Insights into Mechanisms Used by <i>Staphylococcus aureus</i> to Avoid Destruction by Human Neutrophils

Voyich, Jovanka M.; Braughton, Kevin R.; Sturdevant, Daniel E.; Whitney, Adeline R.; Saïd-Salim, Battouli; Porcella, Stephen F.; Long, Rodney; Dorward, David W.; Gardner, Donald J.; Kreiswirth, Barry N.; Musser, James M.; DeLeo, Frank R.

doi:10.4049/jimmunol.175.6.3907

Cited by 504 publications

(616 citation statements)

References 59 publications

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“…SaeRS regulates transcription of multiple toxins, including γ-toxin (hlgA, hlgB, hlgC), LukSF-PVL, and LukAB/LukGH, which have been shown to contribute to PMN lysis (26)(27)(28)(29)(30)(31). Additionally, transcription of the saePQRS operon and SaeR target genes are activated in response to PMN phagocytosis and PMN components (32)(33)(34). Collectively, these data suggest sensing and responding to PMNs is a central function of the sae system.…”

Section: Mutagenesis Of the Predicted Extracellular Loop Of Saes Idenmentioning

confidence: 91%

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Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Flack

Zurek

Meishery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the histidine kinase SaeS recognizes specific host stimuli is unknown. After mutagenizing the predicted extracellular loop of SaeS, we discovered one methionine residue (M31) was essential for the ability of S. aureus to transcribe sae target genes, including hla, lukAB/lukGH, and hlgA. This single M31A mutation also significantly reduced cytotoxicity in human neutrophils to levels observed in cells following interaction with ΔsaeS. Another important discovery was that mutation of two aromatic anchor residues (W32A and F33A) disrupted the normal basal signaling of SaeS in the absence of inducing signals, yet both mutant kinases had appropriate activation of effector genes following exposure to neutrophils. Although the transcriptional profile of aromatic mutation W32A was consistent with that of WT in response to human α-defensin 1, mutant kinase F33A did not properly transcribe the γ-toxin genes in response to this stimulus. Taken together, our results provide molecular evidence for how SaeS recognizes host signals and triggers activation of select virulence factors to facilitate evasion of innate immunity. These findings have important implications for signal transduction in prokaryotes and eukaryotes due to conservation of aromatic anchor residues across both of these domains and the important role they play in sensor protein structure and function.host-pathogen interactions | membrane proteins

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Section: Mutagenesis Of the Predicted Extracellular Loop Of Saes Idenmentioning

confidence: 91%

“…PMNs (or neutrophils) were isolated from healthy human donors following procedures described elsewhere (33). All procedures were performed in accordance with a protocol approved by the Institutional Review Board for Human Subjects at Montana State University.…”

Section: Methodsmentioning

confidence: 99%

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Flack

Zurek

Meishery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…aureus is not an obligatory intracellular pathogen. However, the intrinsic virulence of isolates is associated with their ability to reside in the cytoplasm of host epithelial or endothelial cells, particularly in chronic infections (Sinha et al, 1999;Voyich et al, 2005). Invasion of epithelial cells by representative isolates (the parental (S123 and S124) and donor (S100) strains, LA isolates (S1 and S130), non-LA isolates (S89 and S94), and two control strains (Cowan and KH11) was evaluated.…”

Section: Invasion Experimentsmentioning

confidence: 99%

Analysis of prophages harbored by the human-adapted subpopulation of Staphylococcus aureus CC398

Mee-Marquet

Corvaglia

Valentin

et al. 2013

Infection, Genetics and Evolution

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a b s t r a c tStaphylococcus aureus clonal complex 398 is a livestock-associated pathogen that poses a worldwide threat because of its ability to colonize and infect both humans and animals. We used high-resolution whole-genome microarrays, prophage profiling, immune evasion cluster characterization and wholegenome sequencing to investigate the roles of prophages in the emerging human-adapted subpopulation of CC398 that has been associated with invasive infections in humans living in animal-free environments.We characterized one phage and two prophages specifically harbored by CC398 isolates belonging to the emerging subpopulation. We introduced the phage into permissive prophage-free isolates. We investigated the effects of lysogeny on the host ability to resist further phage infection and transformation, to acquire the capacity to invade human cells, and to express virulence factors encoded by prophages. We report evidence of a defective /MR11-like helper prophage, named StauST398-5pro, specifically associated with the emerging non-LA CC398 subpopulation. StauST398-5pro confers substantial protection against horizontal genetic transfer to its host. It interacts with a human-associated b-converting prophage encoding immune-modulating proteins such that virulence genes are expressed during stress situations.Our findings provide insight into the role of phages in the expression of virulence and in the spread of genetic information among new host-adapted S. aureus isolates. We demonstrate that functional prophage elements can condition host specificity and confer new virulence traits on emerging intra-species clones of bacteria.

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“…The increased prevalence of MRSA infections and corresponding rise in life-threatening syndromes have made it imperative to elucidate the mechanisms of pathogenesis for S. aureus. The interaction between S. aureus and the host is complex and is mediated by an array of bacterial proteins that both mediate the various pathologies and modify the immune system of the host (4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Ramsland

Willoughby

Trist

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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102

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Infection by Staphylococcus aureus can result in severe conditions such as septicemia, toxic shock, pneumonia, and endocarditis with antibiotic resistance and persistent nasal carriage in normal individuals being key drivers of the medical impact of this virulent pathogen. In both virulent infection and nasal colonization, S. aureus encounters the host immune system and produces a wide array of factors that frustrate host immunity. One in particular, the prototypical staphylococcal superantigen-like protein SSL7, potently binds IgA and C5, thereby inhibiting immune responses dependent on these major immune mediators. We report here the three-dimensional structure of the complex of SSL7 with Fc of human IgA1 at 3.2 Å resolution. Two SSL7 molecules interact with the Fc (one per heavy chain) primarily at the junction between the C␣2 and C␣3 domains. The binding site on each IgA chain is extensive, with SSL7 shielding most of the lateral surface of the C␣3 domain. However, the SSL7 molecules are positioned such that they should allow binding to secretory IgA. The key IgA residues interacting with SSL7 are also bound by the leukocyte IgA receptor, Fc␣RI (CD89), thereby explaining how SSL7 potently inhibits IgAdependent cellular effector functions mediated by Fc␣RI, such as phagocytosis, degranulation, and respiratory burst. Thus, the ability of S. aureus to subvert IgA-mediated immunity is likely to facilitate survival in mucosal environments such as the nasal passage and may contribute to systemic infections.Staphylococcus aureus is an important human pathogen causing conditions ranging from minor superficial skin infections to life-threatening syndromes, including sepsis, toxic shock syndrome, osteomyelitis, pneumonitis, and endocarditis. It is carried without symptoms in at least 20% of individuals (1, 2). The emergence in the 1960s of pandemic penicillin-resistant S. aureus has been followed by a variety of hospital-associated and community-associated methicillin-resistant strains (HA-and CA-MRSA) (2, 3). The increased prevalence of MRSA infections and corresponding rise in life-threatening syndromes have made it imperative to elucidate the mechanisms of pathogenesis for S. aureus. The interaction between S. aureus and the host is complex and is mediated by an array of bacterial proteins that both mediate the various pathologies and modify the immune system of the host (4-10).SSL7 (formerly named SET1) is the first described member of a new family of putative S. aureus toxins, the staphylococcal superantigen-like (SSL) proteins (11, 12), related to the staphylococcal enterotoxins (SEs) or superantigens (13). The SSL proteins have Ϸ30% sequence identity with toxic shock syndrome 1 (TSST-1) and 25% or less identity with other SEs. Despite the sequence differences, the SSL proteins have a typical SE tertiary structure consisting of a distinct oligonucleotide/oligosaccharide binding (OB-fold) linked to a ␤-grasp domain (14 -16).Similar to the se genes, the ssl genes are located in a pathogenicity island (SaPIn2) and ...

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Insights into Mechanisms Used by Staphylococcus aureus to Avoid Destruction by Human Neutrophils

Cited by 504 publications

References 59 publications

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Analysis of prophages harbored by the human-adapted subpopulation of Staphylococcus aureus CC398

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

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