The Rsp virulence regulator: new review in Trends in Microbiology

In the September issue of Trends in Microbiology, Mark Smeltzer casts the spotlight on the story of rsp, a virulence regulator in Staphylococcus aureus that evolves within infected patients and may play a role in disease.

The new review covers recent work on the rsp gene including a series papers that my collaborators and my group have contributed: 
Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation.
Das, S., Lindemann, C., Young, B. C., Muller, J., Österreich, B., Ternette, N., Winkler, A.-C., Paprotka, K., Reinhardt, R., Förstner, K. U., Allen, E., Flaxman, A., Yamaguchi, Y., Rollier, C. S., Van Diemen, P., Blättner, S., Remmele, C. W., Selle, M., Dittrich, M., Müller, T., Vogel, J., Ohlsen, K., Crook, D., Massey, R., Wilson, D. J., Rudel, T., Wyllie, D. H., and M. J. Fraunholz (2016)
Proceedings of the National Academy of Sciences USA 113: E3101–E3110. (abstract pdf)

Evolutionary trade-offs underlie the multi-faceted virulence of Staphylococcus aureus.
Laabei, M., Uhlemann, A.-C., Lowy, F. D., Austin, E. D., Yokoyama, M., Ouadi, K., Feil, E., Thorpe, H. A., Williams, B., Perkins, M., Peacock, S. J., Clarke, S. R., Dordel, J., Holden, M., Votintseva, A. A., Bowden, R., Crook, D. W., Young, B. C., Wilson, D. J., Recker, M. and R. C. Massey (2015)
PLoS Biology 13: e1002229. (abstract pdf)

Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease.
Young, B. C., Golubchik, T., Batty, E. M., Fung, R., Larner-Svennson, H., Votintseva, A., Miller, R. R., Godwin, H., Knox, K., Everitt, R. G., Iqbal, Z., Rimmer, A. J., Cule, M., Ip C. L. C., Didelot, X., Harding, R. M., Donnelly, P. J., Peto, T. E., Crook, D. W., Bowden, R. and D. J. Wilson (2012)
Proceedings of the National Academy of Sciences USA 109: 4550-4555. (abstract pdf F1000)

New paper: How low-toxic Staph. aureus mutants cause severe infections

Published today in PNAS Early Edition, our new paper that reveals naturally occurring mutations in the poorly-described rsp gene of Staph. aureus
reduce toxicity while maintaining the ability to survive, proliferate and cause infection within the human body.

In previous work, we have found that Staph. aureus evolves by mutation within the body quickly enough to influence the progression of disease, and that diversity generated by evolution in the body is a widespread phenomenon. In the case of one patient who we followed longitudinally for over a year, we identified that bacteria in the bloodstream differed from those in the nose by several mutations, of which a loss-of-function mutation in the rsp regulatory gene represented the most likely candidate for playing a possible role in causing severe infection.

We collaborated with Ruth Massey at Bath who discovered to our surprise that while rsp loss-of-function mutants do indeed show differences in toxicity - one of several traditional correlates of virulence readily measured in the laboratory - they showed reduced toxicity. Going further, Ruth and her collaborators showed that bloodstream infections in general show reduced toxicity compared to milder skin infections and asymptomatically carried nose populations, overturning previous views on the relationship between Staph. aureus toxicity and virulence.

Today's new paper offers a detailed dissection of rsp. Working with Claudia Lindemann and David Wyllie at the University of Oxford and Martin Fraunholz and collaborators at the University of Würzburg, we found that although rsp mutants show reduced toxicity, crucially they retain their capacity to survive, grow, spread through the body and cause abscesses. In other words, rsp uncouples toxicity from pathogenicity. This decoupling could be important for evading the immune system and establishing severe infections. To find out more, see the full paper.