MICROBE 2018 recap - Microbes that Know No Borders - Emergence and Transmission

Dr. Julian Parkhill, Sanger Institute
Signatures of emergence and transmission in bacterial pathogens

Dr. Parkhill has been involved on analysis of transmission and emergence of pathogens for almost 2 decades now. A glance through his publication record shows involvement in epidemic analysis and antimicrobial resistance in Burkholderia, Campylobacter, Neisseria, Legionella, Cholera, Mycobacteria and has assisted in the development of tools and analysis for better visualization and annotation of sequence data, faster phylogenetic analysis, whole genome sequencing, SNPs and AMR, population structure and much more.

Today we looked at Extraintestinal Pathogenic E. coli (ExPEC) and Uropathogenic E. coli (UPEC), and once again we are looking at ST131 in particular as we did in the AMR Highlights blog.

• ST131 clones are said to have emerged in 2000, sequentially acquiring fluoroquinolone resistance followed by beta-lactam resistance (blaCTXM15), rapidly expanded and have remained stable ever since in terms of population size.

But is this really 'emergence'?

• A huge diversity of E. coli can be found in blood stream infections with both old and recent clades in phylogenetic analysis.
• What is driving emergence and stability of ST131 (or any ST for that matter - like ST69 which is also very successful).
• In looking at virulence factors we find that ST131 doesn't really have very many as compared to say ST69.
• In terms of antibiotic resistance genes ST69 has very few and many other STs have none (pan-susceptible).
• So antibiotic resistance gene complement and virulence factors don't appear to play a role in expansion and stability of successfully emerging/spreading STs.
• ST131 in particular - there are susceptible types and resistant types which are found temporally interspersed in it's evolutionary history. Additionally, it has lost and gained the blaCTXM15 resistance factor multiple times in it's history as evidenced by clades over time persisting with and without virulence and antibiotic resistance genes.

So what is the driver?

• Turns out, frequency dependent selection is the population structure driver...
• Once stable, they lose their selective advantage and the lack of growth or stability is a reflection of negative frequency dependent selection.
• You have inter-clone competition
• You have the gain and loss of factors
• This all occurs in the guts of the general population
• Blood infections are spillover from general infections with E. coli
• Additionally, treatment does not appear to have an impact on driving the success or failure of emergence, it all appears to be internal bacterial competition

Putting E. coli aside - let's look at Serratia marcescens

• Environmental bug - water and soil. 
• Previously considered non-pathogenic
• Found increasingly in nosocomial infections AND with increasing drug resistance
• Compared to E. coli where phylogenetically you see a lot of topology of old and young clades, S. marcescens is quite young, but these young clades are spreading.
• Reconstructing transmission networks we find a lot of local transmission (links within the same hospital).
• Specifically multidrug resistant (MDR) Serratia is composed of recent clones and there is geographical structuring with transmission within hospitals and hospitals that are geographically related (probability of transfer between the two hospitals is high - movement of patients or staff etc).

Moving to Mycobacterium abscessus and Cystic Fibrosis (CF)

• Prior to 1990 we rarely isolated this bug from CF patients
• Now it is one of the top infections seen in CF and it is environmentally acquired.
• It has a naturally high antibiotic resistance and is resistant to all frontline antibiotics used to treat tuberculosis (TB).
• It is associated with decline in lung function
• Phylogenetically we see a combination of young and old clades with 3 subspecies
• We've seen a global spread of outbreak strains but what is driving expansion and virulence?
• Some strains can infect macrophages more readily, survive longer and cause more virulent disease
• Phylogenetically we are seeing the same changes/mutations on independent branches for genes potentially involved in human adaptation suggestive of convergent evolution.
• Some publications to help you with the idea of convergent evolution and bacterial pathogens:
• Bryant, J., et al. "Whole-Genome Sequencing Reveals Global Spread Of Mycobacterium Abscessus Clones Amongst Patients With Cystic Fibrosis." Am J Respir Crit Care Med 195 (2017): A7650.
• Tan, Joon Liang, et al. "Genomic Comparisons Reveal Microevolutionary Differences in Mycobacterium abcessus Subspecies." Frontiers in microbiology 8 (2017): 2042.
• Didelot, Xavier, et al. "Within-host evolution of bacterial pathogens." Nature Reviews Microbiology 14.3 (2016): 150.
• Tortoli, Enrico, et al. "The new phylogeny of the genus Mycobacterium: the old and the news." Infection, Genetics and Evolution 56 (2017): 19-25.

We know that susceptible populations are challenged by opportunistic pathogens. Many will adapt to that host. Some will be able to be transferred directly to new hosts. Repeated transmission events "jumps" into new hosts can and does lead to adaptation to the new host or environment facilitating continued and improved transmissibility over time. With abscessus we are seeing direct and indirect transmission in the hospital setting.