Mechanisms of phagocytosis and host clearance of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for a high incidence of acute and chronic pulmonary infection. These infections are particularly prevalent in patients with chronic obstructive pulmonary disease and cystic fibrosis: much of the morbidity and pathophysiology associated with these diseases is due to a hypersusceptibility to bacterial infection. Innate immunity, primarily through inflammatory cytokine production, cellular recruitment, and phagocytic clearance by neutrophils and macrophages, is the key to endogenous control of P. aeruginosa infection. In this review, we highlight recent advances toward understanding the innate immune response to P. aeruginosa, with a focus on the role of phagocytes in control of P. aeruginosa infection. Specifically, we summarize the cellular and molecular mechanisms of phagocytic recognition and uptake of P. aeruginosa, and how current animal models of P. aeruginosa infection reflect clinical observations in the context of phagocytic clearance of the bacteria. Several notable phenotypic changes to the bacteria are consistently observed during chronic pulmonary infections, including changes to mucoidy and flagellar motility, that likely enable or reflect their ability to persist. These traits are likewise examined in the context of how the bacteria avoid phagocytic clearance, inflammation, and sterilizing immunity.

Keywords: Pseudomonas aeruginosa; clearance; inflammation; lung; phagocytosis.

Fig. 1.

Flagellar motility is a key bacterial determinant for phagocytic susceptibility of Pseudomonas aeruginosa by both murine and human phagocytes, with motile bacteria phagocytosed ∼100-fold more efficiently than nonmotile bacteria (top). Although the cell surface phagocytic receptor(s) for P. aeruginosa require further elucidation, independent reports indicate that bacterial engulfment is actin dependent and controlled by the PI3K/Akt signaling pathway. P. aeruginosa has also been proposed to invade epithelial cells (bottom), particularly on the basolateral surfaces of these cells, through alterations in cell polarity and in breaches in the monolayer. Proposed mechanisms include invasion via cell surface lipid rafts in conjunction with the caveolin-2 protein, and via heparin sulfate proteoglycans (HSPGs). The HSPG-mediated pathway is subsequently dependent on intracellular PI3K/Akt activity, and RhoA and/or Cdc42 activation. The relationship between the HSPG and lipid raft-mediated pathways is currently unclear.