Browsing by Subject "Pathogen"
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Item Open Access Coevolution of the Ipomoea-Coleosporium Natural Plant-Fungus Pathosystem(2010) Chappell, ThomasPlants and their pathogens coevolve, with pathogen infection and host resistance acting in evolutionary antagonism of each other. Plant-pathogen coevolution has been shown to effect genetic divergence between populations and species, resulting in localized or specialized interactions between hosts and pathogens. Because most of the studies to date investigating plant-pathogen coevolution have been carried out in managed systems and have focused on pairwise interactions, we know little about three aspects of plant pathosystems in natural settings: 1) the role in nature of the gene-for-gene paradigm for genetic determination of resistance; 2) the relationship of host community diversity and structure, and host-pathogen interaction structure, to the coevolutionary process; and 3) the factors which underlie and drive local adaptation and specialization of interactions.
This dissertation constitutes the results of research in which I have begun addressing these aspects in a natural plant-fungus pathosystem comprising three Ipomoea host species and a single rust pathogen, Coleosporium ipomoeae. I have expanded previous characterization of the genetics of plant resistance in one constituent host species in the system by genetic crosses to characterize the basis of resistance in two additional species, finding support for the expectation that the gene-for-gene paradigm of interaction is important in natural systems. I conducted a cross-inoculation experiment designed to assess host and pathogen variation in infectivity and resistance, to investigate patterns of community interaction structure, and the role that antagonistic coevolution may play in structuring the communities which compose pathosystems. In these experiments I found that the coevolutionary interaction in this system leads to genetic divergence and the substantial amount of host and pathogen variation I discovered, but that it tends to preserve one pattern of community interaction structure across communities. I expanded my cross-inoculation experimental design to facilitate analysis of quantitative aspects of pathogenesis by measuring the intensity of infections, to test existing hypotheses concerning local adaptation and specialization in pathosystems. In this analysis I found strong host local adaptation and pathogen local maladaptation for the qualitative interaction trait of infectivity, and I found weak host local maladaptation and pathogen local adaptation for the quantitative interaction trait of aggressiveness. I also found host specialization among pathogens, and specialized resistance among hosts, to be common in this system. In light of these results, I hypothesize that the geographic scale of host-pathogen coevolution in this system is that of the local community, and that differences between host species result in persistent but incomplete host specialization in pathogen races.
Item Open Access Evolutionary Dynamics in an Individual Spatial and a Mean Field Differential Equation Host-Pathogen Model(2013-04-30) Zhang, WilliamWe examine a host-pathogen model in which three types of species exist: empty sites, healthy hosts, and infected hosts. In this model six different transitions can occur: empty sites can be colonized by healthy hosts, healthy hosts can be infected, and infected hosts can either recover or die. We implement this general model in both a spatial context with discrete time and in a homogeneously mixing model in continuous time. We then explore evolution for pairs of parameters, calculating viable regions in the ODE model and and evolutionary vector fields in both models. Our results show that results from the spatial model do not always converge to our ODE model results, that stochasticity in the spatial evolutionary vector field can be used as a measure of the magnitude of evolutionary pressure and as an indicator of non-viable parameters, and that the evolutionary pressures on different parameters are not necessarily independent. For example, a lower transmissibility greatly lowers the magnitude of evolutionary pressure for all parameters associated with transitions from infected hosts.Item Open Access Utilizing Natural Variation and De Novo Mutation to Understand Cryptococcus Evolution(2022) Sauters, Thomas John CThe evolution of pathogenesis, in many cases, is a story of competition between host and microbe; however, many opportunistic pathogens are primarily found in niches other than the host environment. Such pathogens frequently lack host-to-host transmission, and there may be limited opportunities for an infectious population to be re-dispersed back into the environment. Observations such as these motivate the hypothesis that the evolution of virulence traits in opportunistic pathogens may be primarily driven by environmental selective pressures, rather than the host-environment per se.
For Cryptococcus the ability to survive interactions with macrophages and the ability to grow at host body temperatures are indispensable to its pathogenic capabilities. The work presented here aims to dissect the genetic underpinnings of these virulence traits using the abundant natural variation of Cryptococcus and using the accumulation de novo mutations associated with growth under relevant stressors.
An important aspect of the hypotheses surrounding Cryptococcus evolution is the predator-prey interactions it has with free-living amoeba. Amoebae are able to consume Cryptococcus cells in a manner similar to how macrophages phagocytose and digest infectious cells. This similarity is the basis of the “Amoeboid Predator-Fungal Animal Virulence Hypothesis” which posits that amoeba act as training grounds for environmental fungal pathogens and thus inadvertently select for resistance to immune phagocytes. I tested this hypothesis by using QTL mapping to identify genes and alleles that are involved in amoebae resistance in both C. neoformans and C. deneoformans. I identified QTL that contribute to amoeba resistance, and discovered that the largest effect QTL in both species localize to homologous regions of the genome, suggesting a shared mechanism of amoeba resistance. In C. neoformans, this QTL also contributes to variation in melanization. I identified a causal variant for this QTL, a non-coding deletion upstream of a transcription factor, BZP4. Contrary to the predictions of the Amoeboid Predator-Fungal Animal Virulence Hypothesis, I did not find an association between the ability to survive amoeba predation and virulence in either in vitro or in vivo models of infection. These findings suggest a re-evaluation of the amoeba predation model for the evolution of pathogenesis, suggesting that factors other than amoeba may provide the significant selective pressures that underlie virulence ability.
I extended my quantitative analyses of Cryptococcus to two important factors involved in both environmental and disease contexts: thermal and low pH tolerance. In doing so, I discovered multiple pleiotropic QTL involved in general growth that also dictate stress tolerance in both high temperature and low pH environments. By fitting growth data to a Gompertz growth model and QTL mapping based on the parameters of this model, I discovered a novel QTL that effects lag, the time it takes for a population of cells to begin growing at an exponential rate. This lag QTL is pleiotropic across growth conditions. I identified a candidate allele for the lag QTL, a 9-bp deletion in CNAG_01111, a gene that has been found to impact growth initiation in other species of fungi.
Finally, taking a complimentary approach to understanding the role of genes in environmental survival, I experimentally evolved a C. neoformans strain in conditions of thermal stress and fludioxonil stress. I discovered that strains evolved at high temperatures lose tolerance to fludioxonil and strains evolved in fludioxonil lose temperature tolerance. Furthermore, the loss of fludioxonil tolerance in the high temperature evolved strains can be partially rescued by growing them on media containing fludioxonil. This rescue results in a proportional loss of thermal tolerance. Studying the genomic changes behind the evolved phenotypes I discovered multiple large scale deletions and one multi-gene duplication associated with fludioxonil resistance and a single multi-gene deletion associated with thermal tolerance. There are also a variety of small scale mutations associated with each evolved condition, including mutations of genes in the HOG and ergosterol pathway that are responsible for fludioxonil resistance. Mutations in uncharacterized multidrug transporters are frequently associated with fludioxonil resistance, suggesting that the evolved strains might also have altered resistance to other antifungals. These findings highlight the polygenic and pleiotropic genetic architecture of adaptation in C. neoformans on an ever warming planet with increased use of agricultural antifungals. The trade-offs found may represent a good sign for the use of phenylpyrroles as an agricultural antifungal.
Collectively, my work sheds light on genes and alleles involved in environmental survival while also making important connections back to human disease. It also exhibits the importance of utilizing the natural variation of fungal pathogens to study the evolutionary hypothesis surrounding virulence traits. The studies reported here also provide significant groundwork for many new insights into virulence genes and the origins of Cryptococcus pathogenicity.