Characterization of a novel Escherichia coli IgA-binding antigen impairing neutrophil activation
Year: 2012
Type: dissertation
Abstract: Extraintestinal pathogenic Escherichia coli (ExPEC) possess a unique ability to cause disease outside the host intestinal tract and are responsible for a heterogeneous group of disorders, including urinary tract infections, sepsis and neonatal meningitis, that collectively cause considerable morbidity, lost productivity and high healthcare costs. Considering the incidence and also the increasing antibiotic resistance of ExPEC strains, the prevention of extraintestinal E. coli infections is of pressing concern from both the public health and economic perspectives. Since conventional attempts to develop a highly immunogenic, safe and polyvalent vaccine against ExPEC had failed, we decided to apply the reverse vaccinology approach for the identification of protective and broadly conserved vaccine antigens. Although some of the protective candidates have been previously described, most of them have just putative or hypothetical functions assigned and, therefore, their characterization could contribute to the understanding of ExPEC pathogenesis. In this study, vaccine antigen c5321 has been characterized. Besides being able to induce protection in a sepsis mouse model, it has been shown to be also immunogenic and specifically expressed in vivo during E. coli infection of the human urinary tract. Antigen expression has also been confirmed under in vitro conditions and has been found to be regulated by ion concentration. The determination of the crystal structure of the protein has revealed that c5321 is composed of twelve Sel1-like repeats (SLRs) stacked on top of each other forming an α/α-superhelix, which shows a high structural homology with a protein-protein recognition domain of human O-linked N-acetylglucosamine transferase and with Helicobacter cysteine-rich protein C. SLRs 3 and 4 have been found to participate in octahedral coordination of magnesium, suggesting that ions, in addition to regulating antigen expression, may also have a structural relevance. As many bacterial SLR proteins, c5321 has demonstrated a capability to interact with the host immune system and, in particular, with human immunoglobulins A (IgA), leading to the inhibition of IgA-mediated neutrophil activation, oxidative burst and chemotaxis. These data suggest that c5321 is a novel E. coli IgA-binding protein with specific immunomodulatory properties that could allow the bacterium to avoid clearance by impairing production of reactive oxygen species, as well as neutrophil recruitment to the infection site.
Author: Ilaria Pastorello
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W207957681