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Controlling infectious disease spread and preventing disease onset are ongoing challenges, especially in the presence of newly emerging diseases. While vaccines have successfully eradicated smallpox and reduced occurrence of many diseases, there still exists challenges such as fear of vaccination, the cost and difficulty of transporting vaccines, and the ability of attenuated viruses to evolve, leading to instances such as vaccine derived poliovirus. Antibiotic resistance due to mistreatment of antibiotics and quickly evolving bacteria contributes to the difficulty of eradicating diseases such as tuberculosis. Additionally, bacteria and fungi are able to produce an extracellular matrix in biofilms that protects them from antibiotics/antifungals. Mathematical models are an effective way of measuring the success of various control measures, allowing for cost savings and efficient implementation of those measures. While many models exist to investigate the dynamics on a human population scale, it is also beneficial to use models on a microbial scale to further capture the biology behind infectious diseases. In this dissertation, we develop mathematical models at several spatial scales to help improve disease control. At the scale of human populations, we develop differential equation models with quarantine control. We investigate how the distribution of exposed and infectious periods affects the control efficacy and suggest when it is important for models to include realistically narrow distributions. At the microbial scale, we use an agent-based stochastic spatial simulation to model the social interactions between two yeast strains in a biofilm. While cheater strains have been proposed as a control strategy to disrupt the harmful cooperative biofilm, some yeast strains cooperate only with other cooperators via kin recognition. We study under what circumstances kin recognition confers the greatest fitness benefit to a cooperative strain. Finally, we look at a multiscale, two-patch model for the dynamics between wild-type (WT) poliovirus and defective interfering particles (DIPs) as they travel between organs. DIPs are non-viable variants of the WT that lack essential elements needed for reproduction, causing them to steal these elements from the WT. We investigate when DIPs can lower the WT population in the host.

Background: Psychiatric patients have been well documented to have higher rates of physical illness compared to the general population. Treatments of chronic illnesses such as functional gastrointestinal disorders are beginning to incorporate integrated care models to simultaneously address psychiatric and physical symptoms. This is based on recent research emphasizing the importance of the gut-brain axis. However, the intricacies of connections between infectious diseases and mental illness remain unclear. Diarrheal disease and depression account for a disproportionate amount of the total global burden of disease, being the second and fourth greatest contributors respectively. This highlights the need to investigate the possible links between the two, and interactions along the gut-brain axis in general. Objectives: The objectives of this scoping review and thematic analysis was to explore what is known about infectious acute gastrointestinal illness and its relationship to depressive and anxiety symptoms. Ultimately, this review was intended to act as a case study of novel connections between infectious illnesses and mental illness. Methodology: Following Arksey & O’Malley’s framework, five databases (EMBASE, MedLine, PsychInfo, Global Health, HealthStar) were searched resulting in 1156 titles and abstracts. These were screened for inclusion and produced a total of 17 articles included for review and synthesis. Results: Three major themes were identified: 1) Connections between physical and mental status within this context can occur via i) the microbiome, ii) the immune system, iii) the nervous system, and iv) the endocrine system; 2) Bidirectionality of the gut-brain axis is key in understanding cross-talk between symptoms; 3) Integration of care options might result in improved health outcomes. Conclusion: These findings demonstrate that holistic and integrated interventions must be considered not only for chronic and mental illnesses, but also for infectious and mental illnesses, based on the connections between AGI and depressive and anxiety symptoms. More research is required, particularly with human subjects, in order to further understand the connections between the gut and brain. Incorporation of this knowledge into new treatment plans will allow clinicians to deliver more effective care to their patients who suffer from a dual burden of disease. / Thesis / Master of Science (MSc)

Neisseria gonorrhoeae, the causative agent of gonorrhea, is the second most prevalent sexually transmitted infection that leads to substantial morbidity and economic burden worldwide. Improperly treated or untreated gonorrhea can lead to severe and life-threatening complications, including abortion, infertility, pelvic pain, and maternal death. Neisseria gonorrhoeae has developed resistance to the formally and currently used antibiotics. The Centers for Disease Control and Prevention (CDC) have listed multi-drug resistant N. gonorrhoeae as an urgent threat that promptly requires the development of novel therapeutic agents. Traditional drug discovery and development is a time-consuming and costly process associated with high risks. To address the dire need to replenish the dry pipeline of anti-gonorrhea medications, drug repurposing is a promising approach. In this study, an FDA-approved drug library was screened, and 14 drugs were found to exhibit promising anti-gonococcal activity. Interestingly, three extremely potent and narrow-spectrum novel candidates, itraconazole, isavuconazole, and ravuconazole, are azole antifungals, and their activities were further investigated in vitro. Of the three azoles, ravuconazole displayed the most potent activity against N. gonorrhoeae clinical isolates. The time-kill assay revealed that the three azoles showed bactericidal activity. All three azole drugs showed a low frequency of resistance. Besides, isavuconazole and ravuconazole have a longer post-antibiotic effect than azithromycin. All three azoles cleared the burden of intracellular N. gonorrhoeae completely, which is superior to ceftriaxone. In conclusion, itraconazole, isavuconazole, and ravuconazole merit future investigation for the development of anti-gonorrheal therapeutics. This study provided unexplored avenues and promising opportunities that can be further evaluated to combat N. gonorrhoeae infection. / Master of Science / Neisseria gonorrhoeae, the causative agent of gonorrhea, is the second most prevalent sexually transmitted infection that leads to substantial morbidity and economic burden worldwide. Improperly treated or untreated gonorrhea can lead to severe and life-threatening complications, including abortion, infertility, pelvic pain, and maternal death. Due to the increasing prevalence of drug resistance against the formally and currently used antibiotics, the Centers for Disease Control and Prevention (CDC) have classified multi-drug resistant N. gonorrhoeae as an urgent-threat pathogen. Therefore, the discovery of new anti-gonorrheal therapeutics is an urgent need. Drug repurposing is the process of discovering new therapeutic uses for approved or investigational drugs that go beyond the original medical indication. To address the dire need to replenish the dry pipeline of anti-gonorrheal drugs, repurposing FDA-approved drugs is a promising approach as it significantly reduces the time and expense associated with traditional drug development. By screening an FDA-approved drug library, 14 drugs were found to display promising anti-gonococcal activity. Interestingly, three (itraconazole, isavuconazole, and ravuconazole) out of 14 identified drugs were azole antifungal drugs, and their activities were further investigated in vitro. All three azole drugs showed bactericidal activity, meaning that they killed bacteria, had a low propensity to develop resistance, and completely cleared the burden of intracellular N. gonorrhoeae. Besides, our findings suggested that isavuconazole and ravuconazole possessed exceptional activity in the suppression of bacterial growth following brief antibiotic exposure. In conclusion, the three azole drugs exhibited potent anti-gonococcal activity and merited further investigation. This study provided unexplored avenues and promising opportunities that can be further evaluated to combat multidrug-resistant N. gonorrhoeae. Neisseria gonorrhoeae, the causative agent of gonorrhea, is the second most prevalent sexually transmitted infection that leads to substantial morbidity and economic burden worldwide. Improperly treated or untreated gonorrhea can lead to severe and life-threatening complications, including abortion, infertility, pelvic pain, and maternal death. Due to the increasing prevalence of drug resistance against the formally and currently used antibiotics, the Centers for Disease Control and Prevention (CDC) have classified multi-drug resistant N. gonorrhoeae as an urgent-threat pathogen. Therefore, the discovery of new anti-gonorrheal therapeutics is an urgent need. Drug repurposing is the process of discovering new therapeutic uses for approved or investigational drugs that go beyond the original medical indication. To address the dire need to replenish the dry pipeline of anti-gonorrheal drugs, repurposing FDA-approved drugs is a promising approach as it significantly reduces the time and expense associated with traditional drug development. By screening an FDA-approved drug library, 14 drugs were found to display promising anti-gonococcal activity. Interestingly, three (itraconazole, isavuconazole, and ravuconazole) out of 14 identified drugs were azole antifungal drugs, and their activities were further investigated in vitro. All three azole drugs showed bactericidal activity, meaning that they killed bacteria, had a low propensity to develop resistance, and completely cleared the burden of intracellular N. gonorrhoeae. Besides, our findings suggested that isavuconazole and ravuconazole possessed exceptional activity in the suppression of bacterial growth following brief antibiotic exposure. In conclusion, the three azole drugs exhibited potent anti-gonococcal activity and merited further investigation. This study provided unexplored avenues and promising opportunities that can be further evaluated to combat multidrug-resistant N. gonorrhoeae.

Influenza is one of the most common diseases worldwide, yet the vaccines against influenza are only 35% effective at protecting against infection. Creating a more effective vaccine requires an understanding of the foundation and the factors that contribute to a strong and protective adaptive immune response. T-bet [TBX21] is a transcription factor that plays an instrumental role in the orchestration of the type 1 immune response, which is the specialized response used by the immune system for a cell-mediated response against intracellular pathogens, such as influenza. It has yet to be explored in an influenza setting on the role T-bet in the production of antibodies. The aim of this study is to understand T-bet's role in production of antibody isotypes and identify whether expression of T-bet is more important for antibody production in T cells or B cells. We expected T-bet knockout (KO) mice to have IgG2a and that T-bet expression would be more important in T cells for antibody production. An enzyme-linked immunosorbent assay (ELISA) was used to measure the amount of virus-specific antibody in T-bet KO versus wild type (WT) mice infected with influenza. The results show that the T-bet KO and WT mice have relatively the same amount of IgG and IgG1, but the T-bet KO have a significantly lower level of IgG2a, confirming T-bet's importance for its production. To distinguish the importance of T-bet expression while T-bet expression in T cells was constant, a model was developed to allow us to control expression of T-bet in B cells. The results however were inconclusive, and the experiment will have to be repeated to make a firm conclusion on the roles of lymphocytes in the control of IgG isotypes. Overall, these results indicate that the manipulation of T-bet expression can be used as a vector to control IgG antibody levels, which holds potential for the improvement of vaccines.

These recent events of H1N1 flu outbreak illustrate the potential ramifications of infectious diseases on modern society and how society responds to these threats. This thesis addresses the specific case of avian influenza in U.S. poultry production. By building an expected utility maximization model for integrators contracting with growers of varying bio-secure levels, one can investigate the relationship between the bio-secure choice of the poultry industry and their production performance. The model is empiricized using the Phoon, Quek, and Huang (PQH) simulation technique to conduct numerical analysis. The model selects the optimal percentage of bio-secure farms for the integrators to contract, output price reductions due to disease outbreak, and different probabilities of disease outbreak. Results allow the examination of whether alternative USDA/APHIS indemnification rules can sufficiently influence integrators willingness to improve their bio-security level.

Emerging infectious diseases of wildlife have threatened host populations of diverse taxa in recent history, which is largely attributable to anthropogenic global change. In three data chapters, this dissertation examines the drivers of individual- to population-level variation in how host populations respond to novel and emerging pathogens. Each chapter explores these processes in bat populations of North America, predominantly the Northeast and Midwest regions of the United States, impacted by the emerging fungal pathogen that causes white-nose syndrome, Pseudogymnoascus destructans. In Chapter 2, I disentangle the effects of adaptive host traits and environmental influences in driving host population stabilization of the little brown bat (Myotis lucifugus), finding that host-pathogen coexistence in this system is the product of their complex interaction. In Chapter 3, I characterize the range-wide variation in white-nose syndrome impacts on a federally endangered and poorly studied species, the Indiana bat (Myotis sodalis), as well as environmental and demographic determinants of its declines over epidemic time. In Chapter 4, I explore the role of individual variation in roosting microclimate selection of little brown bats in driving their infection severity, yielding important insights into the pathophysiology and environmental dependence of white-nose syndrome. Ultimately, this dissertation characterizes complex drivers of variation in host responses to emerging and invading pathogens, yielding insights essential to the successful mitigation of their impacts. / Doctor of Philosophy / In the same way that Covid-19 swept through our global human population in the year 2020, novel infectious diseases have threatened wildlife populations, sometimes to the point of extinction. Often, however, the processes driving the impacts of novel infectious diseases in wildlife are unknown, despite being important information to protect susceptible populations. In this dissertation, I explore how North American bat populations have been impacted by a recently emerged disease, white-nose syndrome, and what processes cause variation in how individual bats and bat colonies have responded to the disease. In Chapter 2, I explore how the little brown bat (Myotis lucifugus) has evolved to co-exist with its new pathogen and how this coexistence is affected by environmental conditions like temperature and humidity. In Chapter 3, I characterize variation in how populations of the Indiana bat (Myotis sodalis) have responded to white-nose syndrome and how environmental and demographic conditions have affected declines since the disease first emerged. In Chapter 4, I explore how the temperatures used by little brown bats during hibernation affect the severity of their infection, giving us important information on how bats survive with white-nose syndrome and the role of temperature. Altogether, the research in this dissertation describes complex interactions between hosts, pathogens, and their environment in driving the patterns we observe after the emergence of novel infectious diseases.

This dissertation focuses on immunological, epidemiological, and economic modeling of HIV, influenza, and fungal meningitis, and includes three research studies. In the first study on HIV, the study objective is to analyze the dynamics of HIV-1, CD4+ T cells and macrophages during the acute, clinically latent and late phases of HIV infection in order to predict their dynamics from acute infection to clinical latency and finally to AIDS in treatment naive HIV-infected individuals. The findings of the study show that the peak in viral load during acute HIV infection is due to virus production by infected CD4+ T cells, while during the clinically latent and late phases of infection infected macrophages dominate the overall viral production. This leads to the conclusion that macrophage-induced virus production is the significant driver of HIV progression from asymptomatic phase to AIDS in HIV-infected individuals. In the second study on influenza, the study objective is to estimate the direct and indirect epidemiological and economic impact of vaccine interventions during an influenza pandemic in Chicago, and assist in vaccine intervention priorities. Population is distributed among high-risk and non-high risk within 0-19, 20-64 and 65+ years subpopulations. The findings show that based on risk of death and return on investment, high-risk groups of the three age group subpopulations can be prioritized for vaccination, and the vaccine interventions are cost-saving for all age and risk groups. In the third study on fungal meningitis, the study objective is to evaluate the effectiveness and cost of the fungal meningitis outbreak response in New River Valley of Virginia during 2012-2013, from the local public health department and clinical perspectives. We estimate the epidemiological effectiveness of this outbreak response to be 153 DALYs averted among the patients, and the costs incurred by the local health department and clinical facilities to be $30,413 and $39,580 respectively. Moving forward, multi-scale analysis of infectious diseases connecting the different scales of evolutionary, immunological, epidemiological, and economic dynamics has good potential to derive meaningful inferences for decision making in clinical and public health practice, and improve health outcomes. / Ph. D.

Campylobacter spp. infections are an increasing global concern responsible for a significant burden of disease every year. Wildlife and domestic animals are considered important reservoirs, but little is known about host-factors driving pathogen infection dynamics in wild mammal populations. In countries like Botswana, there is significant spatial overlap between humans and wildlife with a large proportion of the population vulnerable to Campylobacter infection, making Botswana an ideal location to study these interactions. This thesis reviews mammalian wildlife species that have been identified as carriers of Campylobacter spp., identifies life-history traits (urban association, trophic level, and sociality) that may be driving Campylobacter infection, and utilizes banded mongoose (Mungos mungo) (n=201) as a study species to illuminate potential Campylobacter spp. transmission at the human-wildlife interface in northern Botswana. Results of the latter study suggest that human-landscapes are critical to C. jejuni infection in banded mongooses, as mongooses utilizing man-made structures as dens had significantly higher levels of C. jejuni than mongooses using natural dens (p=0.019). A similar association was found across all wild mammals with significantly greater number of urban dwelling species positive for C. jejuni than urban avoiders (p = 0.04). Omnivorous and social mammals were significantly associated with C. coli presence (p=0.04 and p<0.00 respectively), but not with C. jejuni indicating there may be important differences in transmission dynamics between Campylobacter species. These results suggest that landscape features and life-history traits can have important influences on Campylobacter species exposure and transmission dynamics in wildlife. / Master of Science / Campylobacter infections are increasing worldwide but we still know little about the true burden of disease in the developing world, and even less about the role of wildlife and environmental reservoirs in human exposure and disease. I reviewed life-history traits (urban association, animal rank on the food chain, and sociality) that might be driving Campylobacter spp. infection in wildlife and investigated interactions between an urbanizing wildlife species, banded mongoose (Mungos mungo), humans, and the environment. Banded mongooses live in close association with humans and infections with C. jejuni were greater among mongooses utilizing man-made structures compared to those using natural dens. Across all wild mammal species tested for Campylobacter spp., mammals associated with urban living were significantly more likely to be positive for C. jejuni than mammals that avoid urban areas. Lowerranking mammals on the food chain and social mammals were associated with presence of C. coli, suggesting life-history rates are playing a role in wild mammal exposures to the pathogen and that these exposures are different for C. coli than C. jejuni. These data suggest that wildlife life-history traits and utilization of human landscapes are important for pathogen presence. In turn, pathogen circulation and transmission in urbanizing wildlife reservoirs may increase human vulnerability to disease, particularly in impoverished populations, where greater environmental exposures are expected. Improvement of waste management and hygiene practices may help reduce transmission between wildlife and humans.

Emerging infectious diseases (EID) pose a serious threat to global public health. Computational epidemiology is a nascent subfield of public health that can provide insight into an outbreak in advance of traditional methodologies. Research in this dissertation will use fuse nontraditional, publicly available data sources with more traditional epidemiological data to build and parameterize models of emerging infectious diseases. These methods will be applied to avian influenza A (H7N9), Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV), and Ebola virus disease (EVD) outbreaks. This effort will provide quantitative, evidenced-based guidance for policymakers and public health responders to augment public health operations. / Ph. D.