TY  - JOUR
A1  - Nguyen, Minh Thu
A1  - Kraft, Beatrice
A1  - Yu, Wenqi
A1  - Demicrioglu, Dogan Doruk
A1  - Hertlein, Tobias
A1  - Burian, Marc
A1  - Schmaler, Mathias
A1  - Boller, Klaus
A1  - Bekeredjian-Ding, Isabelle
A1  - Ohlsen, Knut
A1  - Schittek, Birgit
A1  - Götz, Friedrich
T1  - The vSa\(\alpha\) Specific Lipoprotein Like Cluster (lpl) of S. aureus USA300 Contributes to Immune Stimulation and Invasion in Human Cells
JF  - PLoS Pathogens
N2  - All Staphylococcus aureus genomes contain a genomic island, which is termed vSa\(\alpha\) and characterized by two clusters of tandem repeat sequences, i.e. the exotoxin (set) and 'lipoprotein-like' genes (lpl). Based on their structural similarities the vSa\(\alpha\) islands have been classified as type I to IV. The genomes of highly pathogenic and particularly epidemic S. aureus strains (USA300, N315, Mu50, NCTC8325, Newman, COL, JH1 or JH9) belonging to the clonal complexes CC5 and CC8 bear a type I vSa\(\alpha\) island. Since the contribution of the lpl gene cluster encoded in the vSa\(\alpha\) island to virulence is unclear to date, we deleted the entire lpl gene cluster in S. aureus USA300. The results showed that the mutant was deficient in the stimulation of pro-inflammatory cytokines in human monocytes, macrophages and keratinocytes. Purified lipoprotein Lpl1 was further shown to elicit a TLR2-dependent response. Furthermore, heterologous expression of the USA300 lpl cluster in other S. aureus strains enhanced their immune stimulatory activity. Most importantly, the lpl cluster contributed to invasion of S. aureus into human keratinocytes and mouse skin and the non-invasive S. carnosus expressing the lpl gene cluster became invasive. Additionally, in a murine kidney abscess model the bacterial burden in the kidneys was higher in wild type than in mutant mice. In this infection model the lpl cluster, thus, contributes to virulence. The present report is one of the first studies addressing the role of the vSa\(\alpha\) encoded lpl gene cluster in staphylococcal virulence. The finding that the lpl gene cluster contributes to internalization into non-professional antigen presenting cells such as keratinocytes high-lights the lpl as a new cell surface component that triggers host cell invasion by S. aureus. Increased invasion in murine skin and an increased bacterial burden in a murine kidney abscess model suggest that the lpl gene cluster serves as an important virulence factor.
KW  - resistant Staphylococcus-aureus
KW  - bacterial lipoproteins
KW  - internalization
KW  - evolution
KW  - fibronectin-binding protein
KW  - toll-like receptor 2
KW  - epithelial cells
KW  - genome sequence
KW  - activation
KW  - mechanisms
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151856
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Nguyen, Minh-Thu
A1  - Saising, Jongkon
A1  - Tribelli, Paula Maria
A1  - Nega, Mulugeta
A1  - Diene, Seydina M.
A1  - François, Patrice
A1  - Schrenzel, Jacques
A1  - Spröer, Cathrin
A1  - Bunk, Boyke
A1  - Ebner, Patrick
A1  - Hertlein, Tobias
A1  - Kumari, Nimerta
A1  - Härtner, Thomas
A1  - Wistuba, Dorothee
A1  - Voravuthikunchai, Supayang P.
A1  - Mäder, Ulrike
A1  - Ohlsen, Knut
A1  - Götz, Friedrich
T1  - Inactivation of farR Causes High Rhodomyrtone Resistance and Increased Pathogenicity in Staphylococcus aureus
JF  - Frontiers in Microbiology
N2  - Rhodomyrtone (Rom) is an acylphloroglucinol antibiotic originally isolated from leaves of Rhodomyrtus tomentosa. Rom targets the bacterial membrane and is active against a wide range of Gram-positive bacteria but the exact mode of action remains obscure. Here we isolated and characterized a spontaneous Rom-resistant mutant from the model strain Staphylococcus aureus HG001 (RomR) to learn more about the resistance mechanism. We showed that Rom-resistance is based on a single point mutation in the coding region of farR [regulator of fatty acid (FA) resistance] that causes an amino acid change from Cys to Arg at position 116 in FarR, that affects FarR activity. Comparative transcriptome analysis revealed that mutated farR affects transcription of many genes in distinct pathways. FarR represses for example the expression of its own gene (farR), its flanking gene farE (effector of FA resistance), and other global regulators such as agr and sarA. All these genes were consequently upregulated in the RomR clone. Particularly the upregulation of agr and sarA leads to increased expression of virulence genes rendering the RomR clone more cytotoxic and more pathogenic in a mouse infection model. The Rom-resistance is largely due to the de-repression of farE. FarE is described as an efflux pump for linoleic and arachidonic acids. We observed an increased release of lipids in the RomR clone compared to its parental strain HG001. If farE is deleted in the RomR clone, or, if native farR is expressed in the RomR strain, the corresponding strains become hypersensitive to Rom. Overall, we show here that the high Rom-resistance is mediated by overexpression of farE in the RomR clone, that FarR is an important regulator, and that the point mutation in farR (RomR clone) makes the clone hyper-virulent.
KW  - antibiotic
KW  - Gram-positive bacteria
KW  - rhodomyrtone
KW  - Staphylococcus
KW  - membrane active
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224117
VL  - 10
ER  -