## 2 A. baumanniii and the Host Innate Immune Response
### Mechanisms Protecting A. baumanniii against the Innate Immune Response  
_A. baumanniii_ uses different virulence factors or mechanisms to evade the innate immune response. Surface glycoconjugates play key roles, but other strategies, including secreted proteins and metabolic pathways, also participate in the defense against the immune system [35; 36]. The first barrier that protects _A. baumanniii_ against the immune host response is an exopolysaccharideacnide capsule. The capsule is formed from long-chain polysaccharides composed of repeated carbohydrate units (K units). The synthesis of capsular polysaccharides (CPS) is dependent on a K locus (KL), which contains genes for synthesis of activated sugar precursors, glycosyl transfer, glycan modification, and oligosaccharidesacnide repeat-unit processing [37]. To date, 128 KL gene clusters were identified in _A. baumanniii_[38]. Therefore, the monosaccharide composition and CPS structure are highly variable in _A. baumanniii_ strains [37; 39; 40; 41; 42; 43]. K units vary in length and may consist of two to six residues. Common neutral sugars such as p-glucose, p-galactose, \(N\)-acetyl-p-glucosamine, and \(N\)-acetyl-p-galactosamine or rare sugars, including derivatives of pseudaminic, legionaminic, or acinetaminic acid, can be incorporated into CPS. Interestingly, acinetaminic acid was never found in nature before its detection in _A. baumannii_ isolates with K12 and K13 gene clusters [42]. The CPS of different isolates are linear or branched and may possess non-carbohydrate substituents, including the most frequent \(O\)- and \(N\)-acyl groups [44]. The Wzy pathway encoded by the K locus is responsible for the export and extracellular assembly of CPS [45]. The K locus is regulated by the two-component signal transduction system BfmRS. The global BfmR regulator, along with histidine kinase BfmS, controls a variety of processes, including biogenesis of _A. baumannii_ envelope elements, formation of biofilms, desiccation tolerance, and multiple stress responses [46; 47; 48; 49]. Several studies demonstrated that the production of capsules affects _A. baumanniii_ virulence and persistence in the host [50; 51]. Capsule-enriched strains cause more severe disease or higher lethality [35; 45; 50; 52; 53]. These observations may be partly explained by the high hydrophilicity of CPS and negative charges of CPS monosaccharides that prevent phagocytosis by hindering interactions with the negatively charged surfaces of neutrophils and macrophages, preventing phagocytosis [35]. However, it should be noted that the highly variable structure of the CPS may affect its capacity as a protective barrier against the immune response and other stresses, including complement-mediated killing, lysozyme degradation, and ROS [45; 50; 51; 52; 53; 54]. Another barrier protecting _A. baumanniii_ against the host response is the OM. LPS, the main component of the outer layer of the OM, contains three domains: (1) lipid A, the membrane anchor glycosylated with (2) a core oligosaccharidesacnide which may provide an attachment site for (3) a long-chain \(O\)-antigenic polysaccharide [35]. In _A. baumanniii_, the primary component of the outer layer of the OM is lipooligosaccharide (LOS) which, in contrast to the typical LPS, lacks the O-antigen [37]. _A. baumanniii_ LOS belongs to the group of pathogen-associated molecular patterns (PAMPs) recognized by Toll-like receptor 4 (TLR4) [13; 55]. TLR4 is one of the pattern recognition receptors (PRRs) which function as cell-surface sensors of bacterial infection. _A. baumanniii_ LOS triggers a TLR4-mediated release of tumor necrosis factor (TNF) and interleukin 8 (IL-8) from macrophages [56]. This inflammation response is beneficial for the host; however, if it is upregulated, it can result in a cytokine storm and septic shock [57]. In the case of highly virulent _A. baumanniii_, enhanced TLR4 activation is correlated to increased shedding of LOS into growth medium [58]. _A.