Defining the Intracellular Growth Niche of Foodborne Listeria monocytogenes
Defining the Intracellular Growth Niche of Foodborne Listeria monocytogenes
批准号:
10113535
负责人:
SARAH E. F. D'ORAZIO
金额:
$22.95万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-03-01 至 2024-02-29
关键词:
AnatomyBacteremiaBacteriaBiological AssayBloodBypassC57BL/6 MouseCell surfaceCellsColonCytosolDataDefectDendritic CellsDependenceDisease OutbreaksE-CadherinEatingElderlyEnvironmentEpithelialEventExposure toFecesFlow CytometryFoodFood ContaminationFood SupplyGastroenteritisGastrointestinal tract structureGentamicinsGoalsGrowthGut MucosaHospitalizationImmuneImmune systemImmunoassayIn VitroIncidenceIndividualInfectionIngestionInnate Immune ResponseInterleukin-12Interleukin-18Interleukin-6Intestinal DiseasesIntestinesIntravenousInvadedKnowledgeLamina PropriaLarge IntestineLeadLifeLigationListeria monocytogenesListeriosisM cellMeasuresMediatingMeningoencephalitisMinorModelingMusMyelogenousMyeloid CellsNeuraxisPhagocytesPhasePopulationProcessProductionResistanceRouteSepsisSepticemiaSeveritiesSeverity of illnessSmall IntestinesStainsSubmucosaSurfaceSymptomsSystemic infectionTherapeutic InterventionTimeTissuesVirulenceWorkcell typecytokinecytosolic receptordesigndraining lymph nodeenteric infectionexperienceexperimental studyextracellularfeedingfoodbornefoodborne infectionfoodborne pathogenhuman diseaseileumin vivomacrophagemesenteric lymph nodemonocytemortalitymouse modelneonatepathogenpreventresponsetransmission process
中文摘要
摄入单核细胞增生李斯特菌(Lm)污染的食物会导致严重程度不等的人类疾病
英文摘要
Ingestion of Listeria monocytogenes (Lm)-contaminated food results in human disease ranging in severity
from mild, self-limiting gastroenteritis to life-threatening septicemia and meningoencephalitis. The specific
factors that influence disease severity are not well understood, and our knowledge of the intestinal phase of
listeriosis, in particular, is severely limited. We recently developed a mouse model of foodborne infection to
study the interaction of Lm with intestinal innate immune cells. In preliminary studies, we found that the
majority of Lm in the gut were extracellular. This was an unexpected result, because intracellular growth
and spread from cell-to-cell without encountering the extracellular milieu are generally regarded as the
primary virulence strategies for these facultative intracellular bacteria. LplA1-deficient Lm that were unable
to replicate intracellularly could readily invade the gut mucosa and establish infection in the underlying
lamina propria, but did not persist as well as wildtype Lm, and by three days post-infection had a severe
defect in spreading to the mesenteric lymph nodes (MLN). This suggests that intracellular growth is not
required for the initial stages of intestinal infection, but replication in some as-yet-unidentified cell type in the
gut becomes increasingly more important as the infection proceeds. Multicolor flow cytometry can
discriminate eight different subsets of myeloid-derived phagocytes that are unique to the gut. Preliminary
data provided here verified that intestinal tissue contained at least one cell type that could support
intracellular growth of Lm, and ruled out Ly6Chi monocytes and all three subsets of conventional dendritic
cells as the intracellular niche. The primary goal of this proposal is to identify the cell type(s) in the gut that
support intracellular growth of Lm and to define the innate immune response of intestinal cell types that that
interact primarily with either intracellular or extracellular Lm. We hypothesize that Lm initially interact
primarily with cell types that that they cannot efficiently invade or survive in, and that later in the course of
infection, the bacteria shift to a cell type that serves as a protected intracellular growth niche.!In Aim 1, four
candidate intestinal myeloid cell types will be sort purified, infected directly ex vivo and assayed for both
intracellular localization and replication. In Aim 2, flow cytometry will be used to identify Lm-associated cells
in the lamina propria and submucosa of the ileum and colon as well as the MLN that drain each of these
tissues (SI-MLN and LI-MLN) to track the fate of Lm that invade the gut mucosa in mice. In Aim 3, we will
define the initial response of all eight subsets of intestinal myeloid cells by measuring the production of
cytokines known to be triggered by either host cell surface bound or cytosolic receptors. These exploratory
studies will fill a key knowledge gap in the field by defining the early events that occur in the gut during
foodborne transmission of Lm. !
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Dissemination of intracellular and extracellular Listeria from the gut
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批准号:10417246
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资助金额:$22.95万
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财政年份:2021
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Defining the Intracellular Growth Niche of Foodborne Listeria monocytogenes
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MHC-Ib restricted T cell responses against Listeria monocytogenes
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批准号:7739108
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资助金额:$7.43万
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财政年份:2009
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负责人:SARAH E. F. D'ORAZIO
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依托单位:
MHC-Ib restricted T cell responses against Listeria monocytogenes
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批准号:7873036
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资助金额:$7.35万
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财政年份:2009
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负责人:SARAH E. F. D'ORAZIO
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依托单位:
CYTOTOXIC T CELL RESPONSE AGAINST MYCOBACTERIUM AVIUM
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批准号:2886307
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项目类别:
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资助金额:$4.0万
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财政年份:1999
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负责人:SARAH E. F. D'ORAZIO
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依托单位:
CYTOTOXIC T CELL RESPONSE AGAINST MYCOBACTERIUM AVIUM
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批准号:2520855
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项目类别:
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资助金额:$3.15万
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财政年份:1998
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负责人:SARAH E. F. D'ORAZIO
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依托单位:
海外基金