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DescriptionA
ContributorsLund, Michael (Author) / Varsani, Arvind (Thesis advisor) / Upham, Nathan (Committee member) / Harris, Robin (Committee member) / Arizona State University (Publisher)
Created2023
Description
The human gut microbiome is associated with health outcomes including gastrointestinal and metabolic health, autoimmune disease and cancer. However, the role of the microbiome in many disease processes, including in the preterm gastrointestinal tract and female genital tract, has yet to be defined. Further, the diverse community of viruses within the microbiome (the virome) is understudied compared to bacteria. Here, I examine the microbiome and virome in specific disease models that are poorly understood: necrotizing enterocolitis (NEC), discordant HIV shedding in women living with HIV (WHLIV), female genital tract inflammation and gammaherpesvirus infection. Specifically, I examined the gut virome longitudinally in a cohort of preterm infants at risk for NEC; the female genital tract (FGT) microbiome and virome longitudinally in a cohort of WLHIV from Lima, Peru; the FGT virome in women from Phoenix, Arizona with differing levels of genital inflammation and different microbiome compositions; and the gut microbiome in murine gammaherpesvirus 68 (MHV68) infection. Further, I contributed to research responding to the spread of SARS-CoV-2 in Arizona. I found that 1) gut virome beta diversity decreased before NEC onset in preterm infants, suggesting a role for the virome in NEC; 2) FGT microbiome instability was associated with discordant HIV shedding, while FGT virome composition changed in association with ART duration and immune recovery; 3) FGT virome composition was associated with inflammation and microbiome composition; and 4) MHV68 infection outcomes were independent of microbiome perturbation, which may reflect environmental influences. The results of this research advance understanding of the microbiome and virome in these specific disease processes, and support further investigation of the microbiome and virome in preterm infant gastrointestinal health and FGT health, as well as environmental effects in microbiome research.
ContributorsKaelin, Emily (Author) / Lim, Efrem (Thesis advisor) / Varsani, Arvind (Committee member) / Jacobs, Bertram (Committee member) / McFadden, Grant (Committee member) / Rahman, Masmudur (Committee member) / Arizona State University (Publisher)
Created2024
Description
Arachnids belong to the phylum Arthropoda, the largest phylum in the animal kingdom. Ticks are blood-feeding arachnids that vector numerous pathogens of significant medical and veterinary importance, while scorpions have become a common concern in urban desert cities due to the high level of toxicity in their venom. To date, viruses associated with arachnids have been under sampled and understudied. Here viral metagenomics was used to explore the diversity of viruses present in ticks and scorpions. American dog ticks (Dermacentor variabilis) and blacklegged ticks (Ixodes scapularis) were collected in Pennsylvania while one hairy scorpion (Hadrurus arizonensis) and four bark scorpions (Centruroides sculpturatus) were collected in Phoenix. Novel viral genomes described here belong to the families Polyomaviridae, Anelloviridae, Genomoviridae, and a newly proposed family, Arthropolviridae.
Polyomaviruses are non-enveloped viruses with a small, circular double-stranded DNA (dsDNA) genomes that have been identified in a variety of mammals, birds and fish and are known to cause various diseases. Arthropolviridae is a proposed family of circular, large tumor antigen encoding dsDNA viruses that have a unidirectional genome organization. Genomoviruses and anelloviruses are ssDNA viruses that have circular genomes ranging in size from 2–2.4 kb and 2.1–3.8 kb, respectively. Genomoviruses are ubiquitous in the environment, having been identified in a wide range of animal, plant and environmental samples, while anelloviruses have been associated with a plethora of animals.
Here, 16 novel viruses are reported that span four viral families. Eight novel polyomaviruses were recovered from bark scorpions, three arthropolviruses were recovered from dog ticks and one arthropolvirus from a hairy scorpion. Viruses belonging to the families Polyomaviridae and Arthropolviridae are highly divergent. This is the first more extensive study of these viruses in arachnids. Three genomoviruses were recovered from both dog and deer ticks and one anellovirus was recovered from deer ticks, which are the first records of these viruses being recovered from ticks. This work highlights the diversity of dsDNA and ssDNA viruses in the arachnid population and emphasizes the importance of performing viral surveys on these populations.
Polyomaviruses are non-enveloped viruses with a small, circular double-stranded DNA (dsDNA) genomes that have been identified in a variety of mammals, birds and fish and are known to cause various diseases. Arthropolviridae is a proposed family of circular, large tumor antigen encoding dsDNA viruses that have a unidirectional genome organization. Genomoviruses and anelloviruses are ssDNA viruses that have circular genomes ranging in size from 2–2.4 kb and 2.1–3.8 kb, respectively. Genomoviruses are ubiquitous in the environment, having been identified in a wide range of animal, plant and environmental samples, while anelloviruses have been associated with a plethora of animals.
Here, 16 novel viruses are reported that span four viral families. Eight novel polyomaviruses were recovered from bark scorpions, three arthropolviruses were recovered from dog ticks and one arthropolvirus from a hairy scorpion. Viruses belonging to the families Polyomaviridae and Arthropolviridae are highly divergent. This is the first more extensive study of these viruses in arachnids. Three genomoviruses were recovered from both dog and deer ticks and one anellovirus was recovered from deer ticks, which are the first records of these viruses being recovered from ticks. This work highlights the diversity of dsDNA and ssDNA viruses in the arachnid population and emphasizes the importance of performing viral surveys on these populations.
ContributorsSchmidlin, Kara (Author) / Varsani, Arvind (Thesis advisor) / Van Doorslaer, Koenraad (Committee member) / Stenglein, Mark (Committee member) / Arizona State University (Publisher)
Created2019
Description
Yersinia enterocolitica is a major foodborne pathogen found worldwide that causes approximately 87,000 human cases and approximately 1,100 hospitalizations per year in the United States. Y. enterocolitica is a very unique pathogen with the domesticated pig acting as the main animal reservoir for pathogenic bio/serotypes, and as the primary source of human infection. Similar to other gastrointestinal infections, Yersinia enterocolitica is known to trigger autoimmune responses in humans. The most frequent complication associated with Y. enterocolitica is reactive arthritis - an aseptic, asymmetrical inflammation in the peripheral and axial joints, most frequently occurring as an autoimmune response in patients with the HLA-B27 histocompatability antigen. As a foodborne illness it may prove to be a reasonable explanation for some of the cases of arthritis observed in past populations that are considered to be of unknown etiology. The goal of this dissertation project was to study the relationship between the foodborne illness -Y. enterocolitica, and the incidence of arthritis in individuals with and without contact with the domesticated pig.
ContributorsBrown, Starletta (Author) / Hurtado, Ana M (Thesis advisor) / Chowell-Puente, Gerardo (Committee member) / Hill, Kim (Committee member) / Arizona State University (Publisher)
Created2015
Description
Extraordinary medical advances have led to significant reductions in the burden of infectious diseases in humans. However, infectious diseases still account for more than 13 million annual deaths. This large burden is partly due to some pathogens having found suitable conditions to emerge and spread in denser and more connected host populations, and others having evolved to escape the pressures imposed by the rampant use of antimicrobials. It is then critical to improve our understanding of how diseases spread in these modern landscapes, characterized by new host population structures and socio-economic environments, as well as containment measures such as the deployment of drugs. Thus, the motivation of this dissertation is two-fold. First, we study, using both data-driven and modeling approaches, the the spread of infectious diseases in urban areas. As a case study, we use confirmed-cases data on sexually transmitted diseases (STDs) in the United States to assess the conduciveness of population size of urban areas and their socio-economic characteristics as predictors of STD incidence. We find that the scaling of STD incidence in cities is superlinear, and that the percent of African-Americans residing in cities largely determines these statistical patterns. Since disparities in access to health care are often exacerbated in urban areas, within this project we also develop two modeling frameworks to study the effect of health care disparities on epidemic outcomes. Discrepant results between the two approaches indicate that knowledge of the shape of the recovery period distribution, not just its mean and variance, is key for assessing the epidemiological impact of inequalities. The second project proposes to study, from a modeling perspective, the spread of drug resistance in human populations featuring vital dynamics, stochasticity and contact structure. We derive effective treatment regimes that minimize both the overall disease burden and the spread of resistance. Additionally, targeted treatment in structured host populations may lead to higher levels of drug resistance, and if drug-resistant strains are compensated, they can spread widely even when the wild-type strain is below its epidemic threshold.
ContributorsPatterson-Lomba, Oscar (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Towers, Sherry (Thesis advisor) / Chowell-Puente, Gerardo (Committee member) / Arizona State University (Publisher)
Created2014
Description
Urban scaling analysis has introduced a new scientific paradigm to the study of cities. With it, the notions of size, heterogeneity and structure have taken a leading role. These notions are assumed to be behind the causes for why cities differ from one another, sometimes wildly. However, the mechanisms by which size, heterogeneity and structure shape the general statistical patterns that describe urban economic output are still unclear. Given the rapid rate of urbanization around the globe, we need precise and formal mathematical understandings of these matters. In this context, I perform in this dissertation probabilistic, distributional and computational explorations of (i) how the broadness, or narrowness, of the distribution of individual productivities within cities determines what and how we measure urban systemic output, (ii) how urban scaling may be expressed as a statistical statement when urban metrics display strong stochasticity, (iii) how the processes of aggregation constrain the variability of total urban output, and (iv) how the structure of urban skills diversification within cities induces a multiplicative process in the production of urban output.
ContributorsGómez-Liévano, Andrés (Author) / Lobo, Jose (Thesis advisor) / Muneepeerakul, Rachata (Thesis advisor) / Bettencourt, Luis M. A. (Committee member) / Chowell-Puente, Gerardo (Committee member) / Arizona State University (Publisher)
Created2014
Description
The increased number of novel pathogens that potentially threaten the human population has motivated the development of mathematical and computational modeling approaches for forecasting epidemic impact and understanding key environmental characteristics that influence the spread of diseases. Yet, in the case that substantial uncertainty surrounds the transmission process during a rapidly developing infectious disease outbreak, complex mechanistic models may be too difficult to be calibrated quick enough for policy makers to make informed decisions. Simple phenomenological models that rely on a small number of parameters can provide an initial platform for assessing the epidemic trajectory, estimating the reproduction number and quantifying the disease burden from the early epidemic phase.
Chapter 1 provides background information and motivation for infectious disease forecasting and outlines the rest of the thesis.
In chapter 2, logistic patch models are used to assess and forecast the 2013-2015 West Africa Zaire ebolavirus epidemic. In particular, this chapter is concerned with comparing and contrasting the effects that spatial heterogeneity has on the forecasting performance of the cumulative infected case counts reported during the epidemic.
In chapter 3, two simple phenomenological models inspired from population biology are used to assess the Research and Policy for Infectious Disease Dynamics (RAPIDD) Ebola Challenge; a simulated epidemic that generated 4 infectious disease scenarios. Because of the nature of the synthetically generated data, model predictions are compared to exact epidemiological quantities used in the simulation.
In chapter 4, these models are applied to the 1904 Plague epidemic that occurred in Bombay. This chapter provides evidence that these simple models may be applicable to infectious diseases no matter the disease transmission mechanism.
Chapter 5, uses the patch models from chapter 2 to explore how migration in the 1904 Plague epidemic changes the final epidemic size.
The final chapter is an interdisciplinary project concerning within-host dynamics of cereal yellow dwarf virus-RPV, a plant pathogen from a virus group that infects over 150 grass species. Motivated by environmental nutrient enrichment due to anthropological activities, mathematical models are employed to investigate the relevance of resource competition to pathogen and host dynamics.
Chapter 1 provides background information and motivation for infectious disease forecasting and outlines the rest of the thesis.
In chapter 2, logistic patch models are used to assess and forecast the 2013-2015 West Africa Zaire ebolavirus epidemic. In particular, this chapter is concerned with comparing and contrasting the effects that spatial heterogeneity has on the forecasting performance of the cumulative infected case counts reported during the epidemic.
In chapter 3, two simple phenomenological models inspired from population biology are used to assess the Research and Policy for Infectious Disease Dynamics (RAPIDD) Ebola Challenge; a simulated epidemic that generated 4 infectious disease scenarios. Because of the nature of the synthetically generated data, model predictions are compared to exact epidemiological quantities used in the simulation.
In chapter 4, these models are applied to the 1904 Plague epidemic that occurred in Bombay. This chapter provides evidence that these simple models may be applicable to infectious diseases no matter the disease transmission mechanism.
Chapter 5, uses the patch models from chapter 2 to explore how migration in the 1904 Plague epidemic changes the final epidemic size.
The final chapter is an interdisciplinary project concerning within-host dynamics of cereal yellow dwarf virus-RPV, a plant pathogen from a virus group that infects over 150 grass species. Motivated by environmental nutrient enrichment due to anthropological activities, mathematical models are employed to investigate the relevance of resource competition to pathogen and host dynamics.
ContributorsPell, Bruce (Author) / Kuang, Yang (Thesis advisor) / Chowell-Puente, Gerardo (Committee member) / Nagy, John (Committee member) / Kostelich, Eric (Committee member) / Gardner, Carl (Committee member) / Arizona State University (Publisher)
Created2016
Description
One of the single-most insightful, and visionary talks of the 20th century, “There’s plenty of room at the bottom,” by Dr. Richard Feynman, represented a first foray into the micro- and nano-worlds of biology and chemistry with the intention of direct manipulation of their individual components. Even so, for decades there has existed a gulf between the bottom-up molecular worlds of biology and chemistry, and the top-down world of nanofabrication. Creating single molecule nanoarrays at the limit of diffraction could incentivize a paradigm shift for experimental assays. However, such arrays have been nearly impossible to fabricate since current nanofabrication tools lack the resolution required for precise single-molecule spatial manipulation. What if there existed a molecule which could act as a bridge between these top-down and bottom-up worlds?
At ~100-nm, a DNA origami macromolecule represents one such bridge, acting as a breadboard for the decoration of single molecules with 3-5 nm resolution. It relies on the programmed self-assembly of a long, scaffold strand into arbitrary 2D or 3D structures guided via approximately two hundred, short, staple strands. Once synthesized, this nanostructure falls in the spatial manipulation regime of a nanofabrication tool such as electron-beam lithography (EBL), facilitating its high efficiency immobilization in predetermined binding sites on an experimentally relevant substrate. This placement technology, however, is expensive and requires specialized training, thereby limiting accessibility.
The work described here introduces a method for bench-top, cleanroom/lithography-free, DNA origami placement in meso-to-macro-scale grids using tunable colloidal nanosphere masks, and organosilane-based surface chemistry modification. Bench-top DNA origami placement is the first demonstration of its kind which facilitates precision placement of single molecules with high efficiency in diffraction-limited sites at a cost of $1/chip. The comprehensive characterization of this technique, and its application as a robust platform for high-throughput biophysics and digital counting of biomarkers through enzyme-free amplification are elucidated here. Furthermore, this technique can serve as a template for the bottom-up fabrication of invaluable biophysical tools such as zero mode waveguides, making them significantly cheaper and more accessible to the scientific community. This platform has the potential to democratize high-throughput single molecule experiments in laboratories worldwide.
At ~100-nm, a DNA origami macromolecule represents one such bridge, acting as a breadboard for the decoration of single molecules with 3-5 nm resolution. It relies on the programmed self-assembly of a long, scaffold strand into arbitrary 2D or 3D structures guided via approximately two hundred, short, staple strands. Once synthesized, this nanostructure falls in the spatial manipulation regime of a nanofabrication tool such as electron-beam lithography (EBL), facilitating its high efficiency immobilization in predetermined binding sites on an experimentally relevant substrate. This placement technology, however, is expensive and requires specialized training, thereby limiting accessibility.
The work described here introduces a method for bench-top, cleanroom/lithography-free, DNA origami placement in meso-to-macro-scale grids using tunable colloidal nanosphere masks, and organosilane-based surface chemistry modification. Bench-top DNA origami placement is the first demonstration of its kind which facilitates precision placement of single molecules with high efficiency in diffraction-limited sites at a cost of $1/chip. The comprehensive characterization of this technique, and its application as a robust platform for high-throughput biophysics and digital counting of biomarkers through enzyme-free amplification are elucidated here. Furthermore, this technique can serve as a template for the bottom-up fabrication of invaluable biophysical tools such as zero mode waveguides, making them significantly cheaper and more accessible to the scientific community. This platform has the potential to democratize high-throughput single molecule experiments in laboratories worldwide.
ContributorsShetty, Rishabh Manoj (Author) / Hariadi, Rizal F (Thesis advisor) / Gopinath, Ashwin (Committee member) / Varsani, Arvind (Committee member) / Nikkhah, Mehdi (Committee member) / Tillery, Stephen H (Committee member) / Hu, Ye (Committee member) / Arizona State University (Publisher)
Created2019
Description
The human papillomavirus (HPV) is a double-stranded DNA virus responsible for causing upwards of 80% of head and neck cancers in the oropharyngeal region. Current treatments, including surgery, chemotherapy, and/or radiation, are aggressive and elicit toxic effects. HPV is a pathogen that expresses viral-specific oncogenic proteins that play a role in cancer progression. These proteins may serve as potential targets for immunotherapeutic applications. Engineered T cell receptor (TCR) therapy may be an advantageous approach for HPV-associated cancers. In TCR therapy, TCRs are modified to express a receptor that is specific to an immunogenic antigen (part of the virus/cancer capable of eliciting an immune response). Since HPV-associated oropharyngeal cancers typically express unique viral proteins, it is important to identify the TCRs capable of recognizing these proteins. Evidence supports that head and neck cancers typically experience high levels of immune cell infiltration and are subsequently associated with increased survival rates. Most of the immune cell infiltrations in HPV+ HNSCC are CD8+ T lymphocytes, drawing attention to their prospective use in cellular immunotherapies. While TCRs are highly specific, the TCR repertoire is extremely diverse; enabling the immune system to fight off numerous pathogens. In project 1, I review approaches to analyzing TCR diversity and explore the use of DNA origami in retrieving paired TCR sequences from a population. The results determine that DNA origami can be used within a monoclonal population but requires further optimization before being applied in a polyclonal setting. In project 2, I investigate HPV-specific T-cell dysfunction; I detect low frequency HPV-specific CD8+ T cells, determine that they are tumor specific, and show that HPV+HNSCC patients exhibit increased epitope-specific levels of CD8+T cell exhaustion. In project 3, I apply methods to expand and isolate TCRαβ sequences derived from donors stimulated with a previously identified HPV epitope. Single-cell analysis provide ten unique TCRαβ pairs with corresponding CDR3 sequences that may serve as therapeutic candidates. This thesis contributes to fundamental immunology by contributing to the knowledge of T cell dysfunction within HPV+HNSCC and further reveals TCR gene usage within an HPV stimulated population, thus identifying potential TCR pairs for adoptive cell therapies.
ContributorsUlrich, Peaches Rebecca (Author) / Anderson, Karen S (Thesis advisor) / Lake, Douglas (Committee member) / Maley, Carlo (Committee member) / Varsani, Arvind (Committee member) / Arizona State University (Publisher)
Created2020
Description
Viruses infect organisms in all domains of life and are abundant entities in ecosystems. In particular, single-stranded DNA viruses have been found in a wide variety of hosts and ecosystems. Using a metagenomic approach, novel circular viruses have been identified in multiple environmental samples. This thesis focuses on viruses and virus dynamics from avian sources. As part of this thesis, a novel phapecoctavirus was identified in a pigeon cloacal swab. The phapecoctavirus is most closely related to Klebsiella phage ZCKP1, identified from a freshwater sample. Beyond this, this thesis addresses circoviruses, which are of interest due to disease they cause to avian species. Evolution of circovirus recombination was studied in a closed system of uninfected and infected pigeons. 178 genomes of pigeon circovirus were sequenced, and patterns of recombination determined. Seven genotypes were present in the population and genotype 4 was shown to be present in a majority of samples after the experiment was finished. Circoviruses were also identified in waterfowl feces and the ten genomes recovered represent two new circovirus species. Overall, the research described in this thesis helped to gain a deeper understanding of the diversity and evolution of circular DNA viruses associated with avian species.
ContributorsKhalifeh, Anthony (Author) / Varsani, Arvind (Thesis advisor) / Kraberger, Simona J (Committee member) / Dolby, Greer (Committee member) / Arizona State University (Publisher)
Created2021