Modeling the impact of climate change on tick population dynamics and tick-borne disease spread

There is increasing evidence that Lyme disease is an emerging threat for public health in Canada. In this dissertation, we study the impact of climate change on establishment/extinction of the Lyme disease tick vector Ixodes scapularis and Lyme pathogen Borrelia burgdorferi in the Canadian landscape by utilizing mathematical techniques and computer simulations. We develop principal mathematical frameworks using ordinary differential equations with periodic coefficients, partial differential equations with seasonality and a periodic system of delay differential equations with periodic delay. We develop analysis and tools to predict the long-term status of Lyme disease transmission dynamics in the vector population. We determine factors, which are of interest to public health policy makers, for Lyme disease prevention and control in Canada in varying environmental conditions. We provide the theoretical foundation of a risk map of Lyme disease in Canada

Past and future perspectives on mathematical models of tick-borne pathogens

Ticks are vectors of pathogens which are important both with respect to human health and economically. They have a complex lifecycle requiring several blood meals throughout their life. These blood meals take place on different individual hosts and potentially on different host species. Their lifecycle is also dependent on environmental conditions such as the temperature and habitat type. Mathematical models have been used for the more than 30 years to help us understand how tick dynamics are dependent on these environmental factors and host availability. In this paper we review models of tick dynamics and summarise the main results. This summary is split into two parts, one which looks at tick dynamics and one which looks at tick borne-pathogens. In general, the models of tick dynamics are used to determine when the peak in tick densities is likely to occur in the year and how that changes with environmental conditions. The models of tick borne pathogens focus more on the conditions under which the pathogen can persist and how host population densities might be manipulated to control these pathogens. In the final section of the paper we identify gaps in the current knowledge and future modelling approaches

Influenza Prevalence in the US Associated with Climatic Factors, Analyzed at Multiple Spatial and Temporal Scales.

Linkages between influenza prevalence and climate (e.g. precipitation, temperatures, El Nino Southern Oscillation ENSO) have been suspected, but definitive evidence remains elusive. This analysis investigated a climatic relationship between influenza mortality (measured by multiple caused pneumonia and influenza deaths) and influenza morbidity (measured by isolates tested for influenza). Influenza-climate linkages were analyzed at multiple spatial scales (e.g. local analysis, and regional analysis) and multiple temporal scales (e.g. annualized mortality counts, and mortality counts based on cumulative percentiles). Influenza mortality and morbidity were found to have significant correlations to seasonal temperatures, precipitation, and ENSO. Influenza-climate associations varied spatially and temporally, and underscore the importance of considering geographic scale in investigative analyses of disease. Evidence for an influenza-climate relationship provides a greater understanding of the enviro-climatic factors that can contribute to an influenza epidemic, and provides an impetus for further studies that incorporate climatic factors in influenza risk modeling

Global dynamics of some vector-borne infectious disease models with seasonality

Vector-borne infectious diseases such as malaria, dengue, West Nile fever, Zika fever and Lyme disease remain a threat to public health and economics. Both vector life cycle and parasite development are greatly influenced by climatic factors. Understanding the role of seasonal climate in vector-borne infectious disease transmission is particularly important in light of global warming. This PhD thesis is devoted to the study of global dynamics of four vector-borne infectious disease models. We start with a periodic vector-bias malaria model with constant extrinsic incubation period (EIP). To explore the temperature sensitivity of the EIP of malaria parasites, we also formulate a functional differential equations model with a periodic time delay. Moreover, we incorporate the use of insecticide-treated bed nets (ITNs) into a climate-based mosquito-stage-structured malaria model. Lastly, we develop a time-delayed Lyme disease model with seasonality. By using the theory of basic reproduction ratio, R0, and the theory of dynamical systems, we derive R0 and establish a threshold type result for the global dynamics in terms of R0 for each model. By conducting numerical simulations of case studies, we propose some practical strategies for the control of the diseases

A Simple Scoring System to Differentiate between Relapse and Re-Infection in Patients with Recurrent Melioidosis

Melioidosis is a serious infectious disease caused by the Gram-negative bacterium, Burkholderia pseudomallei. This organism is present in the environment in areas where melioidosis is endemic (most notably East Asia and Northern Australia), and infection is acquired following bacterial inoculation or inhalation. Despite prolonged oral eradicative treatment, recurrent melioidosis occurs in approximately 10% of survivors of acute melioidosis. Recurrent melioidosis can be caused by relapse (failure of initial eradicative treatment) or re-infection with a new infection. The aim of this study was to develop a simple scoring system to distinguish between re-infection and relapse, since this has implications for antimicrobial treatment of the recurrent episode, but telling the two apart normally requires bacterial genotyping. A prospective study of melioidosis patients in NE Thailand conducted between 1986 and 2005 identified 141 patients with recurrent melioidosis. Of these, 92 patients had relapse and 49 patients had re-infection as confirmed by genotyping techniques. We found that relapse was associated with previous inadequate treatment and shorter time to clinical features of recurrence, while re-infection was associated with renal insufficiency and presentation during the rainy season. A simple scoring index to help distinguish between relapse and re-infection was developed to provide important bedside information where rapid bacterial genotyping is unavailable. Guidelines are provided on how this scoring system could be implemented

Investigation Of The Neurological Manifestations Of Lyme Disease And The Impact Of Borrelia Burgdorferi On The Epigenetic Landscape Of Astrocytes

Lyme disease, caused by the spirochete Borrelia burgdorferi (Bb), is the most commonly reported vector-borne disease in the United States – with 30,000 cases being reported to the CDC annually, though it is estimated that 300,000 individuals are infected each year in the U.S [1–4]. Due to the medical treatment of the disease, this equates to an estimated $712 million -$1.3 billion in medical costs each year [5]. Conclusively, due to the continued geographical spread and increasing incidence rate, Lyme disease is becoming a greater public health threat throughout the world. The symptoms of Lyme disease can range from erythema migrans to more systematic disorders such as arthritis and neurological complications, termed neuroborreliosis [6,7]. Manifestations of neuroborreliosis include radiculoneuritis, meningitis, and facial palsy [8–10]. Interestingly, B. burgdorferi does not produce any known toxins, and it is thought that the resulting host immune response leads to cellular and tissue damage associated with clinical symptoms. Although many individuals will be effectively treated through the administration of antibiotics, up to 20% of patients will experience on-going symptoms termed Post-treatment Lyme Disease Syndrome (PTLDS). PTLDS is marked by persistent musculoskeletal pain and neurological complications. Inflammatory states have been associated to these symptoms with the invasion of peripheral immune cells and an increase of inflammatory cytokines. Furthermore, the neurological complications of PTLDS has been associated with an increase in glial inflammation. It is well-documented that B. burgdorferi is capable of penetrating into the central nervous system (CNS); however, it is unknown how and where the bacterium does so. Additionally, the exact pathogenetic mechanisms of neuroborreliosis and PTLDS are poorly understood. The work within this dissertation aims to provide novel insight into these gaps in knowledge. This dissertation is laid out into three sections relating to understanding the pathogenesis of the neurological effects of Lyme disease. In the first study, we aimed to provide an explanation for the dissemination of B. burgdorferi and peripheral immune cells into the central nervous system. Clinical presentations of neuroborreliosis is associated with an increase of peripheral immune cells, inflammatory chemokines, and live B. burgdorferi in the cerebrospinal fluid (CSF). To this end, we sought to investigate a direct route from hematogenous dissemination into the CSF. The choroid plexus (CP) is a structure within the ventricles of the brain that is responsible for the production of CSF, the formation of the blood-CSF barrier, and regulation of the immune response. This barrier allows for the exchange of specific nutrients, waste, and peripheral immune cells between the blood stream and CSF. We hypothesize that during infection of the choroid plexus, Borrelia burgdorferi will induce an immune response conducive to the chemotaxis of immune cells and subsequently lead to a pro-inflammatory state within the CNS. To investigate this hypothesis, we cultured primary human choroid plexus epithelial cells and infected with the B. burgdorferi strain B31 MI-16 for 48 hours. RNA was isolated and used for RNA sequencing and RT-qPCR validation. Secreted proteins in the supernatant were analyzed via ELISA. Transcriptome analysis based on RNA sequencing determined a total of 160 upregulated genes and 98 downregulated genes. Pathway and biological process analysis determined a significant upregulation in immune and inflammatory genes specifically in chemokine and interferon related pathways. Further analysis revealed downregulation in genes related to cell to cell junctions including tight and adherens junctions. Protein analysis of secreted factors showed an increase in inflammatory chemokines, corresponding to our transcriptome analysis. These data further demonstrate the role of the CP in the modulation of the immune response in a disease state and give insight into the mechanisms by which Borrelia burgdorferi may disseminate into, and act upon, the CNS. Future experiments aim to detail the impact of B. burgdorferi on the blood-CSF-barrier (BCSFB) integrity and inflammatory response within animal models. The second and third study aim to elucidate the pathogenic mechanisms of neuroborreliosis and PTLDS, specifically the manifestations of a persistent inflammatory state. As B. burgdorferi has previously been shown to elicit an inflammatory response in astrocytes, and glial inflammation is associated with PTLDS, we sought to investigate the epigenetic modifications associated with the astrocytic response in order to determine a mechanistic explanation to these disorders. In the second study, we investigated the differential DNA methylation of astrocytes in response to three strains of B. burgdorferi – B31 MI-16, B31 e2, and 297 through the use of beadchip array. This study utilized primary human astrocytes in vitro. This study was met with a limiting factor in biological replicate variability that led to diminished results. Nevertheless, differential methylation within specific genes involving vesicle trafficking and cell communication were observed. This suggests that DNA methylation may be a mechanistic explanation for the changes in gene expression of astrocytes in response to B. burgdorferi. In the third study, we utilized the same astrocyte model of the second study to investigate the effects of B. burgdorferi on chromatin structure of astrocytes. We performed in vitro infection of astrocytes with the B31 MI-16 strain for 24, 48, 72, and 96 hours. Following infection, ATAC-seq was performed to interrogate the chromatin structure of astrocytes in response to B. burgdorferi. We observed a robust change in chromatin accessibility at 24-hours with 25,464 differential peaks. At 48, 72, and 96 hours, these peaks were reduced to 7,266, 3,376, and 3,015 respectively. Additionally, while many of the differential peaks were associated with open chromatin at 24, 48, and 72 hours, the 96-hour time point was marked by a dramatic decrease in chromatin accessibility. Many of the peaks within gene bodies at the first three time points were associated with changes in anatomical and morphological alterations, while the 96-hour time point was highlighted by metabolic and cellular stress. This suggests that astrocytes undergo an acute response following infection observed by a large change in chromatin structure associated with inflammation and immune response genes, which later decrease in accessibility. Motif enrichment analysis provides greater insight into the overall response of astrocytes across time points. The AP-1 transcription factor is involved in the transcription of genes in response to inflammatory stimuli, stress signals, and infection. This transcription factor is made up of a heterodimer that includes the FOS, JUN, ATF, and JDP families. Motif analysis indicated significant enrichment of these family members at each time point, and in fact, analysis of peaks shared amongst all time points indicated AP-1 motif as being the most significantly enriched. These data suggest that the response of astrocytes to B. burgdorferi is in part due to the changes in chromatin accessibility that provides an environment for the transcription of genes associated with the inflammatory and immune response. Furthermore, AP-1 has been implicated as a potential transcription factor responsible for these changes in gene expression. Together, the work within this dissertation demonstrates potential mechanisms for the pathogenesis of neuroborreliosis and PTLDS. This is highlighted by the potential of the choroid plexus as a route of dissemination for B. burgdorferi and peripheral immune cells into the CNS as an explanation for the clinical manifestations of neuroborreliosis. Additionally, these studies are the first to implicate B. burgdorferi as an epimutagen which provides insight into the mechanisms and development of the neurological and persistent symptoms of Lyme disease. In conclusion, this work provides novel insights for the pathogenesis of the neurological effects of Lyme disease which may aid in the development of future therapeutics

A Mathematical Model for Zika Virus Infection and Microcephaly Risk Considering Sexual and Vertical Transmission

We establish a compartmental model for Zika virus disease transmission, with particular attention paid to microcephaly, the main threat of the disease. To this end, we consider separate microcephaly-related compartments for affected infants, as well as the role of asymptomatic carriers, the influence of seasonality and transmission through sexual contact. We determine the basic reproduction number of the corresponding time-dependent model and time-constant model and study the dependence of this value on the mosquito-related parameters. In addition, we demonstrate the global stability of the disease-free periodic solution if R01. We fit our model to data from Colombia between 2015 and 2017 as a case study. The fitting is used to figure out how sexual transmission affects the number of cases among women as well as the number of microcephaly cases. Our sensitivity analyses conclude that the most effective ways to prevent Zika-related microcephaly cases are preventing mosquito bites and controlling mosquito populations, as well as providing protection during sexual contact