Pseudomonas aeruginosa Microevolution during Cystic Fibrosis Lung Infection Establishes Clones with Adapted Virulence

Abstract

Our findings indicate that clonal expansion of P. aeruginosa strains during microevolution within CF lungs leads to populations with altered but not reduced virulence. These P. aeruginosa clones with adapted virulence play a critical role in the pathogenesis of chronic infections and may serve to define virulence determinants as targets for novel therapies.

Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution

“…The latter suggests that either or both strains (PA-B4 and PA-A8) may produce an inhibitory substance(s) that recognizes clonal differences ( Figure 3C). These antagonistic growth patterns observed in clonally unrelated prototroph-auxotroph Pa pairs further conform the common knowledge that a single dominant Pa clone and its radiating isogenic derivatives are often found in the same host lifetime (Bragonzi et al, 2009;Qin et al, 2012;Smith et al, 2006). With parities in nature, a host-niche-adapted Pa may provide host protection against subsequent wild-type Pa colonization, a form of host benefit (Qin et al, 2012).…”

“…In truth, repeat acquisition of clonally unrelated wild-type Pa strains, after laboratory detection of a CF airway-adapted Pa, has rarely been reported (Bragonzi et al, 2009;Smith et al, 2006;Qin et al, 2012).…”

“…Although airway-adapted Pa strains tend to promote prolonged lung infection in a CF mouse model, their ability to cause animal lethality is significantly reduced as compared to that of wild-type Pa (Hoffmann et al, 2005). Lore and colleagues have repeatedly confirmed that CF airway-niche adapted Pa shows reduced virulence and inflicts less lung tissue infiltration when tested in various animal hosts (Bragonzi et al, 2009;Lore et al, 2012). Many of these findings, however, have not to date been recognized as host imprints on pseudomonal allopatric (a disjunct removal from its natural environment) speciation once enclosed inside the CF airway.…”

“…Established pseudomonal syntrophy exhibits inter-clonal antagonistic properties to prevent wild-type Pa from colonizing the same host airway Once a clonally selected Pa syntrophy is established in the host airway, the same host airway becomes immune to subsequent super-colonization by wild-type Pa strains from the living environment of the host (Bragonzi et al, 2009;Burns et al, 2001;Smith et al, 2006;Qin et al, 2012). Not by coincidence, in an ancient bipartite symbiotic system, the various actinomycetous bacteria (Pseudonocardia) associated with Acromyrmex leaf-cutting ants have shown both intraspecific (or sympatric) diversity for antimicrobial metabolite production and antagonistic activity against allopatric ''intruder'' strains, or even unrelated microbes with varying degrees of inhibitory activity (Poulsen et al, 2007).…”

“…Nearly 80 years ago, long before the full spectrum of symbiosis was defined, K. F. Meyer wrote an analysis entitled ''Latent Infections'' and asserted ''symbiosis must be regarded as a condition of life balancing between two extremes: complete immunity and deadly infective diseases'' (Meyer, 1936). Based on microbiological studies, the traditional interpretation of Pa associated with chronic airway infected CF patients has been dominated by such concepts as ''multi-resistance'' or ''pan-resistance'' to antimicrobial agents and a gain of ''biofilm or cell-associated virulence'' (Bragonzi et al, 2009;Cigana et al, 2011;Head & Yu, 2004;Hogardt & Heesemann, 2010;Lee et al, 2006). However, this is paradoxically unsupported by the in vitro properties of CF Pa isolates in which accumulation of mutations in virulence regulators, as well as virulence genes and drug resistant determinants, have been attributed to a ''hyper-mutable'' state (Bragonzi et al, 2009;Cigana et al, 2011;Hoiby et al, 2010;Smith et al, 2006;Livermore, 2002;Mena et al, 2008;Oliver & Mena, 2010).…”