New research provides the first detailed genetic picture of an evolutionary war
between Streptococcus pneumoniae bacteria and the vaccines and antibiotics used against it over recent decades.Large-scale genome sequencing reveals patterns of adaptation and the spread of a drug-resistant lineage ofthe S. pneumoniae bacteria.
The study unmasks the genetic events bywhich bacteria such as S. pneumoniaerespond rapidly to new antibiotics andvaccines. The team suggest that knowingthe enemy better could improve infectioncontrol measures.
S. pneumoniae is responsible for a broadrange of human diseases, includingpneumonia, ear infection and bacterialmeningitis. Since the 1970s, some forms ofthe bacteria have gained resistance to manyof the antibiotics traditionally used to treatthe disease. In 2000 S. pneumoniae wasresponsible for 15 million cases of invasivedisease across the globe. A new vaccine wasintroduced to the US in 2000 in an attemptto control disease resulting from the mostcommon and drug resistant forms of thebacteria.
The new research uses DNA sequencing toprecisely describe the recent evolution andsuccess of a drug-resistant lineage of thebacteria called PMEN1 that has spreadsuccessfully to all continents.
“Drug resistant forms of S. pneumoniaefirst came onto the radar in the 1970s,”says Dr Stephen Bentley, from theWellcome Trust Sanger Institute and seniorauthor on the study. “We sequenced 240samples collected over the course of 24years from the PMEN1 lineage of S.pneumoniae. By comparing thesequences, we can begin to understand how this bacterium evolves and reinvents itself genetically in response to human interventions.”
The power of next-generation sequencing exposes S. pneumoniae as a pathogen that evolves andreinvents itself with remarkable speed. The degree of diversity was a real surprise in such seeminglyclosely related organisms.
First, the team had to distinguish between single letter mutations that are passed down ‘vertically’when cells divide in two, and so-called ‘horizontal’ changes – called recombinations – where chunks ofDNA letters are passed across from one bacterium to another and swapped over, changing thestructure of their genomes.”Separating these two kinds of change was the critical first step in unlocking theevolutionary history of the PMEN1 lineage,” says Professor Julian Parkhill, Head of PathogenGenomics at the Wellcome Trust Sanger Institute. “By looking only at the DNA mutations thatare passed down through direct ancestry, we constructed an evolutionary tree. When welooked at our tree, we could see that the drug-resistant PMEN1 lineage originated around1970 – about the time that saw the introduction of the widespread use of antibiotics to fight pneumococcal disease.”
The team also use their tree to trace the origin of PMEN1 toEurope, and suggest that the lineage may have been introducedto the Americas and Asia on multiple occasions.The ‘vertical’ mutations, however, could not fully account for theevolution and adaptability of this pathogen.The team found that the ‘horizontal’ transfer of DNA had affectedthree-quarters of the S. pneumoniae genome. The team alsofound hotspots – areas of the genome that are particularlyaffected by horizontal transmission.”We found that genes for antigens – the molecules thattrigger our immune response – were particularly prone tothis kind of change,” says Dr William Hanage, AssociateProfessor of Epidemiology at Harvard School of Public Health,and a Visiting Reader at Imperial College London, where heDr Stephen Bentleydevised the study with scientists at the Wellcome Trust SangerInstitute. “The remarkable amount of variation at thesehotspots hints at ways S. pneumoniae can evadevaccines against these antigens.The team also use their tree to trace the origin of PMEN1 toEurope, and suggest that the lineage may have been introducedto the Americas and Asia on multiple occasions.The ‘vertical’ mutations, however, could not fully account for theevolution and adaptability of this pathogen.The team found that the ‘horizontal’ transfer of DNA had affectedthree-quarters of the S. pneumoniae genome. The team alsofound hotspots – areas of the genome that are particularlyaffected by horizontal transmission.”We found that genes for antigens – the molecules thattrigger our immune response – were particularly prone tothis kind of change,” says Dr William Hanage, AssociateProfessor of Epidemiology at Harvard School of Public Health,and a Visiting Reader at Imperial College London, where hedevised the study with scientists at the Wellcome Trust SangerInstitute. “The remarkable amount of variation at thesehotspots hints at ways S. pneumoniae can evade vaccines against these antigens.
The authors also identify differences in the patterns of adaptation in response to antibiotics and vaccines.
“With antibiotics, different strains quite often adapt in the same way to becomeresistant,” says Nicholas Croucher, from the Wellcome Trust Sanger Institute and first author onthe paper. “With vaccines, it is quite different. What we see is a decline in the prevalenceof bacteria that are susceptible to the vaccine. This, in turn, opens the door for bacteriathat can evade the vaccine to fill the niche and become the dominant strain.”While the latest vaccination measures in the USA have almost completely removed the targetpneumococcal strains from the population, the pathogen has deep resources to draw on in response.The research suggests that variants that allowed some bacteria to escape the new vaccine werepresent before the vaccine was introduced. These variants then flourished, expanding to fill a ‘gap in the market’ as the grip of the dominant strain was weakened through vaccination
The researchers suggest that the study provides important new clues into the genetic adaptability ofbacteria like S. pneumoniae. They suggest that further focused sequencing programs may provecrucial to the future control of this, and other, bacterial pathogens that use similar mechanisms to outsmart human control measures.
Courtesy of The Wellcome Trust Sanger Institute
