Andres Floto
University of Cambridge - Cambridge Infectious Diseases, UK
The pathogenic evolution of Mycobacterium abscessus (and other bacteria)
Mycobacterium abscessus is an intrinsically multidrug-resistant species of nontuberculous mycobacteria (NTM) that has recently emerged as a major threat to individuals with Cystic Fibrosis (CF) and other chronic lung conditions, including non-CF bronchiectasis. In CF, M. abscessus drives accelerated inflammatory lung damage, is frequently impossible to treat, and usually prevents safe lung transplantation. Infection rates are increasing globally, which we have shown are driven (at least in part) by indirect person-to-person transmission of M. abscessus, probably through the generation of long-lived infectious aerosols and via fomite spread. Although M. abscessus was originally thought to be independently acquired from the environment, we have shown that over 70% of infections in CF patients are caused by genetically clustered (and thus transmitted) isolates, of which the majority are from three dominant circulating clones (DCCs) that synchronously emerged in the 1960s and have spread globally in mixed transmission networks involving both CF patients and (based on the mutational signatures in the bacteria) smokers. Clustered isolates are more virulent (when tested in vitro and in vivo) and result in worse clinical outcomes, suggesting that they are evolving from environmental saprophytes into professional lung pathogens in a similar way to ancestral M. tuberculosis over 6000 years ago.
M. abscessus has provided a unique opportunity to define the critical (and generalisable) steps involved in pathogenic evolution of mycobacteria involving: (i) saltational evolution of virulence in specific environmental clones driven by horizontal gene transfer; (ii) allopatric, within-host adaptation during chronic infection increasing survival within macrophages; (iii) constrained pathogenic evolution while transmission is via environmental intermediaries; and finally (iv) accelerated evolution into an obligate lung pathogen. I will describe our work on bacterial evolution, host susceptibility, and how these finding might be generalisable across bacterial species, particularly Pseudomonas aeruginosa.
Selected publications
1. Bryant JM, Grogono DM, Rodriguez-Rincon D, Everall I, Brown KP, Moreno P, Verma D, Emily Hill E, Drijkoningen J, Gilligan P, Esther CR, Noone PG, Giddings O, Bell SC, Thomson R, Wainwright CE, Coulter C, Pandey S, Wood ME, Stockwell RE, Ramsay KA, Sherrard LJ, Kidd TJ, Jabbour N, Johnson GR, Knibbs LD, Morawska L, Sly PD, Jones A, Bilton D, Laurenson I, Ruddy M, Bourke S, Bowler ICJW, Chapman SJ, Clayton A, Cullen M, Daniels T, Dempsey O, Denton M, Desai M, Drew RJ, Edenborough F, Evans J, Folb J, Humphrey H, Isalska B, Jensen- Fangel S, Jönsson B, Jones AM, Katzenstein TL, Lillebaek T, MacGregor G, Mayell S, Millar M, Modha D, Nash EF, O’Brien C, O’Brien D, Ohri C, Pao CS, Peckham D, Perrin F, Perry A, Pressler T, Prtak L, Qvist T, Robb A, Rodgers H, Schaffer K, Shafi N, van Ingen J, Walshaw M, Watson D,West N, Whitehouse J, Haworth CS, Harris SR, Ordway D, Parkhill J, Floto RA (2016). Emergence and spread of a human- transmissible multidrug-resistant nontuberculous mycobacterium. Science 354: 751-757
2. Ruis C, Bryant JM, Bell S, Thomson R, Davidson RM, Hasan NH, van Ingen J, Strong M, Floto RA*, Parkhill J*. Dissemination of Mycobacterium abscessus via global transmission networks (2021). Nature Microbiology doi.org/10.1038/s41564-021-00963-3
3. Bryant JM, Brown KP, Burbaud S, Everall I, Belardinelli JM, Rodriguez-Rincon D, Grogono DM, Peterson CM, Verma D, Evans IE, Ruis C, Weimann A, Arora D, Malhotra S, Bannerman B, Passemar C, Templeton K, MacGregor G, Jiwa K, Fisher AJ, Blundell TL, Ordway DJ, Jackson M, Parkhill J, Floto RA. Stepwise pathogenic evolution of Mycobacterium abscessus. Science. 2021 Apr 30;372(6541): eabb8699
4. Boeck L, Burbaud S, Skwark M, Pearson WH, Sangen J, Weimann A, Everall I, Bryant JM, Malhotra S, Bannerman BP, Kierdorf K, Blundell TL, Dionne M, Parkhill J, Floto RA (2022) The pathobiology of Mycobacterium abscessus revealed through phenogenomic analysis. Nature Microbiology 7, 1431–1441
5. Weimann A, Dinan AM, Ruis C, Bernut A, Pont S, Brown K, Ryan J, Santos L, Ellison L, Ukor E, Pandurangan AP, Krokowski S, Blundell TL, Welch M, Blane B, Judge K, Bousfield R, Brown N, Bryant JM, Kukavica-Ibrulj I, Rampioni G, Leoni L, Harrison PT, Peacock SJ, Thomson NR, Gauthier J, Fothergill JL, Levesque RC, Parkhill J, Floto RA. Evolution and host-specific adaptation of Pseudomonas aeruginosa. Science. 2024 Jul 5;385(6704):eadi0908