The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine intracranial abscesses model

Gong, J.; Li, Dong-Zhi; Yan, Jun; Liu, Yu; Li, Di; Dong, Jing; Gao, Yaping; Sun, Tao; Yang, Guang

doi:10.1016/j.bjid.2014.03.005

Cited by 17 publications

(12 citation statements)

References 31 publications

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“…Specifically, it is known that the early phases of abscess formation are largely dependent on Agr-repressed surface factors, such as Spa, SdrD, ClfA, and Coa. Furthermore, the later stages of infection are characterized by the rupturing of the abscess to elicit dissemination, a process known to be dependent on Agr-activated factors, such as secreted toxins and proteases (2,50,51). Accordingly, a defect in quorum sensing, as observed in the mroQ mutant, locks abscess formation in the early stages, preventing development to later phases, which are characterized by necrosis and dissemination to new sites (43).…”

Section: Discussionmentioning

confidence: 99%

MroQ Is a Novel Abi-Domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity

et al. 2019

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Numerous factors have, to date, been identified as playing a role in the regulation of Agr activity in Staphylococcus aureus, including transcription factors, antisense RNAs, and host elements. Herein we investigated the product of SAUSA300_ 1984 (termed MroQ), a transmembrane Abi-domain/M79 protease-family protein, as a novel effector of this system. Using a USA300 mroQ mutant, we observed a drastic reduction in proteolysis, hemolysis, and pigmentation that was fully complementable. This appears to result from diminished agr activity, as transcriptional analysis revealed significant decreases in expression of both RNAII and RNAIII in the mroQ mutant. Such effects appear to be direct, rather than indirect, as known agr effectors demonstrated limited alterations in their activity upon mroQ disruption. A comparison of RNA sequencing data sets for both mroQ and agr mutants revealed a profound overlap in their regulomes, with the majority of factors affected being known virulence determinants. Importantly, the preponderance of alterations in expression were more striking in the agr mutant, indicating that MroQ is necessary, but not sufficient, for Agr function. Mechanism profiling revealed that putative residues for metalloprotease activity within MroQ are required for its Agr-controlling effect; however, this was not wielded at the level of AgrD processing. Virulence assessment demonstrated that both mroQ and agr mutants exhibited increased formation of renal abscesses but decreased skin abscess formation alongside diminished dermonecrosis. Collectively, we present the characterization of a novel agr effector in S. aureus which would appear to be a direct regulator, potentially functioning via interaction with the AgrC histidine kinase.

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Section: Discussionmentioning

confidence: 99%

MroQ Is a Novel Abi-Domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity

et al. 2019

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“…Specifically, it is known that the early phases of abscess formation are largely dependent on Agr repressed surface factors, such as Spa, SdrD, ClfA, and Coa. Furthermore, the later stages of infection are characterized by the rupturing of abscess to elicit dissemination, a process known to be dependent on Agr-activated factors such as secreted toxins and proteases (2, 52, 53). Accordingly, a defect in quorum sensing, as observed in the mroQ mutant, locks abscess formation in the early stages, preventing development to later phases, which are characterized by necrosis and dissemination to new sites (45).…”

Section: Discussionmentioning

confidence: 99%

MroQ is a Novel Abi-domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity

Marroquin

Gimza

Tomlinson

et al. 2019

Preprint

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17Numerous factors have to date been identified as playing a role in the regulation of Agr 18 activity in S. aureus, including transcription factors, antisense RNAs, and host elements. 19Herein we investigate the product of SAUSA300_1984 (termed MroQ), a transmembrane 20Abi-domain/M79 protease-family protein, as a novel effector of this system. Using a 21 USA300 mroQ mutant we observed a drastic reduction in proteolysis, hemolysis and 22 pigmentation that was fully complementable. This appears to result from diminished agr 23 activity, as transcriptional analysis revealed significant decreases in expression of both 24 RNAII and RNAIII in the mroQ mutant. Such effects appear to be direct, rather than 25 indirect, as known agr effectors demonstrated limited alterations in their activity upon 26 mroQ disruption. A comparison of RNA-sequencing datasets for both mroQ and agr 27 mutants reveal a profound overlap in their regulomes, with the majority of factors affected 28 being known virulence determinants. Importantly, the preponderance of alterations in 29 expression were more striking in the agr mutant, indicating that MroQ is necessary, but 30 not sufficient, for Agr function. Mechanism profiling revealed that putative residues for 31 metalloprotease activity within MroQ are required for its Agr controlling effect, however 32 this is not wielded at the level of AgrD processing. Virulence assessment demonstrated 33 that mroQ and agr mutants both exhibited increased formation of renal abscesses, but 34 decreased skin abscess formation, alongside diminished dermonecrosis. Collectively, we 35 present the characterization of a novel agr effector in S. aureus, which would appear to 36 be a direct regulator, potentially functioning via interaction with the AgrC histidine kinase. 37Pathogenicity in S. aureus is both diverse and tightly controlled, being highly adaptive to 39 the surrounding environment and available resources (1). In order to survive and persist 40 within the host, this pathogen produces a wide array of virulence factors throughout the 41 different stages of infection (2). For example, during earlier phases of growth, adhesins 42 and other binding proteins are actively synthesized (e.g. Spa, FnbAB), which play a role 43 in colonization (2, 3). In contrast, in later phases, these surface proteins are repressed, 44 whilst secreted toxins, proteases, and exoenzymes are produced to facilitate invasion and 45 dissemination (2, 4). This coordination is facilitated by an array of global regulators of 46 gene expression (2, 5-10). 47 48The agr quorum sensing system is one of the most important regulators of virulence in S. 49 aureus (11). It is a quorum sensing system comprised of two transcriptional units, RNAII 50 and RNAIII, each controlled by its own promoter, P2 and P3, respectively. RNAII encodes 51 the agr operon, which is comprised of four genes, agrBDCA (12). The quorum sensing 52 system functions in three parts: i) a quorum sensing module comprised of AgrB and AgrD; 53ii) a two-component system (TCS) Agr...

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“…5A. Because agr-knockout mutants display significant reduction in their virulence potential [17][18][19] , we used a positive control Agr-functional S. aureus wild-type strain (NY19335) and its isogenic knockout mutant (MNY19335; Δagr::tetM) as a negative control, to validate this model for S. aureus. As expected, a difference was detected in the survival curves for the agr-functional strain and the isogenic knockout mutant (10.4% and 22.9% of worm survival on the 3rd day of the experiment, respectively), as shown in Fig.…”

Section: Hostmentioning

confidence: 99%

Comparative genomics of MRSA strains from human and canine origins reveals similar virulence gene repertoire

Penna

Silva

Soares

et al. 2021

Sci Rep

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Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen associated with a wide variety of infections in humans. The ability of MRSA to infect companion animals has gained increasing attention in the scientific literature. In this study, 334 dogs were screened for MRSA in two cities located in Rio de Janeiro State. The prevalence of MRSA in dogs was 2.7%. Genotyping revealed isolates from sequence types (ST) 1, 5, 30, and 239 either colonizing or infecting dogs. The genome of the canine ST5 MRSA (strain SA112) was compared with ST5 MRSA from humans—the main lineage found in Rio de Janeiro hospitals—to gain insights in the origin of this dog isolate. Phylogenetic analysis situated the canine genome and human strain CR14-035 in the same clade. Comparative genomics revealed similar virulence profiles for SA112 and CR14-035. Both genomes carry S. aureus genomic islands νSAα, νSAβ, and νSAγ. The virulence potential of the canine and human strains was similar in a Caenorhabditis elegans model. Together, these results suggest a potential of canine MRSA to infect humans and vice versa. The circulation in community settings of a MRSA lineage commonly found in hospitals is an additional challenge for public health surveillance authorities.

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The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine intracranial abscesses model

Abstract: Our data suggested that the agr system of S. aureus is an important virulence determinant in the induction and mortality of intracranial abscesses in mice.

Cited by 17 publications

References 31 publications

MroQ Is a Novel Abi-Domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity

MroQ Is a Novel Abi-Domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity

MroQ is a Novel Abi-domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity

Comparative genomics of MRSA strains from human and canine origins reveals similar virulence gene repertoire

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