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dc.contributor.advisorKatherine A. Fitzgerald, PhD
dc.contributor.authorGhosh, Sreya
dc.date2022-08-11T08:08:46.000
dc.date.accessioned2022-08-23T16:07:45Z
dc.date.available2022-08-23T16:07:45Z
dc.date.issued2017-09-12
dc.date.submitted2017-11-29
dc.identifier.doi10.13028/M2CD6Z
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32310
dc.description.abstractInterferon-inducible PYHIN protein family includes the DNA-binding proteins, AIM2 and IFI16, which form ASC-caspase 1 dependent inflammasomes, important in immunity against cytosolic bacteria, DNA viruses and HIV. The role of other members of this family in the recognition of DNA and/or regulation of immune responses is unclear. We identified an immune regulatory function of p205, another member of the PYHIN family, in the transcriptional control of immune genes. Knockdown of p205 in macrophages revealed that inflammasome activation due to dsDNA and ligands that engage the NLRP3 inflammasome were severely compromised. Detailed mechanistic analysis showed that loss of p205 was associated with a decrease in Asc mRNA and protein levels. p205 knockdown resulted in reduced RNA Polymerase II-mediated endogenous Asc gene transcription and mRNA processing, suggesting a co-transcriptional control of Asc gene expression. Ectopically expressed p205 induced expression of an Asc gene-luciferase reporter and collaborated with other transcription factors, such as c/EBPβ, p65/RelA, to further enhance expression. p205 knockdown also affected the expression of the immune genes Cd86, Cox2, Cxcl2, Il1α, Il10, Il12α, Il6 and Ifnα in LPS-stimulated macrophages. Together these findings suggest that p205 regulates inflammation through control of Asc gene expression, and other immune genes. Fungal infections activate both caspase 1-dependent and -independent inflammasomes. In an independent study, we show that Paracoccidioides brasiliensis fungal infection also induces caspase 8-dependent non-canonical inflammasome. Caspase 8-dependent IL-1β processing required dectin-1, Syk and Asc. Rip3-/- Casp8-/- mice infected with P. brasiliensis displayed increased fungal load and showed worse disease progression compared to wild type and Rip3-/- mice. These results revealed the importance of caspase 8 in activating and regulating inflammasome responses during fungal infection in vivo.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectInnate Immunity
dc.subjectInflammation
dc.subjectInflammasome
dc.subjectGene regulation
dc.subjectTranscription
dc.subjectMacrophage
dc.subjectHost-pathogen interactions
dc.subjectPYHIN
dc.subjectAIM2-like receptors
dc.subjectPathogen Recognition Receptors
dc.subjectImmune System
dc.subjectCytokines
dc.subjectSignal transduction
dc.subjectImmunity
dc.subjectImmunology and Infectious Disease
dc.subjectImmunology of Infectious Disease
dc.subjectMicrobiology
dc.titleDifferent Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1934&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/928
dc.legacy.embargo2017-11-29T00:00:00-08:00
dc.identifier.contextkey11174222
refterms.dateFOA2022-08-26T03:38:28Z
html.description.abstract<p>Interferon-inducible PYHIN protein family includes the DNA-binding proteins, AIM2 and IFI16, which form ASC-caspase 1 dependent inflammasomes, important in immunity against cytosolic bacteria, DNA viruses and HIV. The role of other members of this family in the recognition of DNA and/or regulation of immune responses is unclear. We identified an immune regulatory function of p205, another member of the PYHIN family, in the transcriptional control of immune genes. Knockdown of p205 in macrophages revealed that inflammasome activation due to dsDNA and ligands that engage the NLRP3 inflammasome were severely compromised. Detailed mechanistic analysis showed that loss of p205 was associated with a decrease in Asc mRNA and protein levels. p205 knockdown resulted in reduced RNA Polymerase II-mediated endogenous <em>Asc</em> gene transcription and mRNA processing, suggesting a co-transcriptional control of <em>Asc</em> gene expression. Ectopically expressed p205 induced expression of an <em>Asc</em> gene-luciferase reporter and collaborated with other transcription factors, such as c/EBPβ, p65/RelA, to further enhance expression. p205 knockdown also affected the expression of the immune genes <em>Cd86</em>, <em>Cox2</em>, <em>Cxcl2</em>, <em>Il1α</em>, <em>Il10</em>, <em>Il12α</em>, <em>Il6</em> <em>and Ifnα</em> in LPS-stimulated macrophages. Together these findings suggest that p205 regulates inflammation through control of <em>Asc</em> gene expression, and other immune genes.</p> <p>Fungal infections activate both caspase 1-dependent and -independent inflammasomes. In an independent study, we show that <em>Paracoccidioides brasiliensis</em> fungal infection also induces caspase 8-dependent non-canonical inflammasome. Caspase 8-dependent IL-1β processing required dectin-1, Syk and Asc. <em>Rip3-/- Casp8-/-</em> mice infected with <em>P. brasiliensis</em> displayed increased fungal load and showed worse disease progression compared to wild type and <em>Rip3-/-</em> mice. These results revealed the importance of caspase 8 in activating and regulating inflammasome responses during fungal infection <em>in vivo</em>.</p>
dc.identifier.submissionpathgsbs_diss/928
dc.contributor.departmentProgram in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology
dc.description.thesisprogramImmunology and Microbiology
dc.identifier.orcid0000-0003-2956-4830


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