title: The Pseudomonas aeruginosa type III secretion system has an exotoxin S/T/Y independent pathogenic role during acute lung infection.
abstract: The type III secretion system (T3SS) is a complex nanomachine of many pathogenic gram-negative bacteria. It forms a proteinaceous channel that is inserted into the host eukaryotic cell membrane for injection of bacterial proteins that manipulate host cell signaling. However, few studies have focused on the effector-independent functions of the T3SS. Using a murine model of acute lung infection with Pseudomonas aeruginosa, an important human opportunistic pathogen, we compared the pathogenicity of mutant bacteria that lack all of the known effector toxins ( ΔSTY), with mutant bacteria that also lack the major translocator protein PopB (ΔSTY/ΔPopB) and so cannot form a functional T3SS channel in the host cell membrane. Mortality was higher among mice challenged with ΔSTY compared to mice challenged with ΔSTY/ΔPopB mutant bacteria. In addition, mice infected with ΔSTY showed decreased bacterial clearance from the lungs compared to those infected with ΔSTY/ΔPopB. Infection was in both cases associated with substantial killing of lung infiltrating macrophages. However, macrophages from ΔSTY-infected mice died by pro-inflammatory necrosis characterized by membrane permeabilization and caspase-1 mediated IL-1β production, whereas macrophages from ΔSTY/ΔPopB infected mice died by apoptosis, which is characterized by annexin V positive staining of the cell membrane and caspase-3 activation. This was confirmed in macrophages infected in vitro. These results demonstrate a T3SS effector toxin independent role for the T3SS, in particular the T3SS translocator protein PopB, in the pathogenicity of P. aeruginosa during acute lung infection.
authors: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors: Marlies
authors: M
authors: Galle
authors: Shouguang
authors: S
authors: Jin
authors: Pieter
authors: P
authors: Bogaert
authors: Mira
authors: M
authors: Haegman
authors: Peter
authors: P
authors: Vandenabeele
authors: Rudi
authors: R
authors: Beyaert
mesh_terms: D000208:Acute Disease; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D005098:Exotoxins / Q000378:metabolism; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000382:microbiology; D008171:Lung Diseases / Q000382:microbiology*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D016062:Porosity; D021381:Protein Transport; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D005098:Exotoxins; D053583:Interleukin-1beta; C576076:PopB protein, Pseudomonas aeruginosa