Acinetobacter baumannii: An Ancient Commensal with Weapons of a Pathogen

Abstract

Acinetobacter baumannii is regarded as a life-threatening pathogen associated with community-acquired and nosocomial infections, mainly pneumonia. The rise in the number of A. baumannii antibiotic-resistant strains reduces effective therapies and increases mortality. Bacterial comparative genomic studies have unraveled the innate and acquired virulence factors of A. baumannii. These virulence factors are involved in antibiotic resistance, environmental persistence, host-pathogen interactions, and immune evasion. Studies on host-pathogen interactions revealed that A. baumannii evolved different mechanisms to adhere to in order to invade host respiratory cells as well as evade the host immune system. In this review, we discuss current data on A. baumannii genetic features and virulence factors. An emphasis is given to the players in host-pathogen interaction in the respiratory tract. In addition, we report recent investigations into host defense systems using in vitro and in vivo models, providing new insights into the innate immune response to A. baumannii infections. Increasing our knowledge of A. baumannii pathogenesis may help the development of novel therapeutic strategies based on anti-adhesive, anti-virulence, and anti-cell to cell signaling pathways drugs.

Keywords: Acinetobacter baumannii; adherence; community-acquired infections; internalization; invasion; nosocomial infections; persistence; virulence factors.

Figure 1

Schematic representation of the interrelations between A. baumannii and the respiratory epithelium. A. baumannii has several virulence factors that enable the bacterium to adhere to and invade host cells. Main proteins involved in the interaction with host cells and extracellular host proteins are OmpA, Omp33, OmpW, Ata and FhaB. A. baumannii cells are internalized via a zipper mechanism and reside and survive within membrane-bound vacuoles. Bronchial epithelial cells respond to A. baumannii infections by eliciting the Jak-STAT pathway as well as the intracellular oxidative stress response that eventually lead to apoptosis [169]. TLR2 and TLR4 on type II pneumocytes recognize lipoproteins and LOS and release cytokines (i.e., IL-8) via NF-κB and p38-Erk1/2-dependent pathway to chemoattract neutrophils at the site of infection [163]. A. baumannii can engage CEACAM-1, -5, and -6 to gain access to type II pneumocytes. Internalization through CEACAM-1 triggers IL-8 production together with TLR2 and TLR4 via NF-κB and Erk1/2-dependent pathway; however, IL-8 secretion decreases significantly at 24 h post-infection, possibly due to a bacterial-induced inhibitory activity of CEACAM-1 ITIM on the TLR2 signaling cascade. Conversely, engagement of CEACAM-5 and -6 triggers induce LC3 associated phagocytosis (LAP) for clearance of A. baumannii via the JNK1/2-Rubicon-NOX2 pathway, which inhibits the canonical autophagic pathway [170]. Furthermore, A. baumannii can interact with platelet-activating factor receptors (PAFRs) via ChoP-containing OprD, leading to a signaling cascade that includes G protein-coupled PLC, clathrin, β-arrestins and an increase of intracellular Ca⁺⁺, thereby leading to bacterial internalization [76]. Invasion and persistence of A. baumannii is assisted by TFEB which induces the autophagosome-lysosome system that A. baumannii exploits to traffic intracellularly and persist within lung cells, possibly due to reduced lysosome acidification [150]. It has been hypothesized that both intracellular persistence and apoptosis are A. baumannii strategies to allow bacterial dissemination to deeper tissues and lead to invasive diseases. Individual components are not to scale.

Figure 2

Innate immune responses to A. baumannii in respiratory epithelia. Neutrophils, macrophages, mast cells, NK and DC cells are involved in the clearance of A. baumannii infections. Neutrophils are the main defense against A. baumannii infections [165]. Neutrophils are depicted during phagocytosis and pathogen clearance. Massive recruitment of neutrophils is achieved by secretion of antimicrobial peptides as well as chemoattractant cytokines and chemokines, including interleukin-1 (IL-1), macrophage inflammatory protein-1 (MIP-1), MIP-2, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) [11,19,175]. However, A. baumannii has developed several strategies to evade neutrophil killing activities. Invading A. baumannii can inhibit the production of NETs; in addition, bacteria can adhere to IL-8-activated neutrophils and use them as transporters in vitro [165,176]. Moreover, phagocyted A. baumannii can oppose the killing effects of ROS produced by neutrophils by upregulating bacterial resistance compounds [138]. While phagocyting a significant number of A. baumannii cells, macrophages release proinflammatory cytokines and chemokines, such as IL-6, IL-10, IL-1β, MIP-2 and TNF-α, in order to recruit neutrophils at the site of infection [11,175]. DCs join the innate immune system into the adaptive immune system by producing IL-12 to induce CD4+ Th1 T cell immune responses [175]. Despite that A. baumannii OmpA can activate dendritic cells (DCs), it induces death of DCs via mitochondrial targeting and ROS production, thereby impairing the adaptive immune responses [175]. It seems that the main role of the N-terminal kinase (NK) and mast cells against A. baumannii is to produce neutrophil chemo-attractants, such as IL-8 and TNF-α [11,175]. For simplicity, the toll-like receptors (TLRs) signaling pathways were omitted. Individual components are not to scale.