcriptional regulation between HCV-specific CD8 T cells that do and do not achieve viral control. Using differential gene expression and gene set enrichment analyses we validate HCV-specifcic CD8 T cell transcriptional modules.
2017-01-18 | GSE93711 | GEO
Project description:Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses. We compared gene expression between splenic DCs from B6.FasKI and B6.CD11c-Cre.FasKI mice. DCs were isolated on day 5 after LCMV infection with 3 mice in each group, for a total of 6 samples. Spleens were collagenase-DNAse digested and sorted by flow to isolate DCs.
2014-05-09 | E-GEOD-57443 | biostudies-arrayexpress
Project description:In human cells, the group B Coxsackieviruses can establish persistent infections that have been linked to chronic diseases including type 1 diabetes. Still, only little is known about the changes induced by persistent Coxsackievirus B infection in human pancreas. We have established persistent Coxsackievirus B1 infections in human pancreatic duct cell line using two different virus strains, and studied the consequences of these infections on intracellular protein expression using mass spectrometry-based proteomics. Persistent Coxsackievirus B1 infections caused broad changes in protein expression, for example changes in mitochondrial morphology and energy metabolism and in proteins associated with differentiation and survival of pancreatic beta-cells. Strikingly, many of these changes differed between the virus strains, including extensive shut down of antiviral immune responses by one of the viruses. Our results provide novel information about the changes induced by persistent Coxsackievirus B infection in human pancreas and about the potential heterogeneity in the outcomes of the infections.
2019-08-06 | PXD012153 | Pride
Project description:Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. The causes of altered gut barrier remain, however, mostly unknown. By using murine infection with lymphocytic choriomeningitis virus we demonstrated that, in contrast to an acute viral strain, a persistent viral isolate led to long-term viral replication in hematopoietic and mesenchymal, but not epithelial (IEC), cells in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. IFN-I signaling caused tight junction dysregulation in IEC, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both IFN-I receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrated that infection with a virus that persistently replicated in intestinal mucosa increased epithelial barrier permeability, and revealed IFN-I and CD8 T cells as causative factors of intestinal leakage during chronic infections.
2020-08-26 | GSE155120 | GEO
Project description:Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses.
2014-05-09 | GSE57443 | GEO
Project description:There were important gaps in our knowledge of Israeli acute paralysis virus (IAPV), when IAPV was tightly linked to bee Colony Collapse Disorder (CCD), the mysterious disease that, starting in 2006-2007, has been wiping out honey bees in the US. To fill in these gaps we studied the molecular basis of transmission, pathogenesis, and genetic diversity of IAPV infection in honey bees. We investigated the impact of IAPV infection on colony losses and host transcriptional response to IAPV infections, and exploited the potential of RNAi-based strategies for treating viral diseases in honey bees. Our study clearly shows that IAPV has become established as a persistent infection and is highly prevalent in the honey bee population. The existence of both horizontal and vertical transmission pathways of the virus likely accounts for the high prevalence of IAPV in bees. While IAPV is probably not the only culprit responsible for CCD, its ability to cause increased mortality in honey bees is firmly demonstrated. The phenotypic differences in pathology among different strains of IAPV may be due to their high level of standing genetic variation. The JAK-STAT pathway, along with other signaling events such as mTOR and MAPK pathways, likely involves honey bees’ antiviral immune responses to the IAPV infection. The identification of IAPV-encoded putative suppressor of RNAi and evidence that silencing the RNAi suppressor led to a significant reduction in IAPV replication in infected bees illustrates the therapeutic potential of targeting viral suppressor protein to reduce virus replication. Our study gives direction for developing strategies to reduce colony losses due to viral diseases. Adult worker bees and brood were collected from colonies that were declining and identified with IAPV infections and its control with 6 replications per group.
2014-04-08 | E-GEOD-46278 | biostudies-arrayexpress