The contribution of nutrient metal acquisition and metabolism to Acinetobacter baumannii survival within the host

Abstract

Acinetobacter baumannii is a significant contributor to intensive care unit (ICU) mortality causing numerous types of infection in this susceptible ICU population, most notably ventilator-associated pneumonia. The substantial disease burden attributed to A. baumannii and the rapid acquisition of antibiotic resistance make this bacterium a serious health care threat. A. baumannii is equipped to tolerate the hostile host environment through modification of its metabolism and nutritional needs. Among these adaptations is the evolution of mechanisms to acquire nutrient metals that are sequestered by the host as a defense against infection. Although all bacteria require nutrient metals, there is diversity in the particular metal needs among species and within varying tissue types and bacterial lifecycles. A. baumannii is well-equipped with the metal homeostatic systems required for the colonization of a diverse array of tissues. Specifically, iron and zinc homeostasis is important for A. baumannii interactions with biotic surfaces and for growth within vertebrates. This review discusses what is currently known regarding the interaction of A. baumannii with vertebrate cells with a particular emphasis on the contributions of metal homeostasis systems. Overall, published research supports the utility of exploiting these systems as targets for the development of much-needed antimicrobials against this emerging infectious threat.

Keywords: Acinetobacter; adherence; iron; pathogenesis; persistence; zinc.

Figure 1

Summary of predicted and described iron and non-iron metal acquisition systems in A. baumannii. The iron and non-iron systems encoded within the A. baumannii genome vary dramatically between different strains. (A) This panel depicts the iron acquisition and utilization systems identified or described among the different A. baumannii strains. Secretion of enzymes such as phospholipase C and others may contribute to hemolysis and hemoglobin release from red blood cells. At least five clusters of genes for siderophore synthesis and secretion are dispersed among different strains. These include acinetobactin, fimsbactins A-F, the strain 8399 (om73-entD) siderophore, as well as siderophores produced by the ACICU1672-1683 and the ABAYE1888-1899 clusters. EntA is required for iron acquisition due to its involvement in the biosynthesis of the acinetobactin precursor 2,3-dihydroxybenzoic acid. Siderophores are recognized by TonB-dependent receptors, of which 8–22 have been discovered among the sequenced strains. At least one of multiple encoded TonB/ExbB/ExbD systems generates and provides energy to the TonB-dependent receptors, and at least one FeoAB ferrous iron transport system has been identified in all sequenced strains. Finally, 1–2 heme uptake systems have been identified among A. baumannii strains. NfuA is a Fe-S cluster protein required for iron utilization in the cytoplasm. Regulation of these numerous systems likely depends on the conserved Fur repressor. (B) This panel depicts the zinc acquisition and metabolism systems described in A. baumannii ATCC 17978. Outer membrane transport of zinc may occur via two zinc-regulated TonB-dependent receptors, energized by a zinc-regulated TonB/ExbB/ExbD system. Inner membrane transport is mediated by the ZnuABC transporter. Zur is a conserved repressor that controls the expression of znuABC and likely the other identified zinc systems.

Figure 2

A. baumannii-host cell interactions. Extracellular A. baumannii experiences a metal-limited environment at least in part due to metal-binding host proteins and intracellular localization of metals, e.g., red blood cells (RBCs). A. baumannii attaches to host cells through interactions between fibronectin and bacterial outer membrane proteins (OMPs), such as OmpA, as well as Type IV collagen via Ata. These OMPs may bind to other host cell proteins, for example the interaction of OMP ChoP with platelet activating factor receptor (PFAR). Fimbriae also contribute to eukaryotic cell adherence. Invasion into epithelial cells occurs via host cell actin filament and microtubule reorganization, recruitment of β-arrestin and clathrin, and a bacterial uptake via a zipper-like mechanism. Although A. baumannii can persist intracellularly and includes entry into endosomes, the intracellular trafficking of A. baumannii is not clear. Eukaryotic cell proteins NRAMP1, ZIP8, ZnTs, and other transporters pump essential metals out of endocytic vesicles and the cytoplasm, limiting the intracellular pool available to pathogens. The physiological relevance of the intracellular lifecycle of A. baumannii remains to be understood. One consequence of host cell exposure to A. baumannii is apoptosis. It is possible that cell death and/or host cell invasion serve to permit A. baumannii dissemination to deeper tissues leading to invasive disease.