CipA ofAcinetobacter baumanniiIs a Novel Plasminogen Binding and Complement Inhibitory Protein

Abstract

Acinetobacter baumannii is an emerging opportunistic pathogen, responsible for up to 10% of gram-negative, nosocomial infections. The global increase of multidrug-resistant and pan-resistant Acinetobacter isolates presents clinicians with formidable challenges. To establish a persistent infection,A. baumannii must overcome the detrimental effects of complement as the first line of defense against invading microorganisms. However, the immune evasion principles underlying serum resistance inA. baumannii remain elusive. Here, we identified a novel plasminogen-binding protein, termed CipA. Bound plasminogen, upon conversion to active plasmin, degraded fibrinogen and complement C3b and contributed to serum resistance. Furthermore, CipA directly inhibited the alternative pathway of complement in vitro, irrespective of its ability to bind plasminogen. A CipA-deficient mutant was efficiently killed by human serum and showed a defect in the penetration of endothelial monolayers, demonstrating that CipA is a novel multifunctional protein that contributes to the pathogenesis ofA. baumannii.

The Immune Response against Acinetobacter baumannii, an Emerging Pathogen in Nosocomial Infections

“…Additional virulence factors produced by A. baumannii , such as CipA and PKF, are also implicated in the evasion of the complement system (40, 41). CipA, an outer membrane protein, binds to the active form of plasminogen, plasmin, to degrade fibrinogen and promote bacterial dissemination.…”

“…This CipA–plasmin complex also degrades C3b; however, there is no correlation between the levels of CipA–plasmin and complement resistance so far. Hence, the mechanism through which CipA confers complement resistance still needs to be elucidated (40). PKF, a secreted serine protease, could also have a role in the cleavage of some complement components; nevertheless, the complement components susceptible for the action of this protein remain to be identified.…”

Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options

“…Acinetobacter baumannii CipA is a novel plasminogen binding and complement inhibitory protein that mediates serum resistance (Koenigs et al, 2016). CipA-binding plasminogen is converted to active plasmin that degrades fibrinogen and complement C3b, which contributes to serum resistance of A. baumannii .…”

“…CipA-binding plasminogen is converted to active plasmin that degrades fibrinogen and complement C3b, which contributes to serum resistance of A. baumannii . Therefore, the cipA mutant strain is efficiently killed by human serum and also shows a defect in the penetration of endothelial monolayers (Koenigs et al, 2016). Similar to CipA, the A. baumannii translation elongation factor Tuf is also a plasminogen-binding protein.…”

TheAcinetobactertrimeric autotransporter adhesin Ata controls key virulence traits ofAcinetobacter baumannii

“…Several proteins of A. baumannii have been described to be involved in this processes: e.g. the outer membrane protein A (OmpA) mediates adhesion to epithelial cells and cytotoxicity [4,5], phospholipases D (PLD) support invasion and pathogenicity in vivo [6], and the plasminogen-binding protein (CipA) inactivates the alternative complement system and supports the penetration of endothelial cell layers [7]. Previously, the trimeric autotransporter adhesin Ata, was identified in A. baumannii ATCC 17978, which mediated adhesion to extracellular matrix proteins (ECMs) and virulence in a murine pneumonia model [8,9].…”