Geographic Migration and Evolution of Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae (the pneumococcus) is a human-obligate, opportunistic bacteria. It resides asymptomatically in the nasopharynx of both children and adults. It occasionally goes on to cause local disease such as otitis media, or severe invasive disease as with pneumonia and meningitis. It is prevalent globally and rates of carriage have an inverse relationship with country income. The pneumococcus comprises massive diversity of >800 global lineages and 100 antigenically distinct serotypes. Many lineages and serotypes co-circulate endemically in any given location. Highly immunogenic conjugate vaccines have been implemented in >76% of national immunization schedules; we also have many antimicrobials to which the pneumococcus is susceptible. Following the introduction of the pneumococcal conjugate vaccine in the 2000’s there have been global ecological expansions and contractions of serotypes, lineages, and antimicrobial resistance (AMR). There are distinct qualitative patterns which characterise the global geographic structure of both the endemically circulating pneumococcus and the constantly changing ecology of its genes and loci. The extent and mechanisms of spread, and vaccine-driven changes in fitness and AMR, remain largely unquantified. Using geolocated genome sequences from South Africa (2000-2014) I developed models to reconstruct spread. I implemented simple statistical frameworks which can account for variable surveillance in both space and time. I also pair detailed human mobility data from Facebook users with genomic data within a mechanistic model to describe how human movement drives the geographic spread of the pathogen. I estimated that pneumococci only become homogenously mixed across South Africa after about 50 years of transmission, with the slow spread driven by the focal nature of human mobility. Further, the human population density in the municipality of introduction appears to be important as well — with a more rapid radius of spread when introduced to rural areas. I include both disease and carriage isolates in our models. There are similar ecological shifts among healthy Cambodian children, following vaccination, as among disease isolates. Among South African samples I utilize a logistic model to estimate the population level changes in fitness of strains that are (vaccine type, VT) and are not (non-vaccine type, NVT) as well as differences in strain fitness between those that are and are not resistant to penicillin continuously, across the vaccine period (PCV7: 2009; PCV13: 2011). In the years following vaccine implementation the relative fitness of NVT compared to VT strains increased with an increasing proportion of these NVT strains becoming penicillin resistant. These estimates indicate that initial vaccine-linked decreases in AMR may be transient. Data on human mobility between countries is scarce so to understand between country pneumococcal migration-dynamics I developed a simulation approach using Bayesian optimization for Likelihood-free inference. Incorporating thousands of pneumococcal genomes from South Africa, Malawi, The Gambia, and Kenya I included only neutral sites. I estimated migration rates and directions of migration between countries. I found some heterogeneity between lineages and across demes, and an inverse relationship between migration and the destination country population size. This model could be used to inform modeling frameworks on wider pneumococcal spread and timing and implementation of public health interventions. I also worked to better understand the history and evolution of the hundreds of extant GPSCs by delving into a 5700 year-old metagenome with genomic reads containing high identity to the pneumococcus. While this resulted in identifying a streptococcal ancestor with no polysaccharide capsule it did not further our knowledge of extant pneumococci; as such this paper is included in Appendix A. This work has contributed valuable insight into pneumococcal migration and mech- anisms of spread. I have quantified important fitness dynamics and incorporated them into our mobility models. Furthermore, I have developed a method which can now esti- mate migration parameters asymmetrically between countries elucidating paths of global pneumococcal spread. Together this thesis marks the advancement in our understanding of the geographic migration of Streptococcus pneumoniae and lays the groundwork for understanding its diverse, complex, global spread.