## 2 A. baumanniii and the Host Innate Immune Response  
### The First Line of Host Defense against A. baumannii  
Neutrophils, macrophages, antimicrobial peptides (AMPs), and complement system components are the first line of innate immune defense that _A. baumannii_ encounters during infection. Neutrophils can kill bacteria via phagocytosis, degranulation, or NETosis--a specific type of cell death pathway resulting in the release of the neutrophil extracellular traps (NETs). In NETs, chromatin forms a web-like structure decorated with antibacterial factors, including neutrophil elastase and AMPs [9]. Multiple studies suggest that neutrophils play a crucial role in the control of _A. baumanniii_ infection [12; 13; 14; 15]; however, contradictory results showing that neutrophils do not kill _A. baumanniii_ were also reported [16; 17]. After phagocytosis, neutrophil clearance of _A. baumannii_ is mainly dependent on reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which generates reactive oxygen species (ROS) to kill the pathogen [12]. The stimulation of H\({}_{2}\)O\({}_{2}\) production in the lung of a mouse model in response to _A. baumannii_ infection confirmed this observation [18]. It was also found that _A. baumanniii_ inhibits NETosis, in contrast to other Gram-negative bacteria that trigger NET formation [17; 19; 20]. The role of macrophages in eliminating _A. baumanniii_ remains controversial. Most studies showed that macrophages play a minor role during _A. baumannii_ infection [14; 15; 21]. However, [PERSON] et al. demonstrated that macrophages could be the first line of defense against respiratory _A. baumannii_ infections; the depletion of alveolar macrophages significantly enhanced the susceptibility of mice to _A. baumannii_[22]. In addition, phagocytosis and killing of _A. baumannii_ were observed in vitro, and the macrophages produced nitric oxide and secreted proinflammatory cytokines and chemokines [22].  
AMPs are expressed constitutively or induced in different types of cells and tissues. Most of the AMPs are cationic; therefore, they can easily target the negatively charged surface of bacteria [23; 24]. To date, 139 human host defense peptides were identified [25]. Cathelicidin-derived LL-37 is the best-studied AMP that kills _A. baumannii_ cells through binding to the outer membrane protein A (OmpA) [24; 26]. The LL-37 precursor, human cationic antibacterial peptide (hCAP-18), is produced by epithelial cells and neutrophils [13]. Recently, it was demonstrated that LL-37 forms a dimer of two anti-parallel amphipathic \(\alpha\)-helices without supercoiling [27]. LL-37 helices target and extract lipopolysaccharidesaccharides (LPS) to form holes in the outer membrane (OM). After diffusion into the periplasmic space, LL-37 may extract lipids from the inner membrane, forming a fibril-like structure [27]. Two other AMPs that belong to the human beta defensins, hBD-2 and hBD-3, were shown to kill _A. baumannii_ in a concentration-dependent manner [28].  
Another element of the immune system directed against _A. baumannii_ involves the complement system components. The complement system consists of more than 30 plasma proteins that collaborate as a cascade triggering either bacterial cell lysis or opsonization and phagocytosis [29]. There are three pathways of complement activation: classical, lectin, and alternative pathways. The classical pathway is initiated by immune complexes, whereas the lectin pathway is triggered by pathogen-specific carbohydrates. The alternative pathway, which is responsible for the killing of _A. baumanniii_[30; 31], is permanently active due to spontaneous hydrolysis of the central complement system component, C3, enabling fast detection of pathogens [29; 32]. Several studies reported that the depletion of the complement results in an increase of _A. baumanniii_ viability in human serum or a mouse model of _A. baumanniii_ infection [15; 33; 34].