Sustained Coinfections with<i>Staphylococcus aureus</i>and<i>Pseudomonas aeruginosa</i>in Cystic Fibrosis

Fischer, Anthony J.; Singh, Sunil; LaMarche, Mason; Maakestad, Lucas J; Kienenberger, Zoe; Peña, Tahuanty; Stoltz, David A.; Limoli, Dominique H.

doi:10.1164/rccm.202004-1322oc

Cited by 71 publications

(64 citation statements)

References 29 publications

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“…Furthermore, colonization of the CF airways is usually described as a pattern of succession where S. aureus is the predominant colonizer early on in younger patients before being outcompeted by P. aeruginosa in older patients (60). However, Fischer et al (61) recently showed that P. aeruginosa and S. aureus chronically co-colonize the CF lung. Wakeman et al also showed that P. aeruginosa, S. aureus , and CP colocalize in CF lung explants (51).…”

Section: Discussionmentioning

confidence: 99%

Calprotectin-mediated zinc chelation inhibitsPseudomonas aeruginosaprotease activity in cystic fibrosis sputum

Vermilyea

Crocker

Gifford

et al. 2021

Preprint

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Pseudomonas aeruginosa induces pathways indicative of low zinc availability in the cystic fibrosis (CF) lung environment. To learn more about P. aeruginosa zinc access in CF, we grew P. aeruginosa strain PAO1 directly in expectorated CF sputum. The P. aeruginosa Zur transcriptional repressor controls the response to low intracellular zinc, and we used the NanoString methodology to monitor levels of Zur-regulated transcripts including those encoding a zincophore system, a zinc importer, and paralogs of zinc containing proteins that do not require zinc for activity. Zur-controlled transcripts were induced in sputum-grown P. aeruginosa compared to control cultures, but not if the sputum was amended with zinc. Amendment of sputum with ferrous iron did not reduce expression of Zur-regulated genes. A reporter fusion to a Zur-regulated promoter had variable activity in P. aeruginosa grown in sputum from different donors, and this variation inversely correlated with sputum zinc concentrations. Recombinant human calprotectin (CP), a divalent-metal binding protein released by neutrophils, was sufficient to induce a zinc-starvation response in P. aeruginosa grown in laboratory medium or zinc-amended CF sputum indicating that CP is functional in the sputum environment. Zinc metalloproteases comprise a large fraction of secreted zinc-binding P. aeruginosa proteins. Here we show that recombinant CP inhibited both LasB-mediated casein degradation and LasA-mediated lysis of Staphylococcus aureus, which was reversible with added zinc. These studies reveal the potential for CP-mediated zinc chelation to post-translationally inhibit zinc metalloprotease activity and thereby impact the protease-dependent physiology and/or virulence of P. aeruginosa in the CF lung environment.

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Section: Discussionmentioning

confidence: 99%

Calprotectin-mediated zinc chelation inhibitsPseudomonas aeruginosaprotease activity in cystic fibrosis sputum

Vermilyea

Crocker

Gifford

et al. 2021

Preprint

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“…Such molecules constitute a new avenue for cellular signaling that the host and/or pathogen could leverage to their benefit during infection. These systems become even more complex in the context of polymicrobial infections, a common occurrence with P. aeruginosa and S. aureus in the lungs of CF patients (111)(112)(113). With the additional layering of another organism, the potential number of molecules and interactions increases exponentially.…”

Section: Host-pathogen Metabolic Crosstalkmentioning

confidence: 99%

Crosstalk Between Staphylococcus aureus and Innate Immunity: Focus on Immunometabolism

Horn

Kielian

2021

Front. Immunol.

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Staphylococcus aureus is a leading cause of bacterial infections globally in both healthcare and community settings. The success of this bacterium is the product of an expansive repertoire of virulence factors in combination with acquired antibiotic resistance and propensity for biofilm formation. S. aureus leverages these factors to adapt to and subvert the host immune response. With the burgeoning field of immunometabolism, it has become clear that the metabolic program of leukocytes dictates their inflammatory status and overall effectiveness in clearing an infection. The metabolic flexibility of S. aureus offers an inherent means by which the pathogen could manipulate the infection milieu to promote its survival. The exact metabolic pathways that S. aureus influences in leukocytes are not entirely understood, and more work is needed to understand how S. aureus co-opts leukocyte metabolism to gain an advantage. In this review, we discuss the current knowledge concerning how metabolic biases dictate the pro- vs. anti-inflammatory attributes of various innate immune populations, how S. aureus metabolism influences leukocyte activation, and compare this with other bacterial pathogens. A better understanding of the metabolic crosstalk between S. aureus and leukocytes may unveil novel therapeutic strategies to combat these devastating infections.

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“…During co-infection, P. aeruginosa remains prevalent and dominant, due to its great genomic plasticity, high virulence, and its ability to form biofilm. The pathogenicity of P. aeruginosa can be directly shaped by interactions with other species [107][108][109][110]. In vitro studies have been conducted on P. aeruginosa co-colonising and interacting with S. aureus, Streptococci, B. cepacia complex, A. fumigatus, C. albicans, and S. maltophilia (Table 1).…”

Section: Polymicrobial Interactions With P Aeruginosa In the Cf Airway Microbiomementioning

confidence: 99%

“…In contrast with previous understanding, largely based on the US CFF reports, P. aeruginosa infections did not overtake S. aureus infections. Instead, CF patients were co-colonised with both bacteria at the same time [110].…”

Section: P Aeruginosa and S Aureus Interactionsmentioning

confidence: 99%

Polymicrobial Interactions in the Cystic Fibrosis Airway Microbiome Impact the Antimicrobial Susceptibility of Pseudomonas aeruginosa

2021

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Pseudomonas aeruginosa is one of the most dominant pathogens in cystic fibrosis (CF) airway disease and contributes to significant inflammation, airway damage, and poorer disease outcomes. The CF airway is now known to be host to a complex community of microorganisms, and polymicrobial interactions have been shown to play an important role in shaping P. aeruginosa pathogenicity and resistance. P. aeruginosa can cause chronic infections that once established are almost impossible to eradicate with antibiotics. CF patients that develop chronic P. aeruginosa infection have poorer lung function, higher morbidity, and a reduced life expectancy. P. aeruginosa adapts to the CF airway and quickly develops resistance to several antibiotics. A perplexing phenomenon is the disparity between in vitro antimicrobial sensitivity testing and clinical response. Considering the CF airway is host to a diverse community of microorganisms or ‘microbiome’ and that these microorganisms are known to interact, the antimicrobial resistance and progression of P. aeruginosa infection is likely influenced by these microbial relationships. This review combines the literature to date on interactions between P. aeruginosa and other airway microorganisms and the influence of these interactions on P. aeruginosa tolerance to antimicrobials.

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Sustained Coinfections withStaphylococcus aureusandPseudomonas aeruginosain Cystic Fibrosis

Cited by 71 publications

References 29 publications

Calprotectin-mediated zinc chelation inhibitsPseudomonas aeruginosaprotease activity in cystic fibrosis sputum

Calprotectin-mediated zinc chelation inhibitsPseudomonas aeruginosaprotease activity in cystic fibrosis sputum

Crosstalk Between Staphylococcus aureus and Innate Immunity: Focus on Immunometabolism

Polymicrobial Interactions in the Cystic Fibrosis Airway Microbiome Impact the Antimicrobial Susceptibility of Pseudomonas aeruginosa

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