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

0473551 - MBÚ 2018 RIV US eng J - Journal Article
Černý, Ondřej - Anderson, K.E. - Stephens, L.R. - Hawkins, P.T. - Šebo, Peter
cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity.
Journal of Immunology. Roč. 198, č. 3 (2017), s. 1285-1296. ISSN 0022-1767. E-ISSN 1550-6606
R&D Projects: GA ČR(CZ) GA13-14547S; GA MŠMT(CZ) LM2015064
Institutional support: RVO:61388971
Keywords : BORDETELLA-PERTUSSIS * NADPH OXIDASE * CYCLIC-AMP
OECD category: Microbiology
Impact factor: 4.539, year: 2017

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.
Permanent Link: http://hdl.handle.net/11104/0270687