Staphylococcus lugdunensis Uses the Agr Regulatory System to Resist Killing by Host Innate Immune Effectors

Chin, Denny; Flannagan, Ronald S.; Tuffs, Stephen W.; Chan, Jeremy K; McCormick, John K.; Heinrichs, David E.

doi:10.1128/iai.00099-22

Cited by 8 publications

(9 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is limited information concerning the replication/survival of CoNS in macrophages. The facultative pathogens S. lugdunensis (Chin et al., 2022) and S. epidermidis (Oliveira et al., 2022; Spiliopoulou et al., 2012) were shown to be killed within macrophages. Of note, for S. epidermidis , we could not link biofilm formation to bacterial survival.…”

Section: Discussionmentioning

confidence: 99%

Differential survival of Staphylococcal species in macrophages

Bayer,

Becker,

Liu

et al. 2023

Molecular Microbiology

View full text Add to dashboard Cite

Staphylococcus aureus is considered an extracellular pathogen, yet the bacterium is able to survive within and escape from host cells. An agr/sae mutant of strain USA300 is unable to escape from macrophages but can replicate and survive within. We questioned whether such “non‐toxic” S. aureus resembles the less pathogenic coagulase‐negative Staphylococcal (CoNS) species like S. epidermidis, S. carnosus, S. lugdunensis, S. capitis, S. warneri, or S. pettenkoferi. We show that the CoNS are more efficiently killed in macrophage‐like THP‐1 cells or in human primary macrophages. Mutations in katA, copL, the regulatory system graRS, or sigB did not impact bacterial survival in THP‐1 cells. Deletion of the superoxide dismutases impaired S. aureus survival in primary macrophages but not in THP‐1 cells. However, expression of the S. aureus‐specific sodM in S. epidermidis was not sufficient to protect this species from being killed. Thus, at least in those cells, better bacterial survival of S. aureus could not be linked to higher protection from ROS. However, “non‐toxic” S. aureus was found to be insensitive to pH, whereas most CoNS were protected when phagosomal acidification was inhibited. Thus, species differences are at least partially linked to differences in sensitivity to acidification.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential survival of Staphylococcal species in macrophages

Bayer,

Becker,

Liu

et al. 2023

Molecular Microbiology

View full text Add to dashboard Cite

show abstract

“…There is limited information concerning replication/survival of CoNS in macrophages. The facultative pathogen S.lugdunensis (Chin et al, 2022) and S. epidermidis (Oliveira et al, 2022;Spiliopoulou et al , 2012) were shown to be killed within macrophages. Of note, for S. epidermidis we could not link biofilm formation to bacterial survival.…”

Section: Discussionmentioning

confidence: 99%

Differential survival of Staphylococcal species in macrophages

Wolz

Bayer

Becker

et al. 2023

Preprint

View full text Add to dashboard Cite

The human pathogen Staphylococcus aureus is considered mainly an extracellular, opportunistic pathogen, yet the bacterium is able to survive within and escape from host cells, including macrophages. An agr/ sae mutant of strain USA300 is unable to escape from human macrophages but can replicate and survive within macrophages. We questioned whether such “„non-toxic“” S. aureus resembles the less pathogenic coagulase-negative Staphylococcal species (CoNS) like S. carnosus, S. lugdunensis, S. capitis, S. warneri or S. pettenkoferi. We show that in contrast to the “„non-toxic“” S. aureus strains, the CoNS species are efficiently killed within 24 h post-infection in the macrophage-like THP-1 cells or in human primary macrophages. Bacterial persistence of “„non-toxic“” S . aureus or CoNS induced IL-1ß release but no cell-death. Mutations in genes coding for katalase, copprer transport or the regulatory system GraRS or SigB did not impact bacterial survival in THP-1 cells. Deletion of the superoxide dismutases sodA and sodM impaired S. aureus survival in human primary macrophages but not in THP-1 cells. However, expression of the S. aureus specific sodM in S. epidermidis was not sufficient to protect this species from being killed in THP-1 cells. Thus, at least in those cells better bacterial survival of S. aureus could not be linked to higher protection from ROS. However, “„non-toxic“” S. aureus was found to be insensitive to pH, whereas S. epidermidis was protected when phagosomal acidification was inhibited. Thus, species differences seem to be linked to different sensitivity to acidification.

show abstract

“…S. lugdunensis shares genomic features with S. aureus ( 29 ), and our results showed that the agr system might play a role in lugdunin production. To date, the agr locus in S. lugdunensis has been shown to play a role in biofilm formation and resistance to host immune killing; however, its role in lugdunin production has not been investigated ( 17 , 18 ). Therefore, our study provides a potential role of agr in the regulation and production of S. lugdunensis lugdunin.…”

Section: Discussionmentioning

confidence: 99%

“…Most virulence factors in S. aureus are closely regulated by the agr locus, which encodes a two-component signaling pathway that can be divided into four major agr groups: types I–IV ( 16 ). The agr locus in S. lugdunensis was recently shown to play a role in biofilm formation and resistance to host immune killing ( 17 , 18 ). Hence, despite well-reported evidence regarding the chemical structure and biosynthetic gene clusters of lugdunin, the epidemiology of lugdunin-producing strains and the association of lugdunin production with STs, SCC mec , and agr genotypes are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Lugdunin production and activity in Staphylococcus lugdunensis isolates are associated with its genotypes

Chang,

Kao,

Lin

et al. 2023

Microbiol Spectr

View full text Add to dashboard Cite

Lugdunin produced by Staphylococcus lugdunensis has been shown to have broad inhibitory activity against Gram-positive bacteria; however, lugdunin activity among S. lugdunensis isolates and its association with different agr , SCC mec , and sequence types remain unclear. We used matrix-assisted laser desorption ionization-time-of-flight mass spectrometry to identify S. lugdunensis and collected 202 S . lugdunensis samples for further assays. Agar spot tests were performed to characterize S. lugdunensis lugdunin production and activity. Multilocus sequence typing, SCC mec, and agr genotyping were performed on S. lugdunensis . In all, 91 S taphylococcus aureus strains with varying vancomycin susceptibilities were used to examine lugdunin activity in S. lugdunensis . In total, 48 S . lugdunensis strains (23.8%) were found to be oxacillin-resistant S. lugdunensis (ORSL), whereas 154 (76.2%) were classified as oxacillin-sensitive S. lugdunensis (OSSL). Moreover, 16 (33.3%) ORSL and 35 (22.7%) OSSL strains showed antibacterial activity against S. aureus . Our data showed that most lugdunin-producing ORSL strains (14/48, 29.2%) were of ST3-SCC mec V- agr II genotypes, whereas most lugdunin-producing OSSL strains (15/154, 9.7%) were of ST3- agr II, followed by ST1- agr I (10/154, 6.5%). Our data also revealed that lugdunin exhibited weak inhibitory activity against the VISA ST239 isolate. In addition, we observed that ST239 VSSA was more resistant to lugdunin than ST5, ST59, and ST45 VSSA. Taken together, our data pioneered the epidemiology of lugdunin production in S. lugdunensis isolates and revealed its association with genotypes. However, further molecular and bioinformatics investigations are needed to elucidate the regulatory mechanisms of lugdunin production and activity. IMPORTANCE Lugdunin is active against both methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci by dissipating their membrane potential. However, the association of lugdunin activity with the genotypes of Staphylococcus lugdunensis has not been addressed. Here, we show the high prevalence of lugdunin-producing strains among ST1 (83.3%), ST2 (66.7%), and ST3 (53.3%) S. lugdunensis . Moreover, we identified the antibacterial activity of lugdunin-producing strains against VISA and hVISA. These results shed light on the potential application of lugdunin for the treatment of drug-resistant pathogens.

show abstract

Staphylococcus lugdunensis Uses the Agr Regulatory System to Resist Killing by Host Innate Immune Effectors

Cited by 8 publications

References 69 publications

Differential survival of Staphylococcal species in macrophages

Differential survival of Staphylococcal species in macrophages

Differential survival of Staphylococcal species in macrophages

Lugdunin production and activity in Staphylococcus lugdunensis isolates are associated with its genotypes

Contact Info

Product

Resources

About