Bridging between parasite genomic data and population processes: Trypanosome dynamics and the antigenic archive

QH301 Biology;QH426 Genetics;QA Mathematics;Q Science (General)

Gjini, Erida ; Cobbold, Christina A.

University:University of Glasgow

Department:School of Mathematics and Statistics

关键词: African trypanosome, VSG archive, antigenic variation, within-host dynamics, model, parasite fitness, evolution, diversification, mutation, gene conversion, hidden Markov model, Bayesian inference, diffusion approximation;   

Others  :  http://theses.gla.ac.uk/3375/1/2012gjiniphd.pdf

来源: University of Glasgow

【 摘 要 】

Antigenic variation processes play a central role in parasite invasion and chronic infectious disease, and are likely to respond to host immune mechanisms and epidemiological characteristics. Whether changes in antigenic variation strategies lead to net positive or negative effects for parasite fitness is unclear. To improve our understanding of pathogen evolution, it is important to investigate the mechanisms by which pathogens regulate antigenic variant expression. This involves consideration of the complex interactions that occur between parasites and their hosts, and top-down and bottom-up factors that might drive changes in the genetic architecture of their antigenic archives. Increasing availability of pathogen genomic data offers new opportunities to understand the fundamental mechanisms of immune evasion and pathogen population dynamics during chronic infection. Motivated by the growing knowledge on the antigenic variation system of the sleeping sickness parasite, the African trypanosome, in this thesis, we present different models that analyze antigenic variation of this parasite at different biological scales, ranging from the within-host level, to between-host transmission, and finally the parasite genetics level. First, we describe mechanistically how the structure of the antigenic archive impacts the parasite population dynamics within a single host, and how it interplays with other within-host processes, such as parasite density-dependent differentiation into transmission life-stages and specific host immune responses. Our analysis focuses first on a single parasitaemia peak and then on the dynamics of multiple peaks that rely on stochastic switching between groups of parasite variants. We show that the interplay between the two types of parasite control within the host: specific and general, depends on the modular structure of the parasite antigenic archive. Our modelling reveals that the degree of synchronization in stochastic variant emergence (antigenic block size) determines the relative dominance of general over specific control within a single peak, and can divide infection scenarios into stationary and oscillatory regimes. A requirement for multiple-peak dynamics is a critical switch rate between blocks of antigenic variants, which depends on host characteristics, such as the immune delay, and implies constraints on variant surface glycoprotein (VSG) archive genetic diversification. Secondly, we study the interactions between the structure and function of the antigenic archive at the transmission level. By using nested modelling, we show that the genetic architecture of the archive has important consequences for pathogen fitness within and between hosts.We find host-dependent optimality criteria for the antigenic archive that arise as a result of typical trade-offs between parasite transmission and virulence. Our analysis suggests that different traits of the host population can select for different aspects of the antigenic archive, reinforcing the importance of host heterogeneity in the evolutionary dynamics of parasites. Variant-specific host immune competence is likely to select for larger antigenic block sizes. Parasite tolerance and host life-span are likely to select for whole archive expansion as more archive blocks provide the parasite with a fitness advantage. Within-host carrying capacity, resulting from density-dependent parasite regulation, is likely to impact the evolution of between-block switch rates in the antigenic archive. Our study illustrates the importance of quantifying the links between parasite genetics and within-host dynamics, and suggests that host body size might play a significant role in the evolution of trypanosomes. In Chapters 4 and 5 we consider the genetics behind trypanosome antigenic variation. Antigen switch rates are thought to depend on a range of genetic features, among which, the genetic identity between the switch-off and switch-on gene. The subfamily structure of the VSG archive is important in providing the conditions for this type of switching to occur. We develop a hidden Markov model to describe and estimate evolutionary processes generating clustered patterns of genetic identity between closely related gene sequences. Analysis of alignment data from high-identity VSG genes in the silent antigen gene archive of the African trypanosome identifies two scales of subfamily diversification: local clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and the sparse scale of isolated mismatches, likely to arise from independent point mutations. In addition to quantifying the respective rates of these two processes, our method yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted for a range of models using a Bayesian framework. We find that gene conversion events with lower-identity partners are at least 5 times less common than point mutations for VSG pairs, and the average imported conversion tract is short. However, due to the high frequency of mismatches in converted segments, the two processes have almost equal impact on the rate of sequence diversification between VSG sub-family members. We are able to disentangle the most likely locations of point mutations vs. conversions on each aligned gene pair. Finally we model VSG archive diversification at the global scale, as a result of opposing evolutionary forces: point mutation, which induces diversification, and gene conversion, which promotes global homogenization. By adopting stochastic simulation and theoretical approaches such as population genetics and the diffusion approximation, we find how the stationary identity configuration of the archive depends on mutation and conversion parameters. By fitting the theoretical form of the distribution to the current VSG archive configuration, we estimate the global rates of gene conversion and point mutation. The relative dominance of mutation as an evolutionary force quantifies the high divergence propensity of VSG genes in response to host immune pressures. The success of our models in describing realistic infection patterns and making predictions about the fitness consequences of the parasite antigenic archive illustrates the advantage of using integrative approaches that bridge between different biological scales. Even though quantifying the genetic signatures of antigenic variation remains a challenging task, cross-disciplinary analyses and mechanistic modelling of parasite genomic data can help in this direction, to better understand parasite evolution.