Global Gene Expression of Methicillin-resistant Staphylococcus aureus USA300 During Human and Mouse Infection

Date, Shailesh V.; Modrušan, Zora; Lawrence, Michael; Morisaki, J. Hiroshi; Toy, Karen; Shah, Ishita M.; Kim, Janice; Park, Summer; Xu, Min; Basuino, Li; Chan, Liana C.; Zeitschel, Deborah; Chambers, Henry F.; Tan, Man‐Wah; Brown, Eric J.; Diep, Binh An; Hazenbos, Wouter L. W.

doi:10.1093/infdis/jit668

Cited by 76 publications

(90 citation statements)

References 26 publications

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“…These Eap proteins are potent, highly specific, and promote S. aureus pathogenesis. From previous studies it is clear that all three genes are expressed during S. aureus infections in vivo, both in mice and humans (25,26). The fact that S. aureus evolved three specific NSP inhibitors strongly indicates that NSPs are critical to host defense against this bacterium.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors

Stapels

Ramyar

Bischoff

et al. 2014

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

117

189

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Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomolar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity.immune evasion | bacteria | phagocytes

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Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors

Stapels

Ramyar

Bischoff

et al. 2014

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

117

189

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“…LeuCD are repressed in Bacillus subtilis upon iron starvation (43,44), and a similar link between iron availability and BCAA biosynthesis might exist in S. aureus. This phenotype is relevant when considering the levels of BCAA biosynthesis in vivo, as iron is limited during S. aureus infection (45) and consequently might impart a greater importance to BCAA acquisition in vivo.…”

Section: Discussionmentioning

confidence: 99%

Role of BrnQ1 and BrnQ2 in Branched-Chain Amino Acid Transport and Virulence in Staphylococcus aureus

et al. 2015

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The branched-chain amino acids (BCAAs; Ile, Leu, and Val) not only are important nutrients for the growth of Staphylococcus aureus but also are corepressors for CodY, which regulates virulence gene expression, implicating BCAAs as an important link between the metabolic state of the cell and virulence. BCAAs are either synthesized intracellularly or acquired from the environment. S. aureus encodes three putative BCAA transporters, designated BrnQ1, BrnQ2, and BrnQ3; their functions have not yet been formally tested. In this study, we mutated all three brnQ paralogs so as to characterize their substrate specificities and their roles in growth in vitro and in vivo. We demonstrated that in the community-associated, methicillin-resistant S. aureus (CA-MRSA) strain USA300, BrnQ1 is involved in uptake of all three BCAAs, BrnQ2 transports Ile, and BrnQ3 does not have a significant role in BCAA transport under the conditions tested. Of the three, only BrnQ1 is essential for USA300 to grow in a chemically defined medium that is limited for Leu or Val. Interestingly, we observed that a brnQ2 mutant grew better than USA300 in media limited for Leu and Val, owing to the fact that this mutation leads to overexpression of brnQ1. In a murine infection model, the brnQ1 mutant was attenuated, but in contrast, brnQ2 mutants had significantly increased virulence compared to that of USA300, a phenotype we suggest is at least partially linked to enhanced in vivo scavenging of Leu and Val through BrnQ1. These data uncover a hitherto-undiscovered connection between nutrient acquisition and virulence in CA-MRSA. Staphylococcus aureus is a highly successful human pathogen that succeeds at infecting virtually every body site, causing skin, soft tissue, respiratory, bone, joint, and endovascular infections (1). Maintenance of metabolic homeostasis is important for its infection process, as the majority of genes necessary for infection identified in large-scale signature-tagged mutagenesis (STM) screens fall into the categories of metabolism, transport, and biosynthesis (2, 3). Acquisition of host-derived nutrients, specifically amino acids, appears to be an important mechanism of meeting nutritional needs, as a large proportion of attenuated STM strains contain mutations in amino acid transporters (3).Amino acid transporters are ubiquitous in bacteria and are typically selective for transporting either one amino acid or several amino acids with related structures (4). The branched-chain amino acids (BCAAs; Ile, Leu, and Val) are hydrophobic amino acids typically found in the core in globular proteins or in the transmembrane domain in cell surface proteins (5). The transport mechanisms described for acquisition of the BCAAs in bacteria include secondary transporters belonging to the Leu, Ile, Val:cation symporter (LIVCS) family (e.g., BrnQ, BraB, BraZ, and BcaP) (4, 6-9) and the LIV-I ABC transporter (10-13). With the exception of an ABC transporter in Streptococcus pneumoniae (14), secondary transport, which couples the movement of an ion...

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“…The cultures were centrifuged at 8,000 × g for 5 min, and the supernatant was removed by aspiration. RNA was isolated from the bacteria using the RNAeasy Mini Kit (Qiagen) as previously described (37). RT-qPCR probes and primers were designed using GenScript software (https://www.genscript.com).…”

Section: Methodsmentioning

confidence: 99%

Host-derived fatty acids activate type VII secretion in Staphylococcus aureus

Lopez¹,

Tan²,

Yan³

et al. 2017

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

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The type VII secretion system (T7SS) of Staphylococcus aureus is a multiprotein complex dedicated to the export of several virulence factors during host infection. This virulence pathway plays a key role in promoting bacterial survival and the long-term persistence of staphylococcal abscess communities. The expression of the T7SS is activated by bacterial interaction with host tissues including blood serum, nasal secretions, and pulmonary surfactant. In this work we identify the major stimulatory factors as host-specific cisunsaturated fatty acids. Increased T7SS expression requires host fatty acid incorporation into bacterial biosynthetic pathways by the S. aureus fatty acid kinase (FAK) complex, and FakA is required for virulence. The incorporated cis-unsaturated fatty acids decrease S. aureus membrane fluidity, and these altered membrane dynamics are partially responsible for T7SS activation. These data define a molecular mechanism by which S. aureus cells sense the host environment and implement appropriate virulence pathways.type VII secretion | Staphylococcus aureus | fatty acids | virulence

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Global Gene Expression of Methicillin-resistant Staphylococcus aureus USA300 During Human and Mouse Infection

Cited by 76 publications

References 26 publications

Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors

Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors

Role of BrnQ1 and BrnQ2 in Branched-Chain Amino Acid Transport and Virulence in Staphylococcus aureus

Host-derived fatty acids activate type VII secretion in Staphylococcus aureus

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