Mechanismus působení adenylátcyklázového toxinu na imunitní funkce dendritických buněk

Švédová, Martina

The adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. CyaA primarily penetrates CR3-expressing myeloid phagocytes and subverts cellular signaling by a rapid conversion of ATP to cAMP. In parallel, CyaA can form cation-selective pores within cellular membrane, provoking massive potassium efflux from cell cytosol. An enzymatically inactive adenylate cyclase toxoid (CyaA-AC- ) has then been abundantly used as an efficient antigen delivery tool over the past 20 years. This work focused mainly on the mechanism of action of CyaA toxin and of its toxoid on dendritic cells. We studied the potency of the CyaA toxoid to act as adjuvant, its penetration capacity and its potential use in delivery of influenza epitopes. We show that the pore-forming activity and the activation of MAP kinases JNK and p38 were crucial for the adjuvant effects of the CyaA-AC- , which provokes maturation of dendritic cells (DC) independently of Toll-like receptor (TLR) or inflammasome signaling. Furthermore, such CyaA-AC- -stimulated DC acquired the ability to induce CD8+ and CD4+ T cells responses, as was determined both in vitro and in vivo. We further showed that the first 371 amino acids are dispensable for the capacity of CyaA to deliver its AC domain with inserted...

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