<i>Staphylococcus aureus</i> SaeR/S-regulated factors reduce human neutrophil reactive oxygen species production

Guerra, Fermin E.; Addison, Conrad B.; Jong, Nienke W.M. de; Azzolino, Joseph; Pallister, Kyler B.; Strijp, Jos A. G. van; Voyich, Jovanka M.

doi:10.1189/jlb.4vmab0316-100rr

Cited by 31 publications

(29 citation statements)

References 39 publications

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“…At least two of the 11 ssl genes (ssl5 and ssl8) are regulated via the Sae system (25) and are located directly upstream of the SPIN gene. Thus, we propose that SPIN is largely regulated via the SaeR/S regulon and likely contributes to the SaeR/S-dependent reduction of neutrophil ROS (13).…”

Section: Discussionmentioning

confidence: 89%

“…Moreover, there was no up-regulation observed when bacteria lacking the SaeR/S two-component regulatory system were used. The SaeR/S system plays an important role in neutrophil evasion (19) and regulates factors that reduce neutrophil ROS (13). SaeR/S is up-regulated comparably to spn (≈3-to 10-fold 30 min after phagocytosis) (20) and the promoter of SPIN contains the binding consensus sequence of SaeR (24).…”

Section: Discussionmentioning

confidence: 99%

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Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Jong

Ramyar

Guerra

et al. 2017

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

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113

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Staphylococcus aureus is highly adapted to its host and has evolved many strategies to resist opsonization and phagocytosis. Even after uptake by neutrophils, S. aureus shows resistance to killing, which suggests the presence of phagosomal immune evasion molecules. With the aid of secretome phage display, we identified a highly conserved protein that specifically binds and inhibits human myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. We have named this protein "staphylococcal peroxidase inhibitor" (SPIN). To gain insight into inhibition of MPO by SPIN, we solved the cocrystal structure of SPIN bound to a recombinant form of human MPO at 2.4-Å resolution. This structure reveals that SPIN acts as a molecular plug that prevents H 2 O 2 substrate access to the MPO active site. In subsequent experiments, we observed that SPIN expression increases inside the neutrophil phagosome, where MPO is located, compared with outside the neutrophil. Moreover, bacteria with a deleted gene encoding SPIN showed decreased survival compared with WT bacteria after phagocytosis by neutrophils. Taken together, our results demonstrate that S. aureus secretes a unique proteinaceous MPO inhibitor to enhance survival by interfering with MPO-mediated killing.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Jong

Ramyar

Guerra

et al. 2017

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

Self Cite

113

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“…Furthermore, a msrA1 and msrB double mutant strain of S. aureus is more susceptible to neutrophil killing compared to wild-type (Pang et al, 2014). Finally, the SaeR/S TCS also plays a role in regulating virulence factors that decrease neutrophil hydrogen peroxide and hypochlorous acid production following S. aureus phagocytosis (Guerra et al, 2016). The SaeR/S-regulated virulence factors that decrease neutrophil ROS remain unknown and are an active area of research, but are independent of superoxide dismutase and catalase activity since their expression is not regulated by SaeR/S (Rogasch et al, 2006; Voyich et al, 2009; Nygaard et al, 2010; Sun et al, 2010).…”

Section: S Aureus Evasion Of Oxidative Killingmentioning

confidence: 99%

“…Theoretically, chemical inhibitors and neutralizing antibodies of sensory/regulatory systems could inhibit S. aureus from sensing its environment and producing virulence factors that disrupt host antimicrobial functions. The SaeR/S TCS is an attractive candidate for vaccine development since SaeR/S-regulated factors disrupt key neutrophil functions that include production of ROS, cytokine expression, and cell fate (Watkins et al, 2011, 2013; Nygaard et al, 2013; Zurek et al, 2014; Guerra et al, 2016). Many of the best studied immunomodulatory factors and cytolytic proteins that target neutrophil function are regulated by SaeR/S including Sbi, Efb, HlgABC, Hla, LukG/H (LukA/B), and PVL (Nygaard et al, 2010).…”

Section: Potential Of Therapeutics To Augment Neutrophil Function Agamentioning

confidence: 99%

Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus

Guerra

Borgogna

Patel

et al. 2017

Front. Cell. Infect. Microbiol.

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118

111

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Neutrophils are the most abundant leukocytes in human blood and the first line of defense after bacteria have breached the epithelial barriers. After migration to a site of infection, neutrophils engage and expose invading microorganisms to antimicrobial peptides and proteins, as well as reactive oxygen species, as part of their bactericidal arsenal. Ideally, neutrophils ingest bacteria to prevent damage to surrounding cells and tissues, kill invading microorganisms with antimicrobial mechanisms, undergo programmed cell death to minimize inflammation, and are cleared away by macrophages. Staphylococcus aureus (S. aureus) is a prevalent Gram-positive bacterium that is a common commensal and causes a wide range of diseases from skin infections to endocarditis. Since its discovery, S. aureus has been a formidable neutrophil foe that has challenged the efficacy of this professional assassin. Indeed, proper clearance of S. aureus by neutrophils is essential to positive infection outcome, and S. aureus has developed mechanisms to evade neutrophil killing. Herein, we will review mechanisms used by S. aureus to modulate and evade neutrophil bactericidal mechanisms including priming, activation, chemotaxis, production of reactive oxygen species, and resolution of infection. We will also highlight how S. aureus uses sensory/regulatory systems to tailor production of virulence factors specifically to the triggering signal, e.g., neutrophils and defensins. To conclude, we will provide an overview of therapeutic approaches that may potentially enhance neutrophil antimicrobial functions.

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“…As observed with S. aureus, it is critical for bacterial survival to demonstrate an effective means for reduce or inhibit ROS production. S. aureus scavenges and neutralizes ROS (superoxide and H2O2) through the use of SODs (SodA and Sod M) and catalases (336)(337)(338). Additionally, S.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Filifactor alocis and its immune evasion strategies employed against human neutrophils.

Armstrong¹

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Staphylococcus aureus SaeR/S-regulated factors reduce human neutrophil reactive oxygen species production

Cited by 31 publications

References 39 publications

Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus

Characterization of Filifactor alocis and its immune evasion strategies employed against human neutrophils.

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