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.