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

Abstract

Bacterial traits that contribute to disease are termed “virulence factors” and there is much interest in therapeutic approaches that disrupt such traits. What remains less clear is whether a virulence factor identified as such in a particular context is also important in infections involving different host and pathogen types. Here, we address this question using a meta-analytic approach. We statistically analyzed the infection outcomes of 81 experiments associated with one well-studied virulence factor—pyoverdine, an iron-scavenging compound secreted by the opportunistic pathogen Pseudomonas aeruginosa. We found that this factor is consistently involved with virulence across different infection contexts. However, the magnitude of the effect of pyoverdine on virulence varied considerably. Moreover, its effect on virulence was relatively minor in many cases, suggesting that pyoverdine is not indispensable in infections. Our works supports theoretical models from ecology predicting that disease severity is multifactorial and context dependent, a fact that might complicate our efforts to identify the most important virulence factors. More generally, our study highlights how comparative approaches can be used to quantify the magnitude and general importance of virulence factors, key knowledge informing future anti-virulence treatment strategies.

High virulence sub-populations in Pseudomonas aeruginosa long-term cystic fibrosis airway infections

“…While these secretions were highly correlated, pyoverdine emerged as the greatest contributor to virulence. A recent meta-analysis has shown that in lab strains such as PAO1 and PA14, the effect of pyoverdine, albeit frequently contributing to disease, is relatively minor, and varies considerably across infection models [ 33 ]. While these strains were initially isolated from clinical settings, they have subsequently undergone evolution in the laboratory environment [ 34 ], and hence may differ substantially from the clinical strains used in this study.…”

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

“…241, 242 A recent meta analysis examined the effect of pyoverdine on both plant, insect, and vertebrate infection models, supporting a limited but consistent contribution to virulence. 243 Furthermore, chemical precedent exists for the intervention in the signaling pathways that induce pyoverdine production. The antifungal 5-fluorocytosine has been shown to inhibit the transcriptional regulation of the pyoverdine operon as mediated by the regulator PvdS.…”

Two Pseudomonas aeruginosa clonal groups belonging to the PA14 clade are indigenous to the Churince system in Cuatro Ciénegas Coahuila, México

“…FpvA is the specific outer-membrane receptor for pyoverdine-iron complexes and is indispensable for its uptake (Schalk et al, 2001). It has been reported that the production of pyoverdine is important for the pathogenesis of P. aeruginosa, but clinical isolates that do not produce this siderophore can be isolated (Tasake et al, 2000;Visca et al, 2006;Kirienko et al, 2013;López-Medina et al, 2015;Granato et al, 2016).…”