CipA mediates complement resistance of Acinetobacter baumannii by formation of a factor I-dependent quadripartite
Julia I Ries1, Marie Heß1, Noura Nouri1
1Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
Abstract:
Multidrug-resistant Acinetobacter baumannii is known to be one of the leading pathogens that cause severe nosocomial infections. To overcome eradication by the innate immune system during infection, A. baumannii developed a number of immune evasion strategies. Previously, we identified CipA as a plasminogen-binding and complement-inhibitory protein. Here we show that CipA inhibits all three complement activation pathways and interacts with key complement components C3, C3b, C4b, C5, Factor B, Factor D, and in particular Factor I. CipA also targets function of the C5 convertase as cleavage of C5 was impaired. Systematic screening of CipA variants identified two separate binding sites for C3b and a Factor I-interacting domain located at the C-terminus. Structure predictions using AlphaFold2 and binding analyses employing CipA variants lacking Factor I-binding capability confirmed that the orientation of the C-terminal domain is essential for the interaction with Factor I. Hence, our analyses point to a novel Factor I-dependent mechanisms of complement inactivation mediated by CipA of A. baumannii. Recruitment of Factor I by CipA initiates the assembly of a quadripartite complex following binding of either Factor H or C4b-binding protein to degrade C3b and C4b, respectively. Loss of Factor I binding in a CipA-deficient strain, or a strain producing a CipA variant lacking Factor I-binding capability, correlated with a higher susceptibility to human serum, indicating that recruitment of Factor I enables A. baumannii to resist complement-mediated killing.
Insights
Acinetobacter baumannii uses CipA to evade the immune system by inhibiting complement pathways. This protein recruits Factor I, a key enzyme, to degrade complement components, preventing bacterial killing by human serum.
Area of Science:
- Microbiology
- Immunology
- Structural Biology
Background:
- Multidrug-resistant *Acinetobacter baumannii* is a significant cause of hospital-acquired infections.
- Bacteria employ immune evasion strategies to survive host defenses.
- CipA was previously identified as a plasminogen-binding and complement-inhibitory protein from *A. baumannii*.
Purpose of the Study:
- To elucidate the mechanism by which CipA inhibits the complement system.
- To identify the specific complement components and pathways targeted by CipA.
- To determine the structural basis for CipA's interaction with complement factors, particularly Factor I.
Main Methods:
- Biochemical assays to assess complement inhibition across all three pathways.
- Protein-protein interaction studies using various complement components (C3, C3b, C4b, C5, Factor B, Factor D, Factor I).
- Systematic screening of CipA variants and structural predictions (AlphaFold2) to map binding sites and functional domains.
Main Results:
- CipA inhibits all three complement activation pathways.
- CipA directly interacts with multiple complement proteins, including Factor I, C3b, and C4b.
- A novel Factor I-dependent mechanism of complement inactivation mediated by CipA was identified, involving the C-terminal domain.
- Impaired C5 convertase activity and reduced cleavage of C5 were observed.
- Loss of Factor I binding capability rendered *A. baumannii* more susceptible to human serum.
Conclusions:
- CipA employs a novel Factor I-dependent mechanism to inactivate the complement system.
- CipA recruits Factor I to form a complex that degrades C3b and C4b, thereby preventing complement-mediated bacterial killing.
- This mechanism is crucial for *A. baumannii*'s survival in the host by resisting innate immunity.
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