TRR 34: Pathophysiology of Staphylococci in the Post-Genome-Era
Biology
Final Report Abstract
Staphylococcus aureus is a dangerous pathogen, a leading cause of bacterial infection in hospitals and in the community world-wide. The microorganism is a prominent example of the crisis of antibiotic resistance, one of the major threats to health in the 21st century. Despite extensive efforts there is no effective anti-S. aureus vaccine. At the same time, S. aureus is a fascinating model organism for the study of host-pathogen interaction. Each of us is exposed to the bacteria, often within the first hours of life. The encounters with this versatile microorganism are multi-facetted ranging from rapid elimination or symptomless colonisation through mild skin infections to life threatening disease. S. aureus is equipped with an impressive assortment of fitness and virulence factors, including a wide variety of immune evasive compounds. Intricate regulation networks enable the bacteria to withstand hostile environmental conditions, such as nutrient limitation, oxidative stress or anaerobic conditions. So, they can adapt to very different niches in their host and in the environment, a basis of their success. The overarching objective of the CRC-TRR34 was a better understanding of the pathophysiology of S. aureus. Complete genome sequences of S. aureus and its human host had become available a few years before the consortium took up its work. The researchers could therefore rely on comprehensive analysis of transcriptional profiles, proteins, and metabolites, and combine these OMICs approaches with proven methods to elucidate mechanisms and causal relationships. This strategy was very fruitful. As a foundation, a (almost) complete quantitative inventory of the S. aureus proteins was generated in a laboratory strain, comprising the intracellular proteins as well as cell wall-bound and extracellular factors. Next, the adaptation of the bacteria to numerous infection-relevant stress conditions was extensively characterized in cell cultures. Molecular signatures were defined, which help to reveal the conditions S. aureus encounters when confronting his host and the pathogen’s reactions to them. It turned out that the bacteria rely on similar adaptation mechanisms inside biofilms, after uptake into host cells, and under the influence of antibiotics. These processes are important in chronic S. aureus infections as they occur in the bone or around implants. Such infections are very difficult to treat, because some bacteria are not destroyed after ingestion by the host cells, but able to persist. Their adaptation mechanisms render them extremely resistant to the immune system and to antibiotics. The same applies to S. aureus in biofilms. In order to elucidate these interactions between the pathogen and the host, members of the CRC-TRR34 have used cell culture systems of increasing complexity, developed suitable infection models in animals, and conducted clinical investigations. Moreover, we now understand much better how S. aureus succeeds in permanently colonizing the human nose. The spatio-temporally finely tuned process is essentially determined by the structure of the wall teichoic acids in the bacterial cell wall, which bind to receptors on the host cell surface. Although the bacteria behave rather harmless there, the immune system has to spend significant resources throughout life to maintain equilibrium between the pathogen and its host. The CRC-TRR34 has also helped to dispel doubts about the adaptive immune system's ability to provide clinical protection against S. aureus. These had come up because the results of efforts to develop a vaccine against the sophisticated pathogen were disappointing. Meanwhile, international research has picked up in this area again. However, it was recognized that the immune response to S. aureus can also cause damage. The suspicion that S. aureus can trigger and sustain allergies was confirmed by the discovery of strong bacterial allergens. The clinical significance of this finding in chronic inflammation involving S. aureus must now be elucidated. In conclusion, during the 12 years of funding much could be achieved, more remains to be done. The scientists involved in the CRC-TRR34 are highly motivated to continue and further expand their cooperation established in the consortium and in its international networks.
Publications
- 2008. Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions. Nat Rev Microbiol 6:276-287
Weidenmaier C, Peschel A
(See online at https://doi.org/10.1038/nrmicro1861) - 2009. GENOVA: A rapid genome visualization and functional genomics software. Online J. Bioinform. 10:201- 207
Liang C, Wolz C, Herbert S, Bernhardt J, Engelmann S, Hecker M, Götz F, Dandekar T
- 2010. Proteomics uncovers extreme heterogeneity in the Staphylococcus aureus exoproteome due to genomic plasticity and variant gene regulation. Proteomics 10:1634-1644
Ziebandt AK, Kusch H, Degner M, Jaglitz S, Sibbald MJ, Arends JP, Chlebowicz MA, Albrecht D, Pantucek R, Doskar J, Ziebuhr W, Bröker BM, Hecker M, van Dijl JM, Engelmann S
(See online at https://doi.org/10.1002/pmic.200900313) - 2010. Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog 6:e1000715
Löffler B, Hussain M, Grundmeier M, Bruck M, Holzinger D, Varga G, Roth J, Kahl BC, Proctor RA, Peters G
(See online at https://doi.org/10.1371/journal.ppat.1000715) - 2010. Structural basis of cell wall cleavage by a staphylococcal autolysin. PLoS Pathog 6:e1000807
Zoll S, Pätzold B, Schlag M, Götz F, Kalbacher H, Stehle T
(See online at https://doi.org/10.1371/journal.ppat.1000807) - 2012. A novel mouse model of Staphylococcus aureus chronic osteomyelitis that closely mimics the human infection: an integrated view of disease pathogenesis. Am J Pathol 181:1206-1214
Horst SA, Hoerr V, Beineke A, Kreis C, Tuchscherr L, Kalinka J, Lehne S, Schleicher I, Kohler G, Fuchs T, Raschke MJ, Rohde M, Peters G, Faber C, Löffler B, Medina E
(See online at https://doi.org/10.1016/j.ajpath.2012.07.005) - 2012. Exometabolome analysis identifies pyruvate dehydrogenase as a target for the antibiotic triphenylbismuthdichloride in multiresistant bacterial pathogens. J Biol Chem 287:2887-2895
Birkenstock T, Liebeke M, Winstel V, Krismer B, Gekeler C, Niemiec MJ, Bisswanger H, Lalk M, Peschel A
(See online at https://doi.org/10.1074/jbc.m111.288894) - 2012. Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci U S A 109:18909-18914
Brown S, Xia G, Luhachack LG, Campbell J, Meredith TC, Chen C, Winstel V, Gekeler C, Irazoqui JE, Peschel A, Walker S
(See online at https://doi.org/10.1073/pnas.1209126109) - 2012. RNase Y of Staphylococcus aureus and its role in the activation of virulence genes. Mol Microbiol 85:817-832
Marincola G, Schäfer T, Behler J, Bernhardt J, Ohlsen K, Goerke C, Wolz C
(See online at https://doi.org/10.1111/j.1365-2958.2012.08144.x) - 2012. The stringent response of Staphylococcus aureus and its impact on survival after phagocytosis through the induction of intracellular PSMs expression. PLoS Pathog 8:e1003016
Geiger T, Francois P, Liebeke M, Fraunholz M, Goerke C, Krismer B, Schrenzel J, Lalk M, Wolz C
(See online at https://doi.org/10.1371/journal.ppat.1003016) - 2013. Both terminal oxidases contribute to fitness and virulence during organ-specific Staphylococcus aureus colonization. mBio 4: e00976-13
Götz F, Mayer S
(See online at https://doi.org/10.1128/mbio.00976-13) - 2013. Methionine biosynthesis in Staphylococcus aureus is tightly controlled by a hierarchical network involving an initiator tRNA-specific T-box riboswitch. PLoS Pathog 9:e1003606
Schoenfelder SM, Marincola G, Geiger T, Goerke C, Wolz C, Ziebuhr W
(See online at https://doi.org/10.1371/journal.ppat.1003606) - 2013. Wall teichoic acid structure governs horizontal gene transfer between major bacterial pathogens. Nat Commun 4:2345
Winstel V, Liang C, Sanchez-Carballo P, Steglich M, Munar M, Bröker BM, Penades JR, Nubel U, Holst O, Dandekar T, Peschel A, Xia G
(See online at https://doi.org/10.1038/ncomms3345) - 2014. Deletion of membrane-associated Asp23 leads to upregulation of cell wall stress genes in Staphylococcus aureus. Mol Microbiol 93:1259-68
Müller M, Reiß S, Schlüter R, Mäder U, Beyer A, Reiß W, Marles-Wright J, Lewis RJ, Pförtner H, Völker U, Riedel K, Hecker M, Engelmann S, Pané-Farré J
(See online at https://doi.org/10.1111/mmi.12733) - 2014. Inactivation of thyA in Staphylococcus aureus attenuates virulence and has a strong impact on metabolism and virulence gene expression. mBio 5:e01447-14
Kriegeskorte A, Block D, Drescher M, Windmüller N, Mellmann A, Baum C, Neumann C, Lorè NI, Bragonzi A, Liebau E, Hertel P, Seggewiss J, Becker K, Proctor RA, Peters, G, Kahl BC
(See online at https://doi.org/10.1128/mbio.01447-14) - 2014. Mechanisms of infective endocarditis: pathogen-host interaction and risk states. Nat Rev Cardiol 11(1):35-50
Werdan K, Dietz S, Löffler B, Niemann S, Bushnaq H, Silber R, Peters G, Mueller-Werdan U
(See online at https://doi.org/10.1038/nrcardio.2013.174) - 2014. Nutrient limitation governs Staphylococcus aureus niche adaptation in the human nose. PLoS Pathog 10:e1003862
Krismer B, Liebeke M, Janek D, Nega M, Rautenberg M, Hornig G, Unger C, Weidenmaier C, Lalk M, Peschel A
(See online at https://doi.org/10.1371/journal.ppat.1003862) - 2014.Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection. PLoS Pathog 10:e1004298
Cheung GY, Kretschmer D, Duong AC, Yeh AJ, Ho TV, Chen Y, Joo HS, Kreiswirth BN, Peschel A, Otto M
(See online at https://doi.org/10.1371/journal.ppat.1004298) - 2015. Sigma factor SigB is crucial to mediate Staphylococcus aureus adaptation during chronic infections. PLoS Pathog 11:e1004870
Tuchscherr L, Bischoff M, Lattar SM, Noto Llana M, Pförtner H, Niemann S, Geraci J, Van de Vyver H, Fraunholz MJ, Cheung AL, Herrmann M, Völker U, Sordelli DO, Peters G, Löffler B
(See online at https://doi.org/10.1371/journal.ppat.1004870) - 2015. Structural and enzymatic analysis of TarM from Staphylococcus aureus reveals an oligomeric protein specific for the glycosylation of wall teichoic acid. J. Biol. Chem. 290:9874-85
Koç C, Gerlach D, Beck S, Peschel A, Xia G, Stehle T
(See online at https://doi.org/10.1074/jbc.m114.619924) - 2015. The fall of a dogma? Unexpected high T cell memory response to S. aureus in humans. J Infect Dis 212(5):830-8
Kolata J, Kühbandner I, Link C, Normann N, Vu HC, Steil L, Weidenmaier C, Bröker BM
(See online at https://doi.org/10.1093/infdis/jiv128) - 2015. The νSaα Specific Lipoprotein Like Cluster (lpl) of S. aureus USA300 Contributes to Immune Stimulation and Invasion in Human Cells. PLoS Pathog 11: e1004984
Nguyen MT, Kraft B, Yu W, Demicrioglu DD, Hertlein T, Burian M, Schmaler M, Boller K, Bekeredjian- Ding I, Ohlsen K, Schittek B, Götz F
(See online at https://doi.org/10.1371/journal.ppat.1004984) - 2015. Wall Teichoic Acid Glycosylation Governs Staphylococcus aureus Nasal Colonization. mBio 6(4):e00632
Winstel V, Kühner P, Salomon F, Larsen J, Skov R, Hoffmann W, Peschel A, Weidenmaier C
(See online at https://doi.org/10.1128/mbio.00632-15) - 2016. Costs of life - Dynamics of the protein inventory of Staphylococcus aureus during anaerobiosis. Sci Rep 6:28172
Zühlke D, Dörries K, Bernhardt J, Maaß S, Muntel J, Liebscher V, Pané-Farré J, Riedel K, Lalk M, Völker U, Engelmann S, Becher D, Fuchs S, Hecker M
(See online at https://doi.org/10.1038/srep28172) - 2016. Dynamic in vivo mutations within the ica operon during persistence of Staphylococcus aureus in the airways of cystic fibrosis patients. PlosPathog 12:e1006024
Schwartbeck B, Birtel J, Treffon J, Langhanki L, Mellmann A, Kale D, Kahl J, Hirschhausen N, Neumann C, Lee JC, Götz F, Rohde H, Henke H, Küster P, Peters G, Kahl BC
(See online at https://doi.org/10.1371/journal.ppat.1006024) - 2016. Global analysis of the impact of linezolid onto virulence factor production in S. aureus USA300. Int J Med Microbiol 306:131-40
Bonn F, Pané-Farré J, Schlüter R, Schaffer M, Fuchs S, Bernhardt J, Riedel K, Otto A, Völker U, Dijl JM, Hecker M, Mäder U, Becher D
(See online at https://doi.org/10.1016/j.ijmm.2016.02.004) - 2016. Global antibody response to Staphylococcus aureus live-cell vaccination. Sci. Rep. 6:24754
Selle M, Hertlein T, Oesterreich B, Klemm T, Kloppot P, Müller E, Ehricht R, Stentzel S, Bröker BM, Engelmann S, Ohlsen K
(See online at https://doi.org/10.1038/srep24754) - 2016. Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation. Proc Natl Acad Sci U S A. 113:E3101-10
Das S, Lindemann C, Young BC, Muller J, Österreich B, Ternette N, Winkler AC, Paprotka K, Reinhardt R, Förstner KU, Allen E, Flaxman A, Yamaguchi Y, Rollier CS, van Diemen P, Blättner S, Remmele CW, Selle M, Dittrich M, Müller T, Vogel J, Ohlsen K, Crook DW, Massey R, Wilson DJ, Rudel T, Wyllie DH, Fraunholz MJ
(See online at https://doi.org/10.1073/pnas.1520255113) - 2016. Staphylococcus aureus exploits a non-ribosomal cyclic dipeptide to modulate survival within epithelial cells and phagocytes. PLoS Pathog 12:e1005857
Blättner S, Das S, Paprotka K, Eilers U, Krischke M, Kretschmer D, Remmele CW, Dittrich M, Müller T, Schuelein-Voelk C, Hertlein T, Mueller MJ, Huettel B, Reinhardt R, Ohlsen K, Rudel T, Fraunholz MJ
(See online at https://doi.org/10.1371/journal.ppat.1005857) - 2016. Staphylococcus aureus transcriptome architecture: From laboratory to infection-mimicking conditions. PLoS Genet 12: e1005962
Mäder U, Nicolas P, Depke M, Pane-Farre J, Débarbouillé M, van der Kooi-Pol MM, Guérin C, Dérozier S, Hiron A, Jarmer H, Leduc A, Michalik S, Reilman E, Schaffer M, Schmidt F, Bessières P, Noirot P, Hecker M, Msadek T, Völker U, van Dijl JM
(See online at https://doi.org/10.1371/journal.pgen.1005962) - 2016. Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants. Nat Commun 7:12304
Hanzelmann D, Joo HS, Franz-Wachtel M, Hertlein T, Stevanovic S, Macek B, Wolz C, Götz F, Otto M, Kretschmer D, Peschel A
(See online at https://doi.org/10.1038/ncomms12304) - 2017. Reduced Immunoglobulin (Ig) G Response to Staphylococcus aureus in STAT3 Hyper-IgE Syndrome. Clin Infect Dis. 64:1279-1282
Stentzel S, Hagl B, Abel F, Kahl BC, Rack-Hoch A, Bröker BM, Renner ED
(See online at https://doi.org/10.1093/cid/cix140) - 2017. Spls are pacemakers of allergic airway reactions to Staphylococcus aureus. J Allergy Clin Immunol. 139:492-500
Stentzel S, Teufelberger A, Nordengrün M, Kolata J, Schmidt F, van Crombruggen K, Michalik S, Kumpfmüller J, Tischer S, Schweder T, Hecker M, Engelmann S, Völker U, Krysko O, Bachert C, Bröker BM
(See online at https://doi.org/10.1016/j.jaci.2016.03.045) - 2017. The commensal lifestyle of Staphylococcus aureus and its interactions with the nasal microbiota. Nat Rev Microbiol. 15:675-687
Krismer B, Weidenmaier C, Zipperer A, Peschel A
(See online at https://doi.org/10.1038/nrmicro.2017.104) - 2017. Wall teichoic acids mediate increased virulence in Staphylococcus aureus. Nat Microbiol 2:16257. Erratum in: Nat Microbiol. 2017 Mar 13:17048
Wanner S, Schade J, Keinhörster D, Weller N, George SE, Kull L, Bauer J, Grau T, Winstel V, Stoy H, Kretschmer D, Kolata J, Wolz C, Bröker BM, Weidenmaier C
(See online at https://doi.org/10.1038/nmicrobiol.2016.257 https://doi.org/10.1038/nmicrobiol.2017.48) - A global Staphylococcus aureus proteome resource applied to the in vivo characterization of host-pathogen interactions. 2017. Sci Rep 7:9718
Michalik S, Depke M, Murr A, Gesell Salazar M, Kusebauch U, Sun Z, Meyer TC, Surmann K, Pförtner H, Hildebrandt P, Weiss S, Palma Medina LM, Gutjahr M, Hammer E, Becher D, Pribyl T, Hammerschmidt S, Deutsch EW, Bader SL, Hecker M, Moritz RL, Mäder U, Völker U, Schmidt F
(See online at https://doi.org/10.1038/s41598-017-10059-w) - 2018. Adaptation of Staphylococcus aureus to airway environments in patients with cystic fibrosis by upregulation of superoxide dismutase M and iron-scavenging proteins. J Infect Dis 217:1453-1461
Treffon J, Block D, Moche M, Reiss S, Fuchs S, Engelmann S, Becher D, Langhanki L, Mellmann A, Peters G, Kahl BC
(See online at https://doi.org/10.1093/infdis/jiy012) - 2018. AureoWiki ̵ The repository of the Staphylococcus aureus research and annotation community. Int J Med Microbiol 308(6):558-568
Fuchs S, Mehlan H, Bernhardt J, Hennig A, Michalik S, Surmann K, Pané-Farré J, Giese A, Weiss S, Backert L, Herbig A, Nieselt K, Hecker M, Völker U, Mäder U
(See online at https://doi.org/10.1016/j.ijmm.2017.11.011) - 2018. From the genome sequence via the proteome to cell physiology - Pathoproteomics and pathophysiology of Staphylococcus aureus. Int J Med Microbiol 308(6):545-557
Hecker Ma, Mäder U, Völker U
(See online at https://doi.org/10.1016/j.ijmm.2018.01.002) - 2018. Secreted immunomodulatory proteins of Staphylococcus aureus activate platelets and induce platelet aggregation. Thromb Haemost 118:745-757
Binsker U, Palankar R, Wesche J, Kohler TP, Prucha J, Burchhardt G, Rohde M, Schmidt F, Bröker BM, Mamat U, Pané-Farré J, Graf A, Ebner P, Greinacher A, Hammerschmidt S
(See online at https://doi.org/10.1055/s-0038-1637735) - Patent EP 2466308, Immunoassay and use of the device (immunoassay), 2018
Bröker BM et al.
