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

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 <1%. We suggest, however, that the SCV phenotype is not rare but, instead, is extremely difficult to recover. The issues that are associated with isolating and identifying SCVs in the clinical microbiology laboratory are also discussed.

Abstract

Small colony variants constitute a slow-growing subpopulation of bacteria with distinctive phenotypic and pathogenic traits. Phenotypically, small colony variants have a slow growth rate, atypical colony morphology and unusual biochemical characteristics, making them a challenge for clinical microbiologists to identify. Clinically, small colony variants are better able to persist in mammalian cells and are less susceptible to antibiotics than their wild-type counterparts, and can cause latent or recurrent infections on emergence from the protective environment of the host cell. This Review covers the phenotypic, genetic and clinical picture associated with small colony variants, with an emphasis on staphylococci, for which the greatest amount of information is available.

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Figure 1: Small colony variants.
Figure 2: Hypothetical model of the metabolic and energetic pathways that are associated with the small colony variant (SCV) phenotype.
Figure 3: Haemin-auxotrophic small colony variants.
Figure 4: Thymidine-auxotrophic small colony variants (SCVs).
Figure 5: Altered cellular morphology of haemin-auxotrophic small colony variants.

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Acknowledgements

A list of additional references related to SCVs is available online (see Supplementary information S2 (box)). This work was supported by grants from the National Institutes of Health (United States) to R.A.P. and P.M., by a grant from the Bundesministerium für Bildung und Forschung (Germany) (Pathogenomic Network: Alliance Gram-positive cocci, Project staphylococci) to C.v.E., K.B. and G.P., and by grants from the Deutsche Forschungsgemeinschaft (Germany) to B.C.K. and C.v.E.

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DATABASES

Entrez Genome Project

Bacillus subtilis

Brucella melitensis

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Lactobacillus acidophilus

Neisseria gonorrhoeae

Pseudomonas aeruginosa

Salmonella enterica

Serratia marcescens

Staphylococcus aureus

Staphylococcus epidermidis

Vibrio cholerae

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Proctor, R., von Eiff, C., Kahl, B. et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4, 295–305 (2006). https://doi.org/10.1038/nrmicro1384

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