Promiscuous bacteria have staying power

An insight article with Ruth Massey on John Lees' and Stephen Bentley's new paper was published in eLife on Friday:

Streptococcus pneumoniae is a notorious bacterial pathogen hiding in plain sight. A common resident of the nose and throat, between 68% and 84% of young infants will carry this species at any given time (Turner et al., 2012). In most cases it causes no harm, yet the presence of pneumococci – as the bacteria are known – can predispose a person to life-threatening infections like pneumonia or meningitis. Indeed, pneumococci are responsible for around 10% of all deaths in young children around the world (O'Brien et al., 2009), with the vast majority of cases being in developing countries.
Research into S. pneumoniae is complicated because the species is a patchwork of distinctive strains and some of these strains remain in the nose and throat for longer than others. Now, in eLife, John Lees and Stephen Bentley – both at the Wellcome Trust Sanger Institute – and colleagues report that strains rendered impotent by a virus do not linger for as long as other strains (Lees et al., 2017).

Click here to read the full piece.

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.

PLoS Biology: Staphylococcus aureus invading the blood are less toxic

Toxicity in nose, blood and skin bacteria.

Collaborative work with Ruth Massey's group at the University of Bath taking forward a study of within-host evolution of Staphylococcus aureus during infection has been published in PLoS Biology. Previously we reported in PNAS that in one patient, bacteria causing a serious bloodstream infection differed by just eight mutations from a persistently carried nose population. We identified one of those mutations as playing a potentially causative role in transforming the nose bacteria into a form capable of bloodstream infection - a regulatory protein called rsp. To investigate further, Ruth applied a number of tests to characterize bacteria taken prior to and during infection. In this new paper, we report the surprising result that the bloodstream isolates show reduced toxicity and that rsp is the responsible for this change.

The notion that isolates responsible for serious human infection are less toxic challenges some long-held beliefs about the mechanism of disease in Staphylococcus aureus infections. Most models of disease assume a straightforward relationship between increased toxicity and greater virulence - the propensity to cause, or severity of, disease.

To test her observation, Ruth collaborated with groups from New York and Cambridge to investigate whether the pattern observed in one patient held more generally across 134 Staphylococcus aureus belonging to the notorious USA300 strain. It did.

Curiously, bacteria isolated from the skin and from superficial infections were equally toxic to nose bacteria. These findings raise new questions about the role of toxicity in colonization, transmission and serious infections of Staphylococcus aureus. One possibility that we wish to investigate further is whether toxicity might be required for the usual transmission of Staphylococcus aureus populations in the nose, skin or superficial infections (such as impetigo), whereas loss of toxicity may promote transition to deep tissue and bloodstream infections by evading immune defences.