## 2 A. baumanniii and the Host Innate Immune Response
### Mechanisms Protecting A. baumanniii against the Innate Immune Response
baumanniii_ constitutively synthesizes hepta-acylated lipid A, under standard growth conditions, in contrast to other Gram-negative bacteria that upregulate its synthesis only under stress conditions [59]. Constitutive hepta-acylation of lipid A fortifies the OM to protect _A. baumannii_ from cationic AMPs, lysozyme, and colistin, which is the last-resort antibiotic to treat MDR _A. baumannii_ infections [59]. Colistin resistance may result from a complete lack of LOS or the addition of galactosamine to LOS. LOS deficiency significantly alters the interaction of _A. baumannii_ with the host innate immune system. The overall pro-inflammatory response to LOS-deficient _A. baumannii_ is reduced due to the lack of TLR-4 mediated stimulation. Instead of the TLR4-dependent mechanism, the TLR2-dependent mechanism is activated [60]. This alternative response is probably a consequence of increased expression of specific lipoproteins, transporters, and other surface components that compensate for the lack of LOS [61]. Although LOS-deficient strains are colistin-resistant, they exhibit decreased virulence and increased susceptibility to LL-37 and lysozyme [62; 63; 64; 60]. Apart from the surface glycoconjugates, essential virulence factors of _A. baumannii_ are OM proteins. The best-characterized _A. baumannii_ OM protein, OmpA porin, is responsible for adhesion and invasion of _A. baumannii_ into human epithelial cells [65; 66; 67; 68]. It was found that the overproduction of OmpA is a risk factor for the development of _A. baumannii_ pneumonia and bacteraemia, as well as for an increased mortality rate [69]. Consistently, the deletion of the _ompA_ gene reduced _A. baumannii_ bacterial dissemination and development of secondary pneumonia in the murine peritoneal sepsis model [69]. OmpA is secreted and enters epithelial cells via outer membrane vesicles (OMVs) [70; 71; 72]. OMVs are used by Gram-negative bacteria to deliver toxins, virulence factors, and other effector molecules to host cells. After entering the epithelial cell, OmpA migrates to mitochondria and stimulates the release of cytochrome \(c\), finally promoting apoptosis [65]. In addition, OmpA triggers cell death by inducing the expression of TLR2 and production of nitrogen oxide. [PERSON] et al. found that high concentrations of OmpA induces ROS production, leading to early-onset apoptosis and delayed-onset necrosis in dendritic cells (DCs) [73]. These results demonstrate that OmpA can cause the death of DSC, thereby impairing T-cell responses against _A. baumannii_. Other studies revealed that the interaction of OmpA with the fluid-phase complement regulator factor H (FH) enables _A. baumannii_ to escape complement and to survive in human serum [31]. Two other _A. baumannii_ proteins, CipA and the protein killing factor (PKF) serine protease, also contribute to serum resistance. The recently identified CipA is a plasminogen-binding protein exposed on the OM [32]. Plasminogen, in the complex with CipA, is cleaved and converted to the active serine protease plasmin, which degrades fibrinogen and the complement component C3b. Thus, CipA can prevent entrapment of _A. baumannii_ in fibrin thrombi, and it facilitates dissemination of the pathogen. Regardless of plasminogen binding, CipA can also inhibit the alternative complement pathway [32]. The PKF serine protease is involved in serum resistance possibly through degradation of yet unidentified complement components [74]. It was suggested that both CipA and PKF are secreted via a type II secretion system (T2 SS) [75]. The T2 SS enables secretion of effector proteins including multiple enzymes critical for _A. baumannii_ virulence [9]. The hypothesis that the T2 SS participates in the secretion of CipA and PKF is based on results showing that deletion of the T2 SS gene _ggD_ resulted in significantly decreased resistance to human serum [75]. Recent studies revealed that, in addition to the aforementioned proteins and structures, _A.