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dc.contributor.authorErnst, Orna
dc.contributor.authorKhan, Mohd M
dc.contributor.authorOyler, Benjamin L
dc.contributor.authorYoon, Sung Hwan
dc.contributor.authorSun, Jing
dc.contributor.authorLin, Fang-Yu
dc.contributor.authorManes, Nathan P
dc.contributor.authorMacKerell, Alexander D
dc.contributor.authorFraser, Iain D C
dc.contributor.authorErnst, Robert K
dc.contributor.authorGoodlett, David R
dc.contributor.authorNita-Lazar, Aleksandra
dc.date.accessioned2021-08-05T17:56:23Z
dc.date.available2021-08-05T17:56:23Z
dc.date.issued2021-08-03
dc.identifier.urihttp://hdl.handle.net/10713/16306
dc.description.abstractThe innate immune system is the body's first line of defense against pathogens and its protection against infectious diseases. On the surface of host myeloid cells, Toll-like receptor 4 (TLR4) senses lipopolysaccharide (LPS), the major outer membrane component of Gram-negative bacteria. Intracellularly, LPS is recognized by caspase 11 through the noncanonical inflammasome to induce pyroptosis-an inflammatory form of lytic cell death. While TLR4-mediated signaling perturbations result in secretion of cytokines and chemokines that help clear infection and facilitate adaptive immunity, caspase 11-mediated pyroptosis leads to the release of damage-associated molecular patterns and inflammatory mediators. Although the core signaling events and many associated proteins in the TLR4 signaling pathway are known, the complex signaling events and protein networks within the noncanonical inflammasome pathway remain obscure. Moreover, there is mounting evidence for pathogen-specific innate immune tuning. We characterized the major LPS structures from two different pathogens, modeled their binding to the surface receptors, systematically examined macrophage inflammatory responses to these LPS molecules, and surveyed the temporal differences in global protein secretion resulting from TLR4 and caspase 11 activation in macrophages using mass spectrometry (MS)-based quantitative proteomics. This integrated strategy, spanning functional activity assays, top-down structural elucidation of endotoxins, and secretome analysis of stimulated macrophages, allowed us to identify crucial differences in TLR4- and caspase 11-mediated protein secretion in response to two Gram-negative bacterial endotoxins. IMPORTANCE Macrophages and monocytes are innate immune cells playing an important role in orchestrating the initial innate immune response to bacterial infection and the tissue damage. This response is facilitated by specific receptors on the cell surface and intracellularly. One of the bacterial molecules recognized is a Gram-negative bacteria cell wall component, lipopolysaccharide (LPS). The structure of LPS differs between different species. We have characterized the innate immune responses to the LPS molecules from two bacteria, Escherichia coli and Bordetella pertussis, administered either extracellularly or intracellularly, whose structures we first determined. We observed marked differences in the temporal dynamics and amounts of proteins secreted by the innate immune cells stimulated by any of these molecules and routes. This suggests that there is specificity in the first line of response to different Gram-negative bacteria that can be explored to tailor specific therapeutic interventions.en_US
dc.description.urihttps://doi.org/10.1128/mSystems.00306-21en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofmSystemsen_US
dc.subjectSILCSen_US
dc.subjectToll-like receptorsen_US
dc.subjectcaspase 11en_US
dc.subjectcaspasesen_US
dc.subjectcytokinesen_US
dc.subjecthost responseen_US
dc.subjecthost-pathogen interactionsen_US
dc.subjectinfectionen_US
dc.subjectinflammasomeen_US
dc.subjectinnate immunityen_US
dc.subjectlipopolysaccharideen_US
dc.subjectmacrophagesen_US
dc.subjectproteomicsen_US
dc.subjectsecretomeen_US
dc.subjectsite identification by ligand competitive saturationen_US
dc.titleSpecies-Specific Endotoxin Stimulus Determines Toll-Like Receptor 4- and Caspase 11-Mediated Pathway Activation Characteristicsen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/mSystems.00306-21
dc.identifier.pmid34342534
dc.source.beginpagee0030621
dc.source.endpage
dc.source.countryUnited States


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