Strep A pathogenesis and treatment

Discovering more about how group A streptococcus causes disease and developing treatments to combat it.

My research focuses on the mechanism by which the group A streptococcus (referred to as Streptococcus pyogenes; GAS or simply Strep A) causes invasive disease as well as the development of a vaccine. This bacterium is the cause of numerous suppurative diseases, ranging from mild skin infections such as pharyngitis, scarlet fever, impetigo and cellulitis, to more severe invasive diseases such as septicemia, streptococcal toxic shock syndrome and necrotizing fasciitis. Strep A is placed within the “top 10″ infectious disease causes of human deaths worldwide with Indigenous Australians suffering the highest rates of affliction in the world.

There are over 200 serotypes of Strep A with the most dominant, the M1T1 clone that emerged in the mid 1980's, historically causing the most infections and deaths. A new M1T1 variant has emerged around the world, designated M1uk, that is contributing to the recent upsurge in scarlet fever and Strep A invasive disease. It is imperative that we understand the mechanisms by which Strep A cause disease and develop new and effective treatment methods as well as a vaccine to prevent illness.

Key breakthroughs and discoveries

• Mu, A., Klare, W.P., Baines, S.L., Pang, C.N.I., Guerillot, R., Keller, N., Wilksch, J., Harbison-Price, N., Nhu, N.T.K., Phan, M.D., Keller, B., Nijagal, B., Tull, D., Dayalan, S., Chua, H.H.C., Skoneczny, D., Koval, J., Hachani, A., Shah, A.D., Neha, N., Jadhav, S., Partridge, S.R., Gustafsson, J., Cork, A.J., Peters,K., Brouwer, S., Hancock, S.J., Álvarez-Fraga, L., De Oliveira, D.M.P., Forde, B., Fitzgerald, A., Lum, M., Correa-Ospina, C., Roy Chowdhury, P., Parton, R.G., De Voss, J., Beckett, J., Monty, F., McKinnon, J., Song, X., Stephen, J.R., Everest, M., Bellgard, M.I., Tinning, M., Leeming, M., Wang, N., Ben Zakour, N., Yasar, S.A., Vecchiarelli, S., Russell, T., Zaw, T., Chen, T., Teng, D., Kassir, Z., Lithgow, T., Jenney, A., Sorrell, T.C., Peleg, A.Y., Paterson, D.L., Beatson, S.A., Wu, J., Molloy, M.P., Syme, A.E., Goode, R.J.A., Hunter, A.A., Bowland, G., West, N.P., Wilkins, M.R., Djordjevic, S.P., Davies, M.R., Seemann, T., Howden, B.P., Pascovici, D., Tyagi, S., Schittenhelm, R.B., De Souza, D.P., McConville, M.J., Iredell, J., Cordwell, S.J., Strugnell, R.A., Stinear, T.P., Schembri, M.A., Walker, M.J. (2023) Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.  Nature Communications 14: 1530.
• Davies, M.R., Keller, N., Brouwer, S., Cork, A.J., Jesperson, M.G., Hayes, A., de Oliveira, D.M.P.O, Harbison Price, N., Smith, H.V., Sanderson-Smith, M.L., Fang, N.X., Irwin, A.D., Grimwood, K., Jennison, A.V., Walker, M.J. (2023) Detection of Streptococcus pyogenes M1UK in Australia and characterization of the mutation driving enhanced expression of superantigen SpeA. Nature Communications 14: 1051.
• Brazel, E.B., Tan, A., Neville, S.L., Iverson, A.R., Udagedara, S.R., Cunningham, B.A., Sikanyika, M., De Oliveira, D.M.P, Steiner, B., Bohlmann, L., El-Deeb, I.M., Ganio, K., Eijkelkamp, B.A., McEwan, A.G., von Itzstein, M., Maher, M.J., Walker, M.J., Rosch, J.W., McDevitt, C.A. (2022) Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model. Cell Reports 38: 110202.  
• Osowicki, J., Azzopardi, K.I., Fabri, L., Frost, H.R., Rivera-Hernandez, T., et al, Walker, M.J., Carapetis, J.R., Smeesters, P.R., Steer, A.C.  (2021) A controlled human infection model of Streptococcus pyogenes pharyngitis. Lancet Microbe 2: e291-e299. 
• De Oliveira, D.M.P., Bohlmann, L., Conroy, T., Jen, F., Everest-Dass, A., Hansford, K.A., Bolisetti, R., El-Deeb, I.M., Forde, B.M., Phan, M.D., Lacey, J.A., Tan, A., Rivera-Hernandez, T., Brouwer, S., Keller, N., Kidd, T.J., Cork, A.J., Bauer, M.J., Cook, G.M., Davies, M.R., Beatson, S.A., Paterson, D.L., McEwan, A.G., Li, J., Schembri, M.A., Blaskovich, M.A.T., Jennings, M.P., McDevitt, C.A., von Itzstein, M., Walker, M.J. (2020) Repurposing a neurodegenerative disease drug to overcome Gram-negative antibiotic-resistant bacterial sepsis. Science Translational Medicine 12: eabb3791. 
• Brouwer, S., Barnett, T.C., Ly, D., Kasper, K.J., De Oliveira, D.M.P., Rivera-Hernandez, T., Cork, A.J., Richter, H., Dougan, G., Nizet, V., Yuen, K.Y., You, Y., McCormick, J.K., Sanderson-Smith, M.L., Davies, M.R., Walker, M.J. (2020) Prophage exotoxin genes enhance colonization fitness in North-East Asian scarlet fever-causing Streptococcus pyogenes. Nature Communications 11: 5018. 
• Davies, M.R., McIntyre, L., Mutreja, A., Lacey, J.A., Lees, J.A., Towers, R., Duchene, S., Smeeters, P.R., Frost, H.R., Price, D.J., Holden, M.T.G., David, S., Giffard, P.M., Worthing, K.A., Seale, A.C., Berkley, J.A., Harris, S.R., Rivera-Hernandez, T., Berking, O., Walker, A.J., de Almeida Torres, R.S., Lithgow, T., Strugnell, R.A., Bergmann, R., Nitsche-Schmitz, P., Chhatwal, G.S., Bentley, S.D., Fraser, J.D., Moreland, N.J., Carapetis, J.R., Steer, A.C., Parkhill, J., Saul, A., Williamson, D.A., Currie, B.J., Tong, S.Y.C., Dougan, G., Walker, M.J. (2019) Atlas of group A streptococcal vaccine candidates compiled using high-throughput genomics. Nature Genetics 51: 1035-1043. 
• Edgar, R.J., van Hensbergen, V.P., Ruda, A., Turner, A.G., Deng, P., Le Breton, Y., El-Sayed, N., Belew, A.T., McIver, K.S., McEwan, A.G., Morris, A.J., Lambeau, G., Walker, M.J., Rush, J.S., Korotkov, K.V., Widmalm, G., van Sorge, N.M., Korotkova, N. (2019) Insights into zinc and antimicrobial toxicity uncovers a glycerol phosphate modification on streptococcal rhamnose polysaccharides. Nature Chemical Biology 15: 463-471. 
• Walker, M.J., Brouwer, S., Sundac, L., Maloney, S., McIntyre, L., Barnett, T.C., Richter, J., Walker, A.J., Irwin, A.D., You, Y., Zhang, J.Z., Dougan, G., Yuen, K.Y., Nizet, V., Grimwood, K., Davies, M.R. (2019) Detection of epidemic scarlet fever group A Streptococcus in Australia. Clinical Infectious Diseases 69: 1232-1234. 
• You, Y., Davies, M.R., Cui, Y., Protani, M., McIntyre, L., Yang, R., Walker, M.J., Zhang, J. (2018) Scarlet fever epidemic in China caused by Streptococcus pyogenes serotype M12. EBioMedicine 28: 128-135. 
• Davies, M.R., Holden, M.T., Coupland, P., Chen, J.H.K., Venturini, C., Barnett, T.C., Ben Zakour, N., Tse, H., Dougan, G., Yuen, K.Y., Walker, M.J. (2015) Emergence of scarlet fever Streptococcus pyogenes M12 clones in Hong Kong is associated with toxin acquisition and multi-drug resistance. Nature Genetics 47: 84-87. 
• Dacunha, V., Davies, M.R., Douarre, P.E., Rosinski-Chupin, I., Margarit, I., Spinali, S., Perkins, T., Lechat, P., Dmytruk, N., Sauvage, E., Ma, L., Tichit, M., Lopez-Sanchez, M.J., Descorps-Declere, S., Buchrieser, C., Trieu-Cuot, P., Moszer, I., Clermont, D., Maione, D., Bouchier, C., McMillan, D.J., Parkhill, J., Telford, J.L., Dougan, G., Walker, M.J., The Devani Consortium, Holden, M.T.G., Poyart C., Glaser P. (2014) Streptococcus agalactiae clones infecting humans have been selected and fixed through the extensive use of tetracycline. Nature Communications 5: 4544. 
• van Sorge, N.M., Cole, J.N., Kuipers, K., Henningham, A., Aziz, R.K., Kasirer-Friede, A., Lin, L., Berends, E.T.M., Davies, M.R., Dougan, G., Zhang, F., Dahesh, S., Shaw, L., Gin, J., Cunningham, M., Merriman, J.A., Rooijakkers, S.H.M., Malley, R., Walker, M.J., Shattil, S.J., Schlievert, P.M., Choudhury, B, Nizet, V. (2014) The classical Lancefield antigen of group A Streptococcus is a virulence determinant with implications for vaccine design. Cell Host & Microbe 15: 729-740. 
• Barnett, T.C., Liebl, D., Seymour, L.M., Gillen, C.M., LaRock, C.N., Davies, M.R., Schulz, B.L., Nizet, V., Teasdale, R.D., Walker, M.J. (2013) The group A Streptococcus M1T1 clone evades autophagy for intracellular replication. Cell Host & Microbe 14: 675-682. 
• Walker, M.J., Hollands, H., Sanderson-Smith, M., Cole, J.N., Kirk, J.K., Henningham, A., McArthur, J.D., Dinkla, K., Aziz, R.K., Kansal, R.G., Buchanan, J.T., Simpson, A.J., Chhatwal, G.S., Kotb, M., Nizet, V. (2007) DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nature Medicine 13: 981-985.