Above photo provided by The Rockefeller University "Streptococcal bacteria showing their polysaccharide capsule".
The Global Pneumococcal Sequencing Project (GPS) By: Stephanie Lo, PhD
Streptococcus pneumoniae (or the pneumococcus) has been known for more than a century as a major cause of bacterial pneumonia. In 1928, a British bacteriologist, Fred Griffith, reported that non-infectious pneumococci could be transformed into virulent forms if they were mixed with dead cells from a virulent strain.1 This fascinating observation prompted Oswald Avery, a Canadian-American medical researcher, to investigate the mechanism behind it, and led to the discovery of “transforming principle”,2 which later became widely known as DNA in the 1950s. Almost seventy years later, ‘DNA’ is no longer scientific jargon and sequencing the complete set of DNA in a bacterial cell is not technologically challenging. So, how do we harness DNA data to understand this deadly pathogen better?
From the accumulated knowledge of a century worth of research, we understand that the polysaccharide capsule that surrounds every pneumococcal bacterial cell is the major virulence factor, protecting the bacteria from attacks by human immune cells.3 There are at least 100 different forms, or serotypes of capsule, categorised based on antigen-antibody reactions. Pneumococcal conjugate vaccines (PCVs), which target the 10-13 serotypes that are most common in disease-causing pneumococci, have saved millions of children’s lives around the world.4 While we rejoice at this victory, this deadly pathogen remains. It is beginning its comeback by changing its serotype to escape from the vaccine.
To understand how some pneumococcal strains are escaping the vaccine, the Global Pneumococcal Sequencing (GPS) project5 was set up to sequence the DNA of over 20,000 pneumococci from 51 countries. Samples were collected before and after PCV introduction, and the DNA sequences of the bacteria and health data of those infected were compared. This makes it possible to determine changes in the pneumococcal population and whether new strains are emerging that would impact disease severity and ease of treatment.
Like previous studies, we have seen that after the introduction of vaccines, pneumococci with vaccine serotypes were replaced by those with non-vaccine serotypes. But we have gone beyond previous studies, looking for the first time at all the strains circulating globally and discovered 621 genetic strains, each associated with one or more serotypes. We found a subset of strains were globally disseminated, many of which were associated with antibiotic resistance and composed of vaccine- and non-vaccine serotypes.6 We saw that the level of non-vaccine type pneumococcus rose after the introduction of PCV in some of those lineages, showing how the pneumococcus evolve in response to the vaccine.7 In addition, the DNA data have also allowed us to unlock the genetic diversity of the capsule and identify nine potential new serotypes,8 and to reveal a previously unknown antibiotic resistance gene.9
The GPS research findings highlight the importance of DNA data in the surveillance of a deadly pathogen and generating new knowledge for better prevention and treatment strategies.
Dr Stephanie Lo, PhD is a lead researcher of the Global Pneumococcal Sequencing (GPS) project. Her research interest is to investigate mechanisms by which the pneumococcus evades vaccine and antimicrobials. The GPS project is led by Prof Stephen Bentley, Dr Lesley McGee and Prof Robert Breiman and co-funded by the Bill & Melinda Gates Foundation, the Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention.
- Griffith F. The Significance of Pneumococcal Types. J Hyg (Lond) 1928; 27: 113-59.
- Avery OT, Macleod CM, McCarty M. Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types : Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type Iii. J Exp Med 1944; 79: 137-58.
- Geno KA, Gilbert GL, Song JY et al. Pneumococcal Capsules and Their Types: Past, Present, and Future. Clin Microbiol Rev 2015; 28: 871-99.
- Wahl B, O'Brien KL, Greenbaum A et al. Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15. Lancet Glob Health 2018; 6: e744-e57.
- Global Pneumococcal Sequencing Project. https://www.pneumogen.net/gps/.
- Gladstone RA, Lo SW, Lees JA et al. International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact. EBioMedicine 2019; 43: 338-46.
- Lo SW, Gladstone RA, van Tonder AJ et al. Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study. Lancet Infect Dis 2019; 19: 759-69.
- van Tonder AJ, Gladstone RA, Lo SW et al. Putative novel cps loci in a large global collection of pneumococci. Microb Genom 2019; 5.
- Lo SW, Gladstone RA, van Tonder AJ et al. A novel mosaic tetracycline resistance gene tet(S/M) detected in a multidrug-resistant pneumococcal CC230 lineage that underwent capsular switching in South Africa. BioRxiv 2019.