## 2 A. baumanniii and the Host Innate Immune Response
### Mechanisms Protecting A. baumanniii against the Innate Immune Response
baumannii_ possesses numerous protective mechanisms against complement-mediated killing, [PERSON] et al. identified 50 genes essential for the survival of _A. baumannii_ in human serum, including the Mla system, which encodes proteins required for the maintenance of OM lipid asymmetry [54]. The Mla proteins prevent the accumulation of phospholipids in the outer leaflet of the OM by transporting them to the inner membrane. This study suggests that the accumulation of surface-exposed phospholipids in _mla_-deficient strains can activate the alternative pathway of the complement system [54]. An example of a metabolic adaptation that enables _A. baumannii_ to evade neutrophil chemotaxis is the phenylacetic acid catabolism pathway encoded by the _paa_ system [14]. The _paa_ genes were identified in 16% of the sequenced bacterial species [76; 77]. The _paa_ operon is involved in degradation of aromatic compounds including phenylacetate to form acetyl-coenzyme A (CoA) and succinyl-CoA [76]. [PERSON] al. demonstrated that the loss of function of this catabolic pathway resulted in the accumulation of phenylacetate, which acted as an attractant of neutrophils, leading finally to bacterial clearance [14]. An interesting example of the _A. baumannii_ virulence strategy is its ability to adhere to neutrophils without being eliminated by phagocytosis. Since neutrophils can transmigrate from the infection site to vasculature, it was proposed that the reverse migration of neutrophils can disseminate the infection to other organs [17]. Moreover, [PERSON] et al. demonstrated that MDR _A. baumannii_ isolates can survive in macrophages after phagocytosis. The MDR strains induced ROS production in macrophages, and they concomitantly exhibited upregulated catalase activity which allowed them to resist oxidative stress [78]. These results indicate that _A. baumannii_ can spread in the infected organism using both neutrophils and macrophages. Most of the strategies described above (Figure 1) allow _A. baumannii_ not only to evade the innate immune response, but also to survive in the external environment. Figure 1: _Acinetobacter baumannii_ uses different mechanisms to evade the innate immune response. 1 Hepta-acylation of lipid A in lipopolysaccharideaccharide (LOS) fortifies the outer membrane (OM) and protects _A. baumannii_ from cationic antimicrobial peptides (AMPs), colistin, and lysozyme. 2 Highly hydrophilic and negatively charged capsular polysaccharides (CPS) hinder interactions with negatively charged surfaces of neutrophils and macrophages; the capsule is also a barrier which protects against complement-mediated killing, lysozyme degradation, and reactive oxygen species (ROS). 3 Outer membrane protein A (OmpA) interacts with factor H (FH), thereby inhibiting the complement-mediated killing; OmpA induces ROS production and the death of dendritic cells (DCs). 4 CipA forms a complex with plasminogen/plasmin, which degrades the complement component C3b; CipA and 5 the protein killing factor (PKF) serine protease inhibit the alternative complement pathway. 6 The type II secretion system (T2 SS) contributes to serum resistance, and it probably participates in CipA and PKF serine protease secretion. 7 Surface-exposed phospholipids are potential activators of the alternative complement pathway. The Mla system prevents the accumulation of phospholipids in the outer leaflet of the OM. 8 Phenyacetate, a derivative of phenylalanine and neutrophil attractant, is removed from the bacterial cell by conversion to acetyl-coenzyme A (CoA) and succinyl-CoA. 8 Enhanced catalase activity enables _A. baumannii_ to survive in macrophages in the presence of ROS. 9 _A. baumannii_ can spread during infection using neutrophils and macrophages.