FACIN a double-edged sword of the emerging periodontal pathogen Filifactor alocis – a metabolic enzyme moonlighting as a complement inhibitor

摘要

Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis but its virulence mechanisms remain largely unknown. We confirmed that F. alocis is prevalent species in periodontitis patients and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease. Further, we found that pre-incubation of human serum with F. alocis resulted in abolished bactericidal activity and that F. alocis was surviving readily in full blood. We demonstrated that one of the key contributors to F. alocis complement resistance is a unique protein, FACIN, which binds to C3, resulting in suppression of all complement pathways. Interestingly, FACIN is a non-classical cell-surface protein, a cytosolic enzyme acetylornithine transaminase, for which we now identified a moonlighting function. FACIN binds to C3 alone but more importantly it also captures C3b within the complex with factor B, thereby locking in the convertase in an inactive state. Due to the indispensable role of alternative pathway convertase in amplifying complement cascades, its inhibition by FACIN results in a very potent downregulation of C3b opsonisation on the pathogen surface, accompanied by reduction of downstream C5 cleavage.