Manipulating virulence factor availability can have complex consequences for infections

Weigert, Michael; Ross‐Gillespie, Adin; Leinweber, Anne; Pessi, Gabriella; Brown, Sam P.; Kümmerli, Rolf

doi:10.1101/062570

Cited by 5 publications

(5 citation statements)

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“…We then used Galleria mellonella larvae as a model to reproduce the spatial structure P. aeruginosa would face in a host during an infection [27]. We infected larvae with mono-and mixed cultures in the presence or absence of gentamicin following a standard protocol of infection [28], using 10 2 -10 3 cells as the inoculum. Single strain infections were performed with MPAO1, ∆fpvA and ∆fpvB in order to obtain survival curves of the animal host in the presence and absence of gentamicin.…”

Section: The ∆Fpvb Mutant Is a Suitable Trojan Horse In Structured Biofilms And In An Animal Modelmentioning

confidence: 99%

Loss of a pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion

et al. 2020

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The rapid emergence of antibiotic resistant bacterial pathogens constitutes a critical problem in healthcare and requires the development of novel treatments. Potential strategies include the exploitation of microbial social interactions based on public goods, which are produced at a fitness cost by cooperative microorganisms, but can be exploited by cheaters that do not produce these goods. Cheater invasion has been proposed as a 'Trojan horse' approach to infiltrate pathogen populations with strains deploying built-in weaknesses (e.g. sensitiveness to antibiotics). However, previous attempts have been often unsuccessful because population invasion by cheaters was prevented by various mechanisms including the presence of spatial structure (e.g. growth in biofilms), which limits the diffusion and exploitation of public goods.Here we followed an alternative approach and examined whether the manipulation of public good uptake and not its production could result in potential 'Trojan horses' suitable for population invasion. We focused on the siderophore pyoverdine produced by the human pathogen Pseudomonas aeruginosa MPAO1 and manipulated its uptake by deleting and/or overexpressing the pyoverdine primary (FpvA) and secondary (FpvB) receptors. We found that receptor synthesis feeds back on pyoverdine production and uptake rates, which led to strains with altered pyoverdine-associated costs and benefits. Moreover, we found that the receptor FpvB was advantageous under iron-limited conditions but revealed hidden costs in the presence of an antibiotic stressor (gentamicin). As a consequence, FpvB mutants became the fittest strain under gentamicin exposure, displacing the wildtype in liquid cultures, and in biofilms and during infections of the wax moth larvae Galleria mellonella, which both represent structured environments. Our findings reveal that an evolutionary trade-off associated with the costs and benefits of a versatile pyoverdine uptake strategy can be harnessed for devising a Trojan horse candidate for medical interventions.

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Section: The ∆Fpvb Mutant Is a Suitable Trojan Horse In Structured Biofilms And In An Animal Modelmentioning

confidence: 99%

Loss of a pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion

et al. 2020

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“…As expected, we observed that all the siderophore genes were significantly upregulated under iron limitation. The expression of toxA and prpL (piv), encoding exotoxinA and protease IV, which are known to be induced in the presence of pyoverdine [44,45], were also significantly upregulated under iron limitation. Next, we focused on two genes encoding the superoxide dismutase SodB (iron-dependent) and SodM (manganese-dependent).…”

Section: Expression Of Siderophore Genes and Other Iron-regulated Gen...mentioning

confidence: 99%

RNA-Seq reveals thatPseudomonas aeruginosamounts growth medium-dependent competitive responses when sensing diffusible cues fromBurkholderia cenocepacia

Leinweber

Laffont

Lardi

et al. 2023

Preprint

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Most habitats on earth are colonized by diverse bacterial communities, offering ample opportunities for inter-species interactions. While competition for space and nutrients might often dominate such interactions, little is known about whether bacteria can sense competitors and mount specific responses to withstand their attacks. The competition-sensing hypothesis proposes that bacteria can do so through nutrient stress and cell damage cues. Here, we conducted a replicated RNAseq-transcriptomic study to test this hypothesis. We exposed Pseudomonas aeruginosa to either its own spent medium or to the supernatant of its competitor Burkholderia cenocepacia. Compared to controls, we detected significant changes in the transcriptome of P. aeruginosa that entail both general responses to spent medium and specific responses to the competitor. Specifically, genes encoding various competitive traits, including the type-VI secretion system, the siderophore pyoverdine, and the toxins phenazines and hydrogen cyanide, were upregulated when exposed to the competitor supernatant. Similarly, several genes coding for stress response and quorum-sensing regulators were overexpressed. Moreover, we found transcriptional responses to vary as a function of iron availability, whereby metabolically more costly responses were launched under iron rich conditions. Altogether, our results reveal nuanced competitive responses of P. aeruginosa when exposed to B. cenocepacia supernatant, integrating both environmental and social cues.

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“…It evolves because antibiotics kill bacteria, and the widespread use of these drugs thus imposes strong selection on the bacteria to survive in their presence. On this basis, a view has emerged that a more evolutionarily robust approach would be to target virulence factors—the microbial molecules responsible for pathogenesis—in order to “disarm rather than kill” the pathogen (Weigert et al, 2017), and there is a growing literature on different aspects of this approach as well as the potential consequences of its implementation (Allen et al, 2014; Brown, Cornforth, & Mideo, 2012; Cegelski, Marshall, Eldridge, & Hultgren, 2008; Defoirdt, 2016; Vale et al, 2016; Wollein Waldetoft & Brown, 2017).…”

Section: Research At the Crossroadsmentioning

confidence: 99%

Proliferation and benevolence—A framework for dissecting the mechanisms of microbial virulence and health promotion

Waldetoft

Råberg

Lood

2020

Evolutionary Applications

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Key topics in the study of host-microbe interactions-such as the prevention of drug resistance and the exploitation of beneficial effects of bacteria-would benefit from concerted efforts with both mechanistic and evolutionary approaches. But due to differences in intellectual traditions, insights gained in one field rarely benefit the other.Here, we develop a conceptual and analytical framework for the integrated study of host-microbe interactions. This framework partitions the health effects of microbes and the effector molecules they produce into components with different evolutionary implications. It thereby facilitates the prediction of evolutionary responses to inhibition and exploitation of specific molecular mechanisms. | INTRODUC TI ONMicrobes have profound effects on the health of their hosts, and host-microbe interactions are therefore subject to intense research from both mechanistic and evolutionary perspectives. Traditionally pursued in isolation, these lines of inquiry are now becoming increasingly intertwined (Bordenstein & Theis, 2015). This is especially so in the work on antibiotic resistance evolution, and the consequent search for molecular targets for evolution-proof drugs, including antivirulence therapeutics (Allen, Popat, Diggle, & Brown, 2014).Progress is hampered, however, by a lack of common conceptual ground; key concepts in one field, such as "virulence factor" in microbial pathogenesis research (Falkow, 1988(Falkow, , 2004 do not fit into the conceptual structure of the other, for example the trade-off paradigm in virulence evolution theory (Alizon, Hurford, Mideo, & Van Baalen, 2009) (because the former is focused on the mechanisms of host harm, whereas the latter disregards mechanism, and assumes relationships between host harm and pathogen fitness). This is unfortunate because pressing public health challenges, most notably antibiotic resistance, are complex and have several aspects that are studied in both fields.The aim of this paper is to lay a foundation for a common conceptual framework for host-microbe interactions, in which mechanistic and evolutionary traditions can be integrated. To this end, we combine the analytical approach of resistance-tolerance theory in evolutionary ecology (Råberg, Sim, & Read, 2007) with the experimental strategy for identifying virulence factors in microbial pathogenesis research (Falkow, 1988). Whilst most commonly applied to pathogens in acute infections, this type of experiment can identify a range of molecules that impact host health, whether the effect is detrimental or beneficial, the microbe obligate or opportunistic, and the condition acute or chronic. And we intend our analysis to be equally broad. The framework we propose is visual and intuitive, but it also has a simple statistical formalization based on generalized linear models, which makes it flexible and open for further developments.In the main text, we develop the concepts and their implications under the assumption that the microbe's health effect and fitness are linearly relat...

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Manipulating virulence factor availability can have complex consequences for infections

Cited by 5 publications

References 74 publications

Loss of a pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion

Loss of a pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion

RNA-Seq reveals thatPseudomonas aeruginosamounts growth medium-dependent competitive responses when sensing diffusible cues fromBurkholderia cenocepacia

Proliferation and benevolence—A framework for dissecting the mechanisms of microbial virulence and health promotion

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