Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection

Abstract

Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia and chronic lung infections in cystic fibrosis patients. Iron is essential for bacterial growth, and P. aeruginosa expresses multiple iron uptake systems, whose role in lung infection deserves further investigation. P. aeruginosa Fe 3؉ uptake systems include the pyoverdine and pyochelin siderophores and two systems for heme uptake, all of which are dependent on the TonB energy transducer. P. aeruginosa also has the FeoB transporter for Fe 2؉ acquisition. To assess the roles of individual iron uptake systems in P. aeruginosa lung infection, single and double deletion mutants were generated in P. aeruginosa PAO1 and characterized in vitro, using iron-poor media and human serum, and in vivo, using a mouse model of lung infection. The iron uptake-null mutant (tonB1 feoB) and the Fe 3؉ transport mutant (tonB1) did not grow aerobically under low-iron conditions and were avirulent in the mouse model. Conversely, the wild type and the feoB, hasR phuR (heme uptake), and pchD (pyochelin) mutants grew in vitro and caused 60 to 90% mortality in mice. The pyoverdine mutant (pvdA) and the siderophore-null mutant (pvdA pchD) grew aerobically in iron-poor media but not in human serum, and they caused low mortality in mice (10 to 20%). To differentiate the roles of pyoverdine in iron uptake and virulence regulation, a pvdA fpvR double mutant defective in pyoverdine production but expressing wild-type levels of pyoverdine-regulated virulence factors was generated. Deletion of fpvR in the pvdA background partially restored the lethal phenotype, indicating that pyoverdine contributes to the pathogenesis of P. aeruginosa lung infection by combining iron transport and virulence-inducing capabilities.

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

“…To our knowledge, this is the first report of a microbial natural product that is a direct inhibitor of a competing species' siderophore transport system. Multiple studies have implicated the pyochelin siderophore system in virulence (74)(75)(76), including genetic abrogation of pyochelin-mediated iron uptake that diminished P. aeruginosa virulence in murine infection models (53,54). In this context, escherichelin-producing Enterobacteriaceae at colonized devices or mucosal surfaces may prevent P. aeruginosa from progressing to symptomatic infection by chemically inhibiting pyochelin-mediated iron uptake.…”

“…Although pyochelin enhances P. aeruginosa growth during infections (53,54), it is functionally redundant with pyoverdin, a second siderophore, during in vitro growth in standard culture media. Escherichelin addition to a defined, iron-restricted minimal medium caused a dose-dependent reduction in growth of a pyoverdin-deficient P. aeruginosa mutant strain, PW5011 ( Figure 3H) (55)(56)(57).…”

Interdependence between iron acquisition and biofilm formation in Pseudomonas aeruginosa

“…Pyoverdine is arguably the most important siderophore in the in vivo growth and pathogenesis of P. aeruginosa , as demonstrated by the avirulence of pyoverdine-deficient mutants in a variety of infection models (Meyer et al ., 1996; Takase et al ., 2000; Kirienko et al ., 2013; Minandri et al ., 2016). Historically, this has been attributed to its ability to also function as a determinant for the activity of the alternate sigma factor PvdS, which controls the expression of several secreted virulence factors, including the translational inhibitor ToxA and the protease PrpL (Lamont et al ., 2002).…”

Do Bacterial “Virulence Factors” Always Increase Virulence? A Meta-Analysis of Pyoverdine Production in Pseudomonas aeruginosa As a Test Case

“…As a test case, we focus on pyoverdine, a siderophore secreted by the opportunistic pathogen Pseudomonas aeruginosa to scavenge iron from the host environment (Visca et al, 2007). Table 1 provides an overview of the workflow of our meta-analysis, where we combined the outcomes of 81 individual virulence experiments from 24 studies (Meyer et al, 1996; Takase et al, 2000; Xiong et al, 2000; Gallagher and Manoil, 2001; Ochsner et al, 2002; Silo-Suh et al, 2002; Salunkhe et al, 2005; Harrison et al, 2006; Attila et al, 2008; Papaioannou et al, 2009; Zaborin et al, 2009; Carter et al, 2010; Nadal Jimenez et al, 2010; Oliver, 2011; Romanowski et al, 2011; Feinbaum et al, 2012; Okuda et al, 2012; Imperi et al, 2013; Kirienko et al, 2013; Ross-Gillespie et al, 2014; Dubern et al, 2015; Lin et al, 2015; Lopez-Medina et al, 2015; Minandri et al, 2016, see also Tables S1, S2 in the Supplemental Material). Using a weighted meta-analysis approach, we were able to investigate the evidence for pyoverdine's contribution to virulence across eight host species, including vertebrates, invertebrates and plants, five tissue infection models and various P. aeruginosa genotypes.…”