Staphylococcus aureus virulence factors and their role in biofilm-associated infections

  • Dragana Božić University of Belgrade – Faculty of Pharmacy, Department of Microbiology and Immunology
Keywords: Staphylococcus aureus, virulence factors, biofilm, biofilm-associated infections

Abstract


Although Staphylococcus aureus colonises the skin and mucous membranes in approximately 30% of healthy individuals, it is also an important pathogen, primarily due to its arsenal of virulence factors that contribute significantly to its ability to cause a variety of infections. These factors include surface proteins that promote adhesion to host tissues, as well as enzymes and toxins that damage host cells and tissue. Important virulence factors such as protein A, which binds to antibodies and evades recognition by the immune system, and various exotoxins such as alpha-toxin and Panton-Valentine leukocidin, which cause cell lysis and tissue destruction, play a crucial role in pathogenesis. The ability of S. aureus to form biofilms on medical devices further increases its persistence and resistance to therapy. Biofilms are structured communities of bacterial cells that are enclosed in a self-produced polymeric matrix and that adhere to biotic or abiotic surfaces. Biofilm-related infections caused by S. aureus, such as infections of medical devices (catheters, prosthetic joints, heart valves, intravascular catheters) and human tissue (chronic rhinosinusitis, chronic wounds, endocarditis and osteomyelitis), are a significant concern in medical settings. Understanding these virulence mechanisms is crucial for the development of targeted therapies and preventive measures to effectively combat S. aureus infections.

References

Piewngam P, Otto M. Staphylococcus aureus colonisation and strategies for decolonisation. Lancet Microbe. 2024;5(6):E606-18.

Cheung GYC, Bae JS, Otto M. Pathogenicity and virulence of Staphylococcus aureus. Virulence. 2021;12(1):547-69.

Laarman AJ, Mijnheer G, Mootz JM, van Rooijen WJ, Ruyken M, Malone CL, et al. Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis. EMBO J. 2012;31(17):3607-19.

Zhang Y, Wu M, Hang T, Wang C, Yang Y, Pan W, et al. Staphylococcus aureus SdrE captures complement factor H's C-terminus via a novel 'close, dock, lock and latch' mechanism for complement evasion. Biochem J. 2017;474(10):1619-31.

Joo HS, Otto M. Mechanisms of resistance to antimicrobial peptides in staphylococci. Biochim Biophys Acta. 2015;1848(11 Pt B):3055-61.

Gotz F. Staphylococci in colonization and disease: prospective targets for drugs and vaccines. Curr Opin Microbiol. 2004;7(5):477-87.

Gotz F. Staphylococcus and biofilms. Mol Microbiol. 2002;43(6):1367-78.

Roche FM, Meehan M, Foster TJ. The Staphylococcus aureus surface protein SasG and its homologues promote bacterial adherence to human desquamated nasal epithelial cells. Microbiology. 2003;149(Pt 10):2759-67.

Foster TJ, Hook M. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 1998;6(12):484-8.

Berube BJ, Bubeck Wardenburg J. Staphylococcus aureus alpha-toxin: nearly a century of intrigue. Toxins (Basel). 2013;5(6):1140-66.

Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux JE. Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science. 1996;274(5294):1859-66.

Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000;13(1):16-34.

Doery HM, Magnuson BJ, Cheyne IM, Sulasekharam J. A phospholipase in staphylococcal toxin which hydrolizes sphingomyelin. Nature (London). 1963;198:1091-2.

Vandenesch F, Lina G, Henry T. Staphylococcus aureus hemolysins, bi-component leukocidins, and cytolytic peptides: a redundant arsenal of membrane-damaging virulence factors? Front Cell Infect Microbiol. 2012;2:12.

Doery HM, Magnuson BJ, Galasekharam J, Pearson JE. The properties of phospholipase enzymes in staphylococcal toxins. J Gen Microbiol. 1965;40(2):283-96.

Woodin AM. Purification of the two components of leukocidin from Staphylococcus aureus. Biochem J. 1960;75(1):158-65.

Ventura CL, Malachowa N, Hammer CH, Nardone GA, Robinson MA, Kobayashi SD, et al. Identification of a novel Staphylococcus aureus two-component leukotoxin using cell surface proteomics. PLoS ONE. 2010;5(7):e11634.

Verdon J, Girardin N, Lacombe C, Berjeaud JM, Hechard Y. Delta-hemolysin, an update on a membrane-interacting peptide. Peptides. 2009;30(4):817-23.

Periasamy S, Joo HSJ, Duong AC, Bach THL, Tan VY, Chatterjee SS, et al. How Staphylococcus aureus biofilm develop their characteristic structure. Proc Natl Acad Sci USA. 2012;109(4):1281-6.

Malachowa N, DeLeo FR. Mobile genetic elements of Staphylococcus aureus. Cell Mol Life Sci. 2010;67(18):3057-71.

Prasad GS, Earhart CA, Murray DL, Novick RP, Schlievert PM, Ohlendorf DH. Structure of toxic shock syndrome toxin-1. Biochemistry. 1993;32(50):13761-6.

Pinchuk IV, Beswick EJ, Reyes VE. Staphylococcal enterotoxins. Toxins. 2010;2(8):2177-97.

Swaminathan S, Furey W, Pletcher J, Sax M. Crystal structure of staphylococcal enterotoxin B, a superantigen. Nature (London). 1992;359(6398):801-6.

Jett M. Brinkley W, Neill R, Gemski P, Hunt R. Staphylococcus aureus enterotoxin B challenge of monkeys: correlation of plasma levels of arachidonic acid cascade products with occurrence of illness. Infect Immun. 1990;58(11):3494-9.

Scheuber PH, Golecki JR, Kickhofen B, Scheel D, Beck G, Hammer DK. Cysteinyl leukotrienes as mediators of staphylococcal enterotoxin B in the monkey. Eur J Clin Invest. 1987;17(5):455-9.

Hanakawa Y, Schechter NM, Lin C, Garza L, Li H, Yamaguchi T, et al. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. J Clin Invest. 2002;110(1):53-60.

Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15(2):167-93.

Rather MA, Gupta K, Mandal M. Microbial biofilm: formation, architecture, antibiotic resistance, and control strategies. Braz J Microbiol. 2021;52(4):1701-1718.

Rani SA, Pitts B, Beyenal H, Veluchamy RA, Lewandowski Z, Davison WM, et al. Spatial patterns of DNA replication, protein synthesis and oxygen concentration within bacterial biofilms reveal diverse physiological states. J Bacteriol. 2007;189(11):4223-33.

Archer NK, Mazaitis MJ, Costerton W, Leid JG, Powers ME, Shirtliff ME. Staphylococcus aureus biofilms. Properties, regulation and roles in human disease. Virulence. 2011;2(5):445-59.

Lewis K. Persister cells and the riddle of biofilm survival. Biochemistry (Mosc). 2005;70(2):267-74.

Peng Q, Tang X, Dong W, Sun N, Yuan W. A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism. Antibiotics (Basel). 2022;12(1):12.

Okshevsky M, Meyer RL. The role of extracellular DNA in the establishment, maintenance and perpetuation of bacterial biofilms. Crit Rev Microbiol. 2015;41(3):341-52.

Jenul C, Horswill AR. Regulation of Staphylococcus aureus Virulence. Microbiol Spectr. 2019;7(2):10.1128/microbiolspec.GPP3-0031-2018.

Novick RP, Projan SJ, Kornblum J, Ross HF, Ji G, Kreiswirth B, et al. The agr P2 operon: an autocatalytic sensory transduction system in Staphylococcus aureus. Mol Gen Genet. 1995;248(4):446-58.

Choudhary KS, Mih N, Monk J, Kavvas E, Yurkovich JT, Sakoulas G, et al. The Staphylococcus aureus Two-Component System AgrAC Displays Four Distinct Genomic Arrangements That Delineate Genomic Virulence Factor Signatures. Front Microbiol. 2018;9:1082.

Saenz HL, Augsburger V, Vuong C, Jack RW, Gotz F, Otto M. Inducible expression and cellular location of AgrB, a protein involved in the maturation of the staphylococcal quorum-sensing pheromone. Arch Microbiol. 2000;174(6):452-5.

Zhang L, Lin J, Ji G. Membrane anchoring of the AgrD N-terminal amphipathic region is required for its processing to produce a quorum-sensing pheromone in Staphylococcus aureus. J Biol Chem. 2004;279(19):19448-56.

Otto M, Sussmuth R, Jung G, Gotz F. Structure of the pheromone peptide of the Staphylococcus epidermidis agr system. FEBS Lett. 1998;424(1-2):89-94.

Huntzinger E, Boisset S, Saveanu C, Benito Y, Geissmann T, Namane A, et al. Staphylococcus aureus RNAIII and the endoribonuclease III coordinately regulate spa gene expression. EMBO J. 2005;24(4):824-35.

Novick RP. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol. 2003;48(6):1429-49.

Giraudo AT, Mansilla C, Chan A, Raspanti C, Nagel R. Studies on the expression of regulatory locus sae in Staphylococcus aureus. Curr Microbiol. 2003;46(4):246-50.

Fournier B, Hooper DC. A new two-component regulatory system involved in adhesion, autolysis, and extracellular proteolytic activity of Staphylococcus aureus. J Bacteriol. 2000;182(14):3955-64.

Fournier B, Klier A, Rapoport G. The two-component system ArlS-ArlR is a regulator of virulence gene expression in Staphylococcus aureus. Mol Microbiol. 2001;41(1):247-61.

Toledo-Arana A, Merino N, Vergara-Irigaray M, Debarbouille M, Penades JR, Lasa I. Staphylococcus aureus develops an alternative, ica-independent biofilm in the absence of the arlRS two-component system. J Bacteriol. 2005;187(15):5318-29.

Yarwood JM, McCormick JK, Schlievert PM. Identification of a novel two-component regulatory system that acts in global regulation of virulence factors of Staphylococcus aureus. J Bacteriol. 2001;183(4):1113-23.

Throup JP, Zappacosta F, Lunsford RD, Annan RS, Carr SA, Lonsdale JT, et al. The srhSR gene pair from Staphylococcus aureus: genomic and proteomic approaches to the identification and characterization of gene function. Biochemistry. 2001;40(34):10392-401.

Mann EE, Rice KC, Boles BR, Endres JL, Ranjit D, Chandramohan L, et al. Modulation of eDNA release and degradation affects Staphylococcus aureus biofilm maturation. PLoS ONE. 2009;4(6):e5822.

Rice KC, Mann EE, Endres JL, Weiss EC, Cassat JE, Smeltzer MS, et al. The cidA murein hydrolase regulator contributes to DNA release and biofilm development in Staphylococcus aureus. Proc Natl Acad Sci USA. 2007;104(19):8113-8.

Takahashi J, Komatsuzawa H, Yamada S, Nishida T, Labischinski H, Fujiwara T, et al. Molecular characterization of an atl null mutant of Staphylococcus aureus. Microbiol Immunol. 2002;46(9):601-12.

Heilmann C, Hussain M, Peters G, Gotz F. Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface. Mol Microbiol. 1997;24(5):1013-24.

Nair SP, Bischoff M, Senn MM, Berger-Bachi B. The sigmaB regulon influences internalization of Staphylococcus aureus by osteoblasts. Infect Immun. 2003;71(7):4167-70.

Senn MM, Giachino P, Homerova D, Steinhuber A, Strassner J, Kormanec J, et al. Molecular analysis and organization of the sigmaB operon in Staphylococcus aureus. J Bacteriol. 2005;187(23):8006-19.

Kavanagh N, Ryan EJ, Widaa A, Sexton G, Fennell J, O'Rourke S, et al. Staphylococcal Osteomyelitis: Disease Progression, Treatment Challenges, and Future Directions. Clin Microbiol Rev. 2018;31(2):e00084-17.

Resch A, Leicht S, Saric M, Pasztor L, Jakob A, Gotz F, et al. Comparative proteome analysis of Staphylococcus aureus biofilm and planktonic cells and correlation with transcriptome profiling. Proteomics. 2006;6(6):1867-77.

Dunman PM, Murphy E, Haney S, Palocios D, Tucker-Kellogg G, Wu S, et al. Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or SarA loci. J Bacteriol. 2001;183(24):7341-53.

Anwar S, Prince LR, Foster SJ, Whyte MK, Sabroe I. The rise and rise of Staphylococcus aureus: laughing in the face of granulocytes. Clin Exp Immunol. 2009;157(2):216-24.

Lew DP, Waldvogel FA. Osteomyelitis. Lancet. 2004;364(9431):369-79.

Costerton JW, Montanaro L, Arciola CR. Biofilm in implant infections: its production and regulation. Int J Artif Organs. 2005;28(11):1062-8.

Lerche CJ, Schwartz F, Theut M, Fosbøl EL, Iversen K, Bundgaard H, et al. Anti-biofilm Approach in Infective Endocarditis Exposes New Treatment Strategies for Improved Outcome. Front Cell Dev Biol. 2021;9:643335.

Schierle CF, De la Garza M, Mustoe TA, Galiano RD. Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen. 2009;17(3):354-9.

Roy S, Santra S, Das A, Dixith S, Sinha M, Ghatak S, et al. Staphylococcus aureus Biofilm Infection Compromises Wound Healing by Causing Deficiencies in Granulation Tissue Collagen. Ann Surg. 2020;271(6):1174-85.

Fastenberg JH, Hsueh WD, Mustafa A, Akbar NA, Abuzeid WM. Biofilms in chronic rhinosinusitis: Pathophysiology and therapeutic strategies. World J Otorhinolaryngol Head Neck Surg. 2016;2(4):219-229.

Lee JW, Somerville T, Kaye SB, Romano V. Staphylococcus aureus Keratitis: Incidence, Pathophysiology, Risk Factors and Novel Strategies for Treatment. J Clin Med. 2021;10(4):758.

Murugan K, Usha M, Malathi P, Al-Sohaibani AS, Chandrasekaran M. Biofilm forming multi drug resistant Staphylococcus spp. among patients with conjunctivitis. Pol J Microbiol. 2010;59(4):233-9.

Heitz-Mayfield LJ, Lang NP. Comparative biology of chronic and aggressive periodontitis vs. peri-implantitis. Periodontol 2000. 2010;53:167-81.

Carolus H, Van Dyck K, Van Dijck P. Candida albicans and Staphylococcus Species: A Threatening Twosome. Front Microbiol. 2019;10:2162.

Dühring S, Schuster S. Studying mixed-species biofilms of Candida albicans and Staphylococcus aureus using evolutionary game theory. PLoS One. 2024;19(3):e0297307.

Published
2024/08/22
Section
Review articles