Acinetobacter baumannii outer membrane protein A targets the nucleus and induces cytotoxicity

Abstract

SummaryAcinetobacter baumannii is an emerging opportunistic pathogen responsible for healthcare-associated infections. The outer membrane protein A of A. baumannii (AbOmpA) is the most abundant surface protein that has been associated with the apoptosis of epithelial cells through mitochondrial targeting. The nuclear translocation of AbOmpA and the subsequent pathology on host cells were further investigated. AbOmpA directly binds to eukaryotic cells. AbOmpA translocates to the nucleus by a novel monopartite nuclear localization signal (NLS). The introduction of rAbOmpA into the cells or a transient expression of AbOmpA-EGFP causes the nuclear localization of these proteins, while the fusion proteins of AbOmpADNLS-EGFP and AbOmpA with substitutions in residues lysine to alanine in the NLS sequences represent an exclusively cytoplasmic distribution. The nuclear translocation of AbOmpA induces cell death in vitro. Furthermore, the microinjection of rAbOmpA into the nucleus of Xenopus laevis embryos fails to develop normal embryogenesis, thus leading to embryonic death. We propose a novel pathogenic mechanism of A. baumannii regarding the nuclear targeting of the bacterial structural protein AbOmpA.

Insights into Acinetobacter baumannii pathogenicity

“…OmpA localized to the mitochondria, causing damage and activation of caspases and apoptosis-inducing factors (14). This work was extended to show that Omp38 binds to a range of eukaryotic cells (HEp-2, Cos-7, and macrophages), is important for A. baumannii cellular invasion, and that it targets both the nucleus and mitochondria (15,16). Furthermore, Omp38 was shown to degrade chromosomal DNA by DNAse Ilike enzymatic activity (36).…”

“…Another outer membrane protein that has been implicated in biofilm formation is OmpA (14)(15)(16)(17). It appears that OmpA is not essential for biofilm development, but is required for the formation of thick biofilms on polystyrene (17).…”

Are we closing in on an "elusive enemy"? The current status of our battle withAcinetobacter baumannii

“…Omps have also been advanced as potential targets for diagnosis of A. baumannii, as they elicit specific IgG, IgM and IgG antibodies. [26][27][28][29] Of tremendous import, an Omp vaccine with multiple surface antigens from the bacterial membrane of A. baumannii elicited protective and therapeutic humoral and cellular responses in a murine sepsis model. 30 How well will this serve as a start to a vaccine remains to be seen.…”

Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting

“…Outer membrane protein A (OmpA), previously known as Omp38, is a lethal and most abundantly expressed surface virulence factor in A. baumannii [165,166]. OmpA belongs to the porin family with low permeability that may be a key factor contributing to its multidrug resistance [167].…”

“…OmpA belongs to the porin family with low permeability that may be a key factor contributing to its multidrug resistance [167]. OmpA can bind with host cell directly, internalize within mitochondria and nuclei compartments of host cell, and induce host cell death [165,166]. Moreover, OmpA is highly conserved within six clinical isolates (99% protein sequence identity) and 14 other NCBI GenBank deposited sequences from diferent isolates of A. baumannii (89% protein sequence identity), while OmpA shows no homology to human proteins [168].…”