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DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection

Nature Medicine volume 13, pages 981–985 (2007)Cite this article

Abstract

Most invasive bacterial infections are caused by species that more commonly colonize the human host with minimal symptoms. Although phenotypic or genetic correlates underlying a bacterium's shift to enhanced virulence have been studied, the in vivo selection pressures governing such shifts are poorly understood. The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with the rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome1. Mutations in the GAS control of virulence regulatory sensor kinase (covRS) operon are associated with severe invasive disease, abolishing expression of a broad-spectrum cysteine protease (SpeB)2,3 and allowing the recruitment and activation of host plasminogen on the bacterial surface4. Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps5,6, serves as a selective force for covRS mutation. The results provide a paradigm whereby natural selection exerted by the innate immune system generates hypervirulent bacterial variants with increased risk of systemic dissemination.

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Figure 1: Molecular and phenotypic analyses of GAS strains 5448 and 5448AP.
Figure 2: Contribution of Sda1 to neutrophil survival and SpeB phenotype-switching.
Figure 3: Model for group A streptococcal invasive disease initiation and progression.

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Acknowledgements

The authors wish to thank A. Jeng and K. Chalasani for constructing the isogenic mutant 5448Δsmez, and R. Attia for assisting with real-time PCR. A. Hollands and A. Henningham are recipients of Australian Postgraduate Awards. This work was supported by the National Health and Medical Research Council of Australia 459103 (M.J.W.), US National Institutes of Health grant AI48176 (V.N.) and a Department of Employment Science and Technology (Australia) International Science Linkages grant CG001195 (M.J.W., V.N., M.K.). The authors thank G. Ellmers and R. Dinnervill for illustrating Figure 3, and M. Wilson for critically reading this manuscript.

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Authors and Affiliations

  1. School of Biological Sciences, University of Wollongong, Wollongong, 2522, New South Wales, Australia

    Mark J Walker, Andrew Hollands, Martina L Sanderson-Smith, Jason N Cole, Joshua K Kirk, Anna Henningham & Jason D McArthur

  2. Department of Microbial Pathogenesis and Vaccine Development, Helmholtz Centre for Infection Research, Braunschweig, D-38124, Germany

    Katrin Dinkla & Gursharan S Chhatwal

  3. Department of Microbiology and Immunology, Cairo University, Cairo, Egypt

    Ramy K Aziz

  4. The Veterans Affairs Medical Center, Memphis, 38163, Tennessee, USA

    Ramy K Aziz, Rita G Kansal & Malak Kotb

  5. The MidSouth Center for Biodefense and Security, Memphis, 38163, Tennessee, USA

    Rita G Kansal & Malak Kotb

  6. Department of Pediatrics, University of California San Diego, La Jolla, 92093-0687, California, USA

    Amelia J Simpson, John T Buchanan & Victor Nizet

  7. Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, 92093-0687, California, USA

    Victor Nizet

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Contributions

M.L.S.-S. and M.J.W. constructed strain 5448RCsda1+. A. Hollands and V.N. constructed strains 5448Δska and 5448Δemm1. M.J.W., J.N.C., J.K.K., A. Hollands and R.K.A. undertook covRS DNA sequence analysis. K.D. and G.S.C. undertook plasminogen binding assays. M.J.W., A. Hollands, J.N.C., and J.K.K. performed SpeB, surface plasmin and western blot analyses. A. Hollands, M.L.S.-S., J.N.C., J.K.K., A. Henningham, J.D.M. and M.J.W. performed survival curves and SpeB phenotype switching studies. M.J.W. and R.G.K. implanted mouse infection chambers and R.K.A., R.G.K. and M.K. undertook real-time PCR analysis. A.J.S., J.T.B., A. Hollands, M.J.W. and V.N. performed DNA NET and neutrophil killing assays. M.J.W., G.S.C., M.K. and V.N. supervised the project. M.J.W. coordinated the project. M.J.W., A. Hollands, M.L.S.-S., J.N.C., R.K.A., R.G.K., J.T.B., G.S.C., M.K. and V.N. contributed to writing the manuscript.

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Correspondence to Mark J Walker.

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Supplementary Figures 1–4, Supplementary Tables 1–3, Supplementary Methods (PDF 504 kb)

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Walker, M., Hollands, A., Sanderson-Smith, M. et al. DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat Med 13, 981–985 (2007). https://doi.org/10.1038/nm1612

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