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Staphylococcus aureus small colony variants (SCVs) and their role in disease

Published online by Cambridge University Press:  15 June 2011

Heba Atalla*
Affiliation:
Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
Carlton Gyles
Affiliation:
Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
Bonnie Mallard
Affiliation:
Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada
*
*Corresponding author. E-mail: [email protected]

Abstract

Persistent or difficult-to-treat Staphylococcus aureus infections in animals and humans may be related to small colony variants (SCVs) that can hide inside host cells and modulate host defenses. S. aureus SCVs have gained much attention in human medicine but have been underestimated and overlooked in veterinary medicine. Recently, an SCV isolated from a dairy cow with a history of chronic mastitis was shown to possess similar phenotypic and transcriptomic properties to those of human SCVs. SCVs form small, colorless, non-hemolytic colonies after 48 h, are only slowly coagulase positive, fail to ferment mannitol, and can revert to the parental phenotype. The phenotype of SCVs is mostly related to alterations in hemin and/or menadione biosynthesis or to thymidine deficiency. Transcriptomic analysis of SCVs shows up-regulation of genes involved in glycolytic and arginine–deiminase pathways, capsular biosynthesis; increased sigma B activity; and down-regulation of genes for α-hemolysin, coagulase and effector molecule RNA III of the global virulence regulator Agr. Similar results are reported at the protein level. SCVs are less virulent but successful persisters in infection models. SCVs persist longer and at higher numbers within non-phagocytes than do their parents. SCVs survive within spacious vacuoles up to 24 h within cultured bovine mammary epithelial cells, likely due to up-regulation of protective mechanisms that counteract the lethal acidic environment of the phagolysosome. Persistence of SCVs within host cells may explain failures in antimicrobial therapy and vaccinations.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011

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References

Abele-Horn, M, Schupfner, B, Emmerling, P, Waldner, H and Goring, H (2000). Persistent wound infection after herniotomy associated with small-colony variants of Staphylococcus aureus. Infection 28: 5354.CrossRefGoogle ScholarPubMed
Acar, JF, Goldstein, FW and Lagrange, P (1978). Human infections caused by thiamine- or menadione-requiring Staphylococcus aureus. Journal of Clinical Microbiology 8: 142147.CrossRefGoogle ScholarPubMed
Alexander, EH and Hudson, MC (2001). Factors influencing the internalization of Staphylococcus aureus and impacts on the course of infections in humans. Applied Microbiology and Biotechnology 56: 361366.CrossRefGoogle ScholarPubMed
Almeida, RA, Matthews, KR, Cifrian, E, Guidry, AJ and Oliver, SP (1996). Staphylococcus aureus invasion of bovine mammary epithelial cells. Journal of Dairy Science 79: 10211026.CrossRefGoogle ScholarPubMed
Atalla, H, Gyles, C, Jacob, CL, Moisan, H, Malouin, F and Mallard, B (2008). Characterization of a Staphylococcus aureus small colony variant (SCV) associated with persistent bovine mastitis. Foodborne Pathogens and Disease 5: 785799.CrossRefGoogle ScholarPubMed
Atalla, H, Gyles, C, Wilkie, B, Leslie, K and Mallard, B (2009). Somatic cell scores and clinical signs following experimental intramammary infection of dairy cows with a Staphylococcus aureus small colony variant (S. aureus SCV) in comparison to other bovine strains. Veterinary Microbiology 137: 326334.CrossRefGoogle ScholarPubMed
Atalla, H, Gyles, C and Mallard, B (2010a). Persistence of a Staphylococcus aureus small colony variants (S. aureus SCV) within bovine mammary epithelial cells. Veterinary Microbiology 143: 319328.CrossRefGoogle ScholarPubMed
Atalla, H, Wilkie, B, Gyles, C, Leslie, K, Mutharia, L and Mallard, B (2010b). Antibody and cell-mediated immune responses to Staphylococcus aureus small colony variants and their parental strains associated with bovine mastitis. Developmental and Comparative Immunology 34: 12831290.CrossRefGoogle ScholarPubMed
Baddour, LM, Tayidi, MM, Walker, E, McDevitt, D and Foster, TJ (1994). Virulence of coagulase-deficient mutants of Staphylococcus aureus in experimental endocarditis. Journal of Medical Microbiology 41: 259263.CrossRefGoogle ScholarPubMed
Balwit, JM, van, LP, Vann, JM and Proctor, RA (1994). Gentamicin-resistant menadione and hemin auxotrophic Staphylococcus aureus persist within cultured endothelial cells. Journal of Infectious Diseases 170: 10331037.Google Scholar
Barkema, HW, Schukken, YH and Zadoks, RN (2006). Invited Review: The role of cow, pathogen, and treatment regimen in the therapeutic success of bovine Staphylococcus aureus mastitis. Journal of Dairy Science 89: 18771895.CrossRefGoogle ScholarPubMed
Bates, DM, von, EC, McNamara, PJ, Peters, G, Yeaman, MR, Bayer, AS and Proctor, RA (2003). Staphylococcus aureus menD and hemB mutants are as infective as the parent strains, but the menadione biosynthetic mutant persists within the kidney. Journal of Infectious Diseases 187: 16541661.CrossRefGoogle ScholarPubMed
Bayles, KW, Wesson, CA, Liou, LE, Fox, LK, Bohach, GA and Trumble, WR (1998). Intracellular Staphylococcus aureus escapes the endosome and induces apoptosis in epithelial cells. Infection and Immunity 66: 336342.Google Scholar
Becker, K, Bierbaum, G, von, EC, Engelmann, S, Gotz, F, Hacker, J, Hecker, M, Peters, G, Rosenstein, R and Ziebuhr, W (2007). Understanding the physiology and adaptation of staphylococci: a post-genomic approach. Int. Journal of Medical Microbiology 297: 483501.CrossRefGoogle ScholarPubMed
Bennedsgaard, TW, Thamsborg, SM, Aarestrup, FM, Enevoldsen, C, Vaarst, M and Christoffersen, AB (2006). Resistance to penicillin of Staphylococcus aureus isolates from cows with high somatic cell counts in organic and conventional dairy herds in Denmark. Acta Veterinaria Scandinavia 48: 24.CrossRefGoogle ScholarPubMed
Besier, S, Ludwig, A, Ohlsen, K, Brade, V and Wichelhaus, TA (2007). Molecular analysis of the thymidine-auxotrophic small colony variant phenotype of Staphylococcus aureus. International Journal of Medical Microbiology 297: 217225.CrossRefGoogle ScholarPubMed
Brouillette, E, Martinez, A, Boyll, BJ, Allen, NE and Malouin, F (2004). Persistence of a Staphylococcus aureus small-colony variant under antibiotic pressure in vivo. FEMS Immunology and Medical Microbiology 41: 3541.CrossRefGoogle ScholarPubMed
Call, DR, Davis, MA and Sawant, AA (2008). Antimicrobial resistance in beef and dairy cattle production. Animal Health Research Reviews 9: 159167.Google Scholar
Casadevall, A (2008). Evolution of intracellular pathogens. Annual Review of Microbiology 62: 1933.CrossRefGoogle ScholarPubMed
Chatterjee, I, Kriegeskorte, A, Fischer, A, Deiwick, S, Theimann, N, Proctor, RA, Peters, G, Herrmann, M and Kahl, BC (2008). In vivo mutations of thymidylate synthase (encoded by thyA) are responsible for thymidine dependency in clinical small-colony variants of Staphylococcus aureus. Journal of Bacteriology 190: 834842.CrossRefGoogle ScholarPubMed
Cifrian, E, Guidry, AJ, O'Brien, CN, Nickerson, SC and Marquardt, WW (1994). Adherence of Staphylococcus aureus to cultured bovine mammary epithelial cells. Journal of Dairy Science 77: 970983.Google Scholar
Clarke, SR and Foster, SJ (2006). Surface adhesins of Staphylococcus aureus. Advances in Microbial Physiology 51: 187224.CrossRefGoogle ScholarPubMed
Crawley, AM, Mallard, B and Wilkie, BN (2005). Genetic selection for high and low immune response in pigs: effects on immunoglobulin isotype expression. Veterinary Immunology and Immunopathology 108: 7176.Google Scholar
Dziewanowska, K, Carson, AR, Patti, JM, Deobald, CF, Bayles, KW and Bohach, GA (2000). Staphylococcal fibronectin binding protein interacts with heat shock protein 60 and integrins: role in internalization by epithelial cells. Infection and Immunity 68: 63216328.CrossRefGoogle ScholarPubMed
Dziewanowska, K, Patti, JM, Deobald, CF, Bayles, KW, Trumble, WR and Bohach, GA (1999). Fibronectin binding protein and host cell tyrosine kinase are required for internalization of Staphylococcus aureus by epithelial cells. Infection and Immunity 67: 46734678.CrossRefGoogle ScholarPubMed
Erskine, R, Cullor, J, Schaellibaum, M, Yancey, B and Zecconi, A (2004). Bovine Mastitis Pathogens and Trends in Resistance to Antimicrobial Drugs. Verona, WI: National Mastitis Council, pp. 400414.Google Scholar
Erskine, RJ, Walker, RD, Bolin, CA, Bartlett, PC and White, DG (2002). Trends in antibacterial susceptibility of mastitis pathogens during a seven-year period. Journal of Dairy Science 85: 11111118.Google Scholar
Estes, DM and Brown, WC (2002). Type 1 and type 2 responses in regulation of Ig isotype expression in cattle. Veterinary Immunology and Immunopathology 90: 110.CrossRefGoogle ScholarPubMed
Foster, TJ (2004). The Staphylococcus aureus “superbug”. Journal of Clinical Investigation 114: 16931696.CrossRefGoogle ScholarPubMed
Frost, AJ (1975). Selective adhesion of microorganisms to the ductular epithelium of the bovine mammary gland. Infection and Immunity 12: 11541156.Google Scholar
Frost, AJ, Wanasinghe, DD and Woolcock, JB (1977). Some factors affecting selective adherence of microorganisms in the bovine mammary gland. Infection and Immunity 15: 245253.Google Scholar
Garzoni, C and Kelley, WL (2009). Staphylococcus aureus: new evidence for intracellular persistence. Trends in Microbiology 17: 5965.Google Scholar
Gilligan, PH, Gage, PA, Welch, DF, Muszynski, MJ and Wait, KR (1987). Prevalence of thymidine-dependent Staphylococcus aureus in patients with cystic fibrosis. Journal of Clinical Microbiology 25: 12581261.CrossRefGoogle ScholarPubMed
Goudie, JG and Goudie, RB (1955). Recurrent infections by a stable dwarf-colony variant of Staphylococcus aureus. Journal of Clinical Pathology 8: 284287.CrossRefGoogle ScholarPubMed
Gresham, HD, Lowrance, JH, TCaver, TE, Wilson, BS, Cheung, AL and Lindberg, FP (2000). Survival of Staphylococcus aureus inside neutrophils contributes to infection. Journal of Immunology 164: 37133722.Google Scholar
Gruenheid, S and Finlay, BB (2003). Microbial pathogenesis and cytoskeletal function. Nature 422: 775781.CrossRefGoogle ScholarPubMed
Gudding, R, McDonald, JS and Cheville, NF (1984). Pathogenesis of Staphylococcus aureus mastitis: bacteriologic, histologic, and ultrastructural pathologic findings. American Journal of Veterinary Research 45: 25252531.Google Scholar
Hendriksen, RS, Mevius, DJ, Schroeter, A, Teale, C, Meunier, D, Butaye, P, Franco, A, Utinane, A, Amado, A, Moreno, M, Greko, C, Stark, K, Berghold, C, Myllyniemi, AL, Wasyl, D, Sunde, M and Aarestrup, FM (2008). Prevalence of antimicrobial resistance among bacterial pathogens isolated from cattle in different European countries: 2002–2004. Acta Veterinaria Scandinavia 50: 28.CrossRefGoogle ScholarPubMed
Hensen, SM, Pavicic, MJ, Lohuis, JA and Poutrel, B (2000). Use of bovine primary mammary epithelial cells for the comparison of adherence and invasion ability of Staphylococcus aureus strains. Journal of Dairy Science 83: 418429.CrossRefGoogle ScholarPubMed
Hoffman, LR, Deziel, E, D'Argenio, DA, Lepine, F, Emerson, J, McNamara, S, Gibson, RL, Ramsey, BW and Miller, SI (2006). Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa. Proceedings of the National Academy of Sciences USA 103: 1989019895.Google Scholar
Hussain, M, Haggar, A, Peters, G, Chhatwal, GS, Herrmann, M, Flock, JI and Sinha, B (2008). More than one tandem repeat domain of the extracellular adherence protein of Staphylococcus aureus is required for aggregation, adherence, and host cell invasion but not for leukocyte activation. Infection and Immunity 76: 56155623.CrossRefGoogle Scholar
Jonsson, IM, von, EC, Proctor, RA, Peters, G, Ryden, C and Tarkowski, A (2003). Virulence of a hemB mutant displaying the phenotype of a Staphylococcus aureus small colony variant in a murine model of septic arthritis. Microbial Pathogenesis 34: 7379.CrossRefGoogle Scholar
Juhász-Kaszanyitzky, E, Janosi, S, Somogyi, P, Dan, A, van der Graaf-van Bloois, L, van Duijkeren, E and Wagenaar, JA (2007). MRSA transmission between cows and humans. Emerging Infectious Diseases 13: 630632.CrossRefGoogle ScholarPubMed
Kahl, B, Herrmann, M, Everding, AS, Koch, HG, Becker, K, Harms, E, Proctor, RA and Peters, G (1998). Persistent infection with small colony variant strains of Staphylococcus aureus in patients with cystic fibrosis. Journal of Infectious Diseases 177: 10231029.CrossRefGoogle ScholarPubMed
Kahl, BC, Belling, G, Becker, P, Chatterjee, I, Wardecki, K, Hilgert, K, Cheung, AL, Peters, G and Herrmann, M (2005). Thymidine-dependent Staphylococcus aureus small-colony variants are associated with extensive alterations in regulator and virulence gene expression profiles. Infection and Immunity 73: 41194126.CrossRefGoogle ScholarPubMed
Kahl, BC, Duebbers, A, Lubritz, G, Haeberle, J, Koch, HG, Ritzerfeld, B, Reilly, M, Harms, E, Proctor, RA, Herrmann, M and Peters, G (2003). Population dynamics of persistent Staphylococcus aureus isolated from the airways of cystic fibrosis patients during a 6-year prospective study. Journal of Clinical Microbiology 41: 44244427.Google Scholar
Kahl, BC, Goulian, M, van, WW, Herrmann, M, Simon, SM, Kaplan, G, Peter, G and Cheung, AL (2000). Staphylococcus aureus RN6390 replicates and induces apoptosis in a pulmonary epithelial cell line. Infection and Immunity 68: 53855392.CrossRefGoogle Scholar
Kerro, DO, van Dijk, JE and Nederbragt, H (2002). Factors involved in the early pathogenesis of bovine Staphylococcus aureus mastitis with emphasis on bacterial adhesion and invasion: a review. Veterinary Quarterly 24: 181198.Google Scholar
Kohler, C, von, EC, Liebeke, M, McNamara, PJ, Lalk, M, Proctor, RA, Hecker, M and Engelmann, S (2008). A defect in menadione biosynthesis induces global changes in gene expression in Staphylococcus aureus. Journal of Bacteriology 190: 63516364.CrossRefGoogle ScholarPubMed
Lammers, A, Nuijten, PJ, Kruijt, E, Stockhofe-Zurwieden, N, Vecht, U, Smith, HE and van Zijderveld, FG (1999). Cell tropism of Staphylococcus aureus in bovine mammary gland cell cultures. Veterinary Microbiology 67: 7789.Google Scholar
Lannergård, J, von, EC, Sander, G, Cordes, T, Seggewiss, J, Peters, G, Proctor, RA, Becker, K and Hughes, D (2008). Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 52: 40174022.CrossRefGoogle ScholarPubMed
Lattar, SM, Tuchscherr, LP, Caccuri, RL, Centron, D, Becker, K, Alonso, CA, Barberis, C, Miranda, G, Buzzola, FR, von, EC and Sordelli, DO (2009). Capsule expression and genotypic differences among Staphylococcus aureus isolates from patients with chronic or acute osteomyelitis. Infection and Immunity 77: 19681975.CrossRefGoogle ScholarPubMed
Lebeau, C, Vandenesch, F, Greenland, T, Novick, RP and Etienne, J (1994). Coagulase expression in Staphylococcus aureus is positively and negatively modulated by an agr-dependent mechanism. Journal of Bacteriology 176: 55345536.Google Scholar
Lee, JH (2003). Methicillin (Oxacillin)-resistant Staphylococcus aureus strains isolated from major food animals and their potential transmission to humans. Applied and Environmental Microbiology 69: 64896494.CrossRefGoogle ScholarPubMed
Lindsay, JA and Holden, MA (2006). Understanding the rise of the superbug: investigation of the evolution and genomic variation of Staphylococcus aureus. Functional and Integrative Genomics 6: 186201.Google Scholar
Lowy, FD, Fant, J, Higgins, LL, Ogawa, SK and Hatcher, VB (1988). Staphylococcus aureus–human endothelial cell interactions. Journal of Ultrastructure and Molecular Structure Research 98: 137146.CrossRefGoogle ScholarPubMed
Luzio, JP, Pryor, PR and Bright, NA (2007). Lysosomes: fusion and function. Nature Reviews Molecular Cell Biology 8: 622632.CrossRefGoogle ScholarPubMed
Massey, RC, Buckling, A and Peacock, SJ (2001). Phenotypic switching of antibiotic resistance circumvents permanent costs in Staphylococcus aureus. Current Biology 11: 18101814.Google Scholar
McNamara, PJ and Proctor, RA (2000). Staphylococcus aureus small colony variants, electron transport and persistent infections. International Journal of Antimicrobial Agents 14: 117122.CrossRefGoogle ScholarPubMed
Menzies, BE (2003). The role of fibronectin binding proteins in the pathogenesis of Staphylococcus aureus infections. Current Opinion in Infectious Diseases 16: 225229.Google Scholar
Menzies, BE and Kourteva, I (1998). Internalization of Staphylococcus aureus by endothelial cells induces apoptosis. Infection and Immunity 66: 59945998.CrossRefGoogle ScholarPubMed
Miller, MH, Edberg, SC, Mandel, LJ, Behar, CF and Steigbigel, NH (1980). Gentamicin uptake in wild-type and aminoglycoside-resistant small-colony mutants of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 18: 722729.Google Scholar
Mitchell, G, Lamontagne, CA, Brouillette, E, Grondin, G, Talbot, BG, Grandbois, M and Malouin, F (2008). Staphylococcus aureus SigB activity promotes a strong fibronectin–bacterium interaction which may sustain host tissue colonization by small-colony variants isolated from cystic fibrosis patients. Molecular Microbiology 70: 15401555.CrossRefGoogle Scholar
Moisan, H, Brouillette, E, Jacob, CL, Langlois-Begin, P, Michaud, S and Malouin, F (2006). Transcription of virulence factors in Staphylococcus aureus small-colony variants isolated from cystic fibrosis patients is influenced by SigB. Journal of Bacteriology 188: 6476.CrossRefGoogle ScholarPubMed
Monecke, S, Kuhnert, P, Hotzel, H, Slickers, P and Ehricht, R (2007). Microarray based study on virulence-associated genes and resistance determinants of Staphylococcus aureus isolates from cattle. Veterinary Microbiology 125: 128140.CrossRefGoogle Scholar
Moon, JS, Lee, AR, Kang, HM, Lee, ES, Joo, YS, Park, YH, Kim, MN and Koo, HC (2007). Antibiogram and coagulase diversity in staphylococcal enterotoxin-producing Staphylococcus aureus from bovine mastitis. Journal of Dairy Science 90: 17161724.CrossRefGoogle ScholarPubMed
Moreillon, P, Entenza, JM, Francioli, P, McDevitt, D, Foster, TJ, Francois, P and Vaudaux, P (1995). Role of Staphylococcus aureus coagulase and clumping factor in pathogenesis of experimental endocarditis. Infection and Immunity 63: 47384743.CrossRefGoogle ScholarPubMed
Morgan, M (2008). Methicillin-resistant Staphylococcus aureus and animals: zoonosis or humanosis? Journal of Antimicrobial Chemotherapy 62: 11811187.CrossRefGoogle ScholarPubMed
Murai, M, Sakurada, J, Seki, K, Shinji, H, Hirota, Y and Masuda, S (1999). Apoptosis observed in BALB/3T3 cells having ingested Staphylococcus aureus. Microbiology and Immunology 43: 653661.CrossRefGoogle ScholarPubMed
Musher, DM, Baughn, RE, Templeton, GB and Minuth, JN (1977). Emergence of variant forms of Staphylococcus aureus after exposure to gentamicin and infectivity of the variants in experimental animals. Journal of Infectious Diseases 136: 360369.CrossRefGoogle ScholarPubMed
Opdebeeck, JP, Frost, AJ and O'Boyle, D (1988). Adhesion of Staphylococcus aureus and Escherichia coli to bovine udder epithelial cells. Veterinary Microbiology 16: 7786.Google Scholar
Phonimdaeng, P, O'Reilly, M, Nowlan, P, Bramley, AJ and Foster, TJ (1990). The coagulase of Staphylococcus aureus 8325–4. Sequence analysis and virulence of site-specific coagulase-deficient mutants. Molecular Microbiology 4: 393404.Google Scholar
Proctor, RA, Balwit, JM and Vesga, O (1994). Variant subpopulations of Staphylococcus aureus as cause of persistent and recurrent infections. Infectious Agents and Disease 3: 302312.Google Scholar
Proctor, RA and Peters, G (1998). Small colony variants in staphylococcal infections: diagnostic and therapeutic implications. Clinical Infectious Diseases 27: 419422.CrossRefGoogle ScholarPubMed
Proctor, RA, van, LP, Kristjansson, M, Maslow, JN and Arbeit, RD (1995). Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. Clinical Infectious Diseases 20: 95102.Google Scholar
Proctor, RA, Kahl, B, von, EC, Vaudaux, PE, Lew, DP and Peters, G (1998). Staphylococcal small colony variants have novel mechanisms for antibiotic resistance. Clinical Infectious Diseases 27 (suppl. 1): S68S74.Google Scholar
Proctor, RA, von Eiff, C, Kahl, BC, Becker, K, McNamara, P, Herrmann, M and Peters, G (2006). Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nature Reviews Microbiology 4: 295305.CrossRefGoogle ScholarPubMed
Sadowska, B, Bonar, A, von Eiff, C, Proctor, RA, Chmiela, M, Rudnicka, W and Rozalska, B (2002). Characteristics of Staphylococcus aureus, isolated from airways of cystic fibrosis patients, and their small colony variants. FEMS Immunology and Medical Microbiology 32: 191197.CrossRefGoogle ScholarPubMed
Schaaff, F, Bierbaum, G, Baumert, N, Bartmann, N and Sahl, HG (2003). Mutations are involved in emergence of aminoglycoside-induced small colony variants of Staphylococcus aureus. International Journal of Medical Microbiology 293: 427435.CrossRefGoogle ScholarPubMed
Schröder, A, Kland, R, Peschel, A, von Eiff, C and Aepfelbacher, M (2006). Live cell imaging of phagosome maturation in Staphylococcus aureus infected human endothelial cells: small colony variants are able to survive in lysosomes. Medical Microbiology and Immunology 195: 185194.CrossRefGoogle ScholarPubMed
Seggewiss, J, Becker, K, Kotte, O, Eisenacher, M, Yazdi, MR, Fischer, A, McNamara, P, Al, LN, Proctor, R, Peters, G, Heinemann, M and von Eiff, C (2006). Reporter metabolite analysis of transcriptional profiles of a Staphylococcus aureus strain with normal phenotype and its isogenic hemB mutant displaying the small-colony-variant phenotype. Journal of Bacteriology 188: 77657777.Google Scholar
Seifert, H, von Eiff, C and Fatkenheuer, G (1999). Fatal case due to methicillin-resistant Staphylococcus aureus small colony variants in an AIDS patient. Emerging Infectious Diseases 5: 450453.CrossRefGoogle Scholar
Sendi, P and Proctor, RA (2009). Staphylococcus aureus as an intracellular pathogen: the role of small colony variants. Trends in Microbiology 17: 5458.CrossRefGoogle ScholarPubMed
Senn, MM, Bischoff, M, von Eiff, C and Berger-Bachi, B (2005). sigmaB activity in a Staphylococcus aureus hemB mutant. Journal of Bacteriology 187: 73977406.Google Scholar
Sifri, CD, Baresch-Bernal, A, Calderwood, SB and von Eiff, C (2006). Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model. Infection and Immunity 74: 10911096.Google Scholar
Sinha, B, Francois, PP, Nusse, O, Foti, M, Hartford, OM, Vaudaux, P, Foster, TJ, Lew, DP, Herrmann, M and Krause, KH (1999). Fibronectin-binding protein acts as Staphylococcus aureus invasion via fibronectin bridging to integrin alpha5beta1. Cellular Microbiology 1: 101117.CrossRefGoogle ScholarPubMed
Sinha, B and Fraunholz, M (2010). Staphylococcus aureus host cell invasion and post-invasion events. International Journal of Medical Microbiology 300: 170175.CrossRefGoogle ScholarPubMed
Sinha, B and Herrmann, M (2005). Mechanism and consequences of invasion of endothelial cells by Staphylococcus aureus. Thrombosis and Haemostasis 94: 266277.Google Scholar
Smagur, J, Guzik, K, Magiera, L, Bzowska, M, Gruca, M, Thogersen, IB, Enghild, JJ and Potempa, J (2009). A new pathway of staphylococcal pathogenesis: apoptosis-like death induced by Staphopain B in human neutrophils and monocytes. Journal of Innate Immunity 1: 98108.CrossRefGoogle ScholarPubMed
Sompolinsky, D, Cohen, M and Ziv, G (1974). Epidemiological and biochemical studies on thiamine-less dwarf-colony variants of Staphylococcus aureus as etiological agents of bovine mastitis. Infection and Immunity 9: 217228.Google Scholar
Sordillo, LM, Doymaz, MZ and Oliver, SP (1989). Morphological study of chronic Staphylococcus aureus mastitis in the lactating bovine mammary gland. Research in Veterinary Science 47: 247252.CrossRefGoogle ScholarPubMed
Sutra, L and Poutrel, B (1994). Virulence factors involved in the pathogenesis of bovine intramammary infections due to Staphylococcus aureus. Journal of Medical Microbiology 40: 7989.CrossRefGoogle ScholarPubMed
Swingle, EL (1935). Studies on small colony variants of Staphylococcus aureus. Journal of Bacteriology 29: 467489.Google Scholar
Tollersrud, T, Kampen, AH and Kenny, K (2006). Staphylococcus aureus enterotoxin D is secreted in milk and stimulates specific antibody responses in cows in the course of experimental intramammary infection. Infection and Immunity 74: 35073512.CrossRefGoogle ScholarPubMed
Vanderhaeghen, W, Cerpentier, T, Adriaensen, C, Vicca, J, Hermans, K and Butaye, P (2010). Methicillin-resistant Staphylococcus aureus (MRSA) ST398 associated with clinical and subclinical mastitis in Belgian cows. Veterinary Microbiology 144: 166171.CrossRefGoogle ScholarPubMed
Vann, JM and Proctor, RA (1987). Ingestion of Staphylococcus aureus by bovine endothelial cells results in time- and inoculum-dependent damage to endothelial cell monolayers. Infection and Immunity 55: 21552163.CrossRefGoogle ScholarPubMed
Vaudaux, P, Francois, P, Bisognano, C, Kelley, WL, Lew, DP, Schrenzel, J, Proctor, RA, McNamara, PJ, Peters, G and von Eiff, C (2002). Increased expression of clumping factor and fibronectin-binding proteins by hemB mutants of Staphylococcus aureus expressing small colony variant phenotypes. Infection and Immunity 70: 54285437.CrossRefGoogle ScholarPubMed
Vesga, O, Groeschel, MC, Otten, MF, Brar, DW, Vann, JM and Proctor, RA (1996). Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. Journal of Infectious Diseases 173: 739742.CrossRefGoogle ScholarPubMed
Vintov, J, Aarestrup, FM, Zinn, CE and Olsen, JE (2003). Association between phage types and antimicrobial resistance among bovine Staphylococcus aureus from 10 countries. Veterinary Microbiology 95: 133147.CrossRefGoogle ScholarPubMed
von Eiff, C (2008). Staphylococcus aureus small colony variants: a challenge to microbiologists and clinicians. International Journal of Antimicrobial Agents 31: 507510.CrossRefGoogle ScholarPubMed
von Eiff, C, Heilmann, C, Proctor, RA, Woltz, C, Peters, G and Gotz, F (1997). A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persists intracellularly. Journal of Bacteriology 179: 47064712.CrossRefGoogle ScholarPubMed
von Eiff, C, Proctor, RA and Peters, G (2000). Small colony variants of Staphylococci: a link to persistent infections. Berliner und Munchener Tierarztliche Wochenschrift 113: 321325.Google ScholarPubMed
von Eiff, C, Peters, G and Becker, K (2006). The small colony variant (SCV) concept – the role of staphylococcal SCVs in persistent infections. Injury 37 (suppl. 2): S26S33.CrossRefGoogle ScholarPubMed
Voyich, JM, Braughton, KR, Sturdevant, DE, Whitney, AR, Said-Salim, B, Porcella, SF, Long, RD, Dorward, DW, Gardner, DJ, Kreiswirth, BN, Musser, JM and DeLeo, FR (2005). Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils. Journal of Immunology 175: 39073919.Google Scholar
Wanasinghe, DD (1981). Adherence as a prerequisite for infection of the bovine mammary gland by bacteria. Acta Veterinaria Scandinavia 22: 109117.Google Scholar
Weidenmaier, C and Peschel, A (2008). Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions. Nature Reviews Microbiology 6: 276287.Google Scholar
Werckenthin, C, Cardoso, M, Martel, JL and Schwarz, S (2001). Antimicrobial resistance in staphylococci from animals with particular reference to bovine Staphylococcus aureus, porcine Staphylococcus hyicus, and canine Staphylococcus intermedius. Veterinary Research 32: 341362.Google Scholar
Wesson, CA, Deringer, J, Liou, LE, Bayles, KW, Bohach, GA and Trumble, WR (2000). Apoptosis induced by Staphylococcus aureus in epithelial cells utilizes a mechanism involving caspases 8 and 3. Infection and Immunity 68: 29983001.Google Scholar
Wise, RI and Spink, WW (1954). The influence of antibiotics on the origin of small colonies (G variants) of Micrococcus pyogenes var. aureus. Journal of Clinical Investigation 33: 16111622.CrossRefGoogle ScholarPubMed