Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections

• Published in: Nature reviews. Microbiology 2006-04, Vol.4 (4), p.295-305
• Main Authors: Proctor, Richard A., von Eiff, Christof, Kahl, Barbara C., Becker, Karsten, McNamara, Peter, Herrmann, Mathias, Peters, Georg
• Format: Article
• Language: English
• Subjects: Aminoglycosides - pharmacology; Animals; Antibiotics; Bacteria; Bacteria - drug effects; Bacteria - genetics; Bacteria - pathogenicity; Bacterial Infections - drug therapy; Bacterial Infections - microbiology; Bacterial Infections - physiopathology; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Cytochrome; E coli; Genetic Variation; Genomes; Genotype & phenotype; Humans; Infectious Diseases; Life Sciences; Mammals; Medical Microbiology; Metabolism; Microbiology; Mutation; Parasitology; Phenotype; review-article; Salmonella; Staphylococcus aureus - enzymology; Staphylococcus aureus - genetics; Staphylococcus infections; Virology; Vitamin B
• ISSN: 1740-1526; 1740-1534
• DOI: 10.1038/nrmicro1384

Key Points Small colony variants (SCVs) of bacteria were first described almost 100 years ago. The first description of the SCV phenotype was for Salmonella enterica serovar Typhi ( S. typhi ), but SCVs have now been reported for a wide range of bacterial genera and species, including Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa . Most data have been collected for Staphylococcus aureus SCVs, so S. aureus SCVs are the focus of this Review article. As their name implies, the most conspicuous feature of SCVs is their colony size — SCVs form colonies that are almost one-tenth the size of colonies associated with wild-type bacteria. In addition, SCVs have fastidious growth requirements and therefore present a challenge to clinical microbiologists. In bacteria, slow growth can be caused by a variety of metabolic alterations. However, two defects are consistently associated with S. aureus SCVs isolated from clinical specimens: a deficiency in electron transport, and a deficiency in thymidine biosynthesis. Electron-transport-defective SCVs have a defect in the biosynthesis of menadione or haemin. Several mutations can produce the electron-transport-defective SCV phenotype, including mutations in menD and hemB , but the genetic basis of the electron-transport deficiency in vivo remains undefined and is a key area for future research. Curiously, the phenotype of thymidine-auxotrophic SCVs is nearly identical to that of SCVs with an electron-transport deficiency, and the basis for this is not understood. Again, the genetic basis of the thymidine deficiency in vivo is undefined and is a key area for future research. In this article, however, we propose that thymidine auxotrophs are double mutants, with a mutation in the gene that encodes NupC (a membrane-spanning protein involved in thymidine uptake) in addition to a mutation in the gene that encodes thymidylate synthase (ThyA). The specific disease states associated with SCV infection that are discussed here include cystic fibrosis and osteomyelitis. For the past decade, researchers have been investigating the connection between the SCV phenotype and persistent, recurrent infections; however, in this Review, we highlight that S. aureus SCVs can also cause aggressive infections in humans and animal models, and we suggest that SCVs are part of the normal life cycle of staphylococci. The incidence of SCVs in clinical specimens varies between studies and can be as high as 30% and as low as