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cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F17%3A00473551" target="_blank" >RIV/61388971:_____/17:00473551 - isvavai.cz</a>

  • Result on the web

    <a href="http://dx.doi.org/10.4049/jimmunol.1601309" target="_blank" >http://dx.doi.org/10.4049/jimmunol.1601309</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.4049/jimmunol.1601309" target="_blank" >10.4049/jimmunol.1601309</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity

  • Original language description

    The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in immune evasion and virulence of the whooping cough agent Bordetella pertussis. CyaA penetrates the complement receptor 3 expressing phagocytes and ablates their bactericidal capacities by catalyzing unregulated conversion of cytosolic ATP to the key second messenger molecule cAMP. We show that signaling of CyaA-generated cAMP blocks the oxidative burst capacity of neutrophils by two converging mechanisms. One involves cAMP/ protein kinase A mediated activation of the Src homology region 2 domain containing phosphatase-1 (SHP-1) and limits the activation of MAPK ERK and p38 that are required for assembly of the NADPH oxidase complex. In parallel, activation of the exchange protein directly activated by cAMP (Epac) provokes inhibition of the phospholipase C by an as yet unknown mechanism. Indeed, selective activation of Epac by the cell-permeable analog 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate counteracted the direct activation of phospholipase C by 2,4,6-trimethyl-N43-(trifluoromethyl)phenylbenzenesulfonamide. Hence, by inhibiting production of the protein kinase C activating lipid, diacylglycerol, cAMP/Epac signaling blocks the bottleneck step of the converging pathways of oxidative burst triggering. Manipulation of neutrophil membrane composition by CyaA-produced signaling of cAMP thus enables B. pertussis to evade the key innate host defense mechanism of reactive oxygen species mediated killing of bacteria by neutrophils.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10606 - Microbiology

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2017

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Journal of Immunology

  • ISSN

    0022-1767

  • e-ISSN

  • Volume of the periodical

    198

  • Issue of the periodical within the volume

    3

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    12

  • Pages from-to

    1285-1296

  • UT code for WoS article

    000392412700031

  • EID of the result in the Scopus database

    2-s2.0-85014714905