The molecular mechanism of acute lung injury caused by Pseudomonas aeruginosa: from bacterial pathogenesis to host response

Teiji Sawa

Pseudomonas aeruginosa is the most common gram-negative pathogen causing pneumonia in immunocompromised patients. Acute lung injury induced by bacterial exoproducts is associated with a poor outcome in P. aeruginosa pneumonia. The major pathogenic toxins among the exoproducts of P. aeruginosa and the mechanism by which they cause acute lung injury have been investigated: exoenzyme S and co-regulated toxins were found to contribute to acute lung injury. P. aeruginosa secretes these toxins through the recently defined type III secretion system (TTSS), by which gram-negative bacteria directly translocate toxins into the cytosol of target eukaryotic cells. TTSS comprises the secretion apparatus (termed the injectisome), translocators, secreted toxins, and regulatory components. In the P. aeruginosa genome, a pathogenic gene cluster, the exoenzyme S regulon, encodes genes underlying the regulation, secretion, and translocation of TTSS. Four type III secretory toxins, namely ExoS, ExoT, ExoU, and ExoY, have been identified in P. aeruginosa. ExoS is a 49-kDa form of exoenzyme S, a bifunctional toxin that exerts ADP-ribosyltransferase and GTPase-activating protein (GAP) activity to disrupt endocytosis, the actin cytoskeleton, and cell proliferation. ExoT, a 53-kDa form of exoenzyme S with 75% sequence homology to ExoS, also exerts GAP activity to interfere with cell morphology and motility. ExoY is a nucleotidal cyclase that increases the intracellular levels of cyclic adenosine and guanosine monophosphates, resulting in edema formation. ExoU, which exhibits phospholipase A2 activity activated by host cell ubiquitination after translocation, is a major pathogenic cytotoxin that causes alveolar epithelial injury and macrophage necrosis. Approximately 20% of clinical isolates also secrete ExoU, a gene encoded within an insertional pathogenic gene cluster named P. aeruginosa pathogenicity island-2. The ExoU secretory phenotype is associated with a poor clinical outcome in P. aeruginosa pneumonia. Blockade of translocation by TTSS or inhibition of the enzymatic activity of translocated toxins has the potential to decrease acute lung injury and improve clinical outcome.