Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Jyoti Batra
PROVIDER: S-SCDT-EMBOJ-2020-105658 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Mathematical modeling of Ebola virus (EBOV)-host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model's predictions. We also explored the model's predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV-host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment.
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Project description:SIGNIFICANCE:Proline metabolism has complex roles in a variety of biological processes, including cell signaling, stress protection, and energy production. Proline also contributes to the pathogenesis of various disease-causing organisms. Understanding the mechanisms of how pathogens utilize proline is important for developing new strategies against infectious diseases. Recent Advances: The ability of pathogens to acquire amino acids is critical during infection. Besides protein biosynthesis, some amino acids, such as proline, serve as a carbon, nitrogen, or energy source in bacterial and protozoa pathogens. The role of proline during infection depends on the physiology of the host/pathogen interactions. Some pathogens rely on proline as a critical respiratory substrate, whereas others exploit proline for stress protection. CRITICAL ISSUES:Disruption of proline metabolism and uptake has been shown to significantly attenuate virulence of certain pathogens, whereas in other pathogens the importance of proline during infection is not known. Inhibiting proline metabolism and transport may be a useful therapeutic strategy against some pathogens. Developing specific inhibitors to avoid off-target effects in the host, however, will be challenging. Also, potential treatments that target proline metabolism should consider the impact on intracellular levels of ?1-pyrroline-5-carboxylate, a metabolite intermediate that can have opposing effects on pathogenesis. FUTURE DIRECTIONS:Further characterization of how proline metabolism is regulated during infection would provide new insights into the role of proline in pathogenesis. Biochemical and structural characterization of proline metabolic enzymes from different pathogens could lead to new tools for exploring proline metabolism during infection and possibly new therapeutic compounds.
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Project description:To gain insight into the changes in gene expression pattern upon Ebola infection, CD45+/+ (100% protein level) and CD45+/- (62% protein level) mice were challenged with mouse adapted Ebola virus. At time-points day 0, 1, 3, 5, 7, 9, 11 and 13, spleen tissue was harvested and splenocytes isolated. Total RNA was isolated for mRNA expression analysis. The mouse genome 430 2.0 array (Affymetrix, Inc.), which consists of over 39,000 genes in a single array, was used. Based on gene expression patterns, the variable genes were grouped into sixteen clusters. Each cluster contained genes associated with cellular immune processes, signaling, cell-cycle, complement coagulation cascade, biosynthesis/metabolism, ubiquitous genes involved in several cascades, and genes of unknown function. Interestingly, gene expression in clusters 2 and 3 were significantly downregulated by day 1 following EBOV challenge in CD45100% mice. In contrast, at day 1 following EBOV infection, the CD45 62% mice maintained gene expression patterns similar to day 0. The differences in gene expression patterns between the CD45 100% and CD45 62% splenocytes were less apparent at day 3 following infection and by days 5 and 7 they became very similar. At day 9, when wild-type mice had succumbed to the disease, the pattern in CD45 62% mice remained similar to the day 7 patterns of CD45 100% and CD45 62% mice. The pattern at days 11 and 13 in the CD45 62% mice had returned to that of day 0 CD45 100% or CD45 62% mice. These results suggested that in CD45 100% mice, subversion of the cell transcriptional machinery during the early stages of EBOV infection (day 1) might represent a major factor leading to death of the mice. In CD45 62% mice, early control of gene regulation likely provided the appropriate antiviral responses leading to regulated inflammation, immune co-stimulation, and survival. Experiment Overall Design: RNA expression in CD45 100% and 62% mice were compared at each time point: days 0, 1, 3, 5, and 7, using an empirical Bayes procedure. From 3 to 8 biological replicates were in each group. Samples for days 9, 11, and 13 (4 biological replicates each) were also available for only CD45 62%. Median expression values for highly variable genes within each group were clustered using agglomerative nesting over all available time points.
2009-09-05 | E-GEOD-17509 | biostudies-arrayexpress
Project description:To gain insight into the changes in gene expression pattern upon Ebola infection, CD45+/+ (100% protein level) and CD45+/- (62% protein level) mice were challenged with mouse adapted Ebola virus. At time-points day 0, 1, 3, 5, 7, 9, 11 and 13, spleen tissue was harvested and splenocytes isolated. Total RNA was isolated for mRNA expression analysis. The mouse genome 430 2.0 array (Affymetrix, Inc.), which consists of over 39,000 genes in a single array, was used. Based on gene expression patterns, the variable genes were grouped into sixteen clusters. Each cluster contained genes associated with cellular immune processes, signaling, cell-cycle, complement coagulation cascade, biosynthesis/metabolism, ubiquitous genes involved in several cascades, and genes of unknown function. Interestingly, gene expression in clusters 2 and 3 were significantly downregulated by day 1 following EBOV challenge in CD45100% mice. In contrast, at day 1 following EBOV infection, the CD45 62% mice maintained gene expression patterns similar to day 0. The differences in gene expression patterns between the CD45 100% and CD45 62% splenocytes were less apparent at day 3 following infection and by days 5 and 7 they became very similar. At day 9, when wild-type mice had succumbed to the disease, the pattern in CD45 62% mice remained similar to the day 7 patterns of CD45 100% and CD45 62% mice. The pattern at days 11 and 13 in the CD45 62% mice had returned to that of day 0 CD45 100% or CD45 62% mice. These results suggested that in CD45 100% mice, subversion of the cell transcriptional machinery during the early stages of EBOV infection (day 1) might represent a major factor leading to death of the mice. In CD45 62% mice, early control of gene regulation likely provided the appropriate antiviral responses leading to regulated inflammation, immune co-stimulation, and survival.
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Project description:Normalized Gene expression data used for meta-analysis from studies: GSE31747, GSE8317, GSE24943, GSE24125. We studied the changes in macaque and human peripheral blood cell gene expression after infection with Ebola Zaire virus (EBZ) to identify host responses that occur before the emergence of symptoms. We integrated data from in vivo and in vitro infection studies of macaque or human peripheral blood. We identified mRNAs that were differentially expressed at early, middle, and late times after infection. The EBZ early genes showing increased or decreased expression were then compared to literature-derived host responses to malaria, rhinovirus and influenza virus which identified the patterns unique to each pathogen. From the group of EBZ-specific genes, we next predicted those that encoded secreted or membrane-associated proteins. Pairs of these host response mRNAs or proteins could become candidates for differential diagnosis of an early EBZ infection, before the emergence of conventional symptoms. Four key immune response pathways that were activated early showed profoundly decreased expression at late times.
2016-06-14 | GSE83331 | GEO