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Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase
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SYSNO ASEP 0451090 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase Tvůrce(i) Černý, Ondřej (MBU-M)
Kamanová, Jana (MBU-M) ORCID, RID
Mašín, Jiří (MBU-M) RID, ORCID
Bíbová, Ilona (MBU-M) RID
Škopová, Karolína (MBU-M)
Šebo, Peter (MBU-M) RID, ORCIDZdroj.dok. Journal of Immunology. - : American Association of Immunologists - ISSN 0022-1767
Roč. 194, č. 10 (2015), s. 4901-4913Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova CYCLIC-AMP ; MURINE MACROPHAGES ; IFN-GAMMA Vědní obor RIV EE - Mikrobiologie, virologie CEP GAP302/12/0460 GA ČR - Grantová agentura ČR GA13-14547S GA ČR - Grantová agentura ČR Institucionální podpora MBU-M - RVO:61388971 UT WOS 000353728800032 DOI 10.4049/jimmunol.1402941 Anotace The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in the virulence of Bordetella pertussis. CyaA penetrates complement receptor 3-expressing phagocytes and catalyzes uncontrolled conversion of cytosolic ATP to the key second messenger molecule cAMP. This paralyzes the capacity of neutrophils and macrophages to kill bacteria by complement-dependent oxidative burst and opsonophagocytic mechanisms. We show that cAMP signaling through the protein kinase A (PKA) pathway activates Src homology domain 2 containing protein tyrosine phosphatase (SHP) 1 and suppresses production of bactericidal NO in macrophage cells. Selective activation of PKA by the cell-permeable analog N-6-benzoyladenosine-3',5'-cyclic monophosphate interfered with LPS-induced inducible NO synthase (iNOS) expression in RAW264.7 macrophages, whereas inhibition of PKA by H-89 largely restored the production of iNOS in CyaA-treated murine macrophages. CyaA/cAMP signaling induced SHP phosphatase-dependent dephosphorylation of the c-Fos subunit of the transcription factor AP-1 and thereby inhibited TLR4-triggered induction of iNOS gene expression. Selective small interfering RNA knockdown of SHP-1, but not of the SHP-2 phosphatase, rescued production of TLR-inducible NO in toxin-treated cells. Finally, inhibition of SHP phosphatase activity by NSC87877 abrogated B. pertussis survival inside murine macrophages. These results reveal that an as yet unknown cAMP-activated signaling pathway controls SHP-1 phosphatase activity and may regulate numerous receptor signaling pathways in leukocytes. Hijacking of SHP-1 by CyaA action then enables B. pertussis to evade NO-mediated killing in sentinel cells of innate immunity. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2016
Počet záznamů: 1