Life Sciences Commons^™

The Sex Chromosome Complement And Gut Microbiome Act Independently And Collaboratively To Impart Sex Dimorphisms In Humoral Immunity, Carly J. Amato-Menker

Graduate Theses, Dissertations, and Problem Reports

Sex dimorphisms in immunity are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones have been extensively documented, recent recognition of the nuanced contributions of the sex chromosome complement (XX vs. XY) and the gut microbiome to immune sex dimorphisms underscores the need for a more comprehensive understanding. Within this context, the work herein focuses on unraveling the individual and collaborative impacts of the sex chromosome complement and gut microbiota on humoral immune activation. We assessed humoral immune responses to immunization with heat-killed Streptococcus pneumoniae (HKSP) in Four Core Genotype (FCG) mice and found elevated IgM-secreting …

Immune Outcomes Affected By Selection For Parasite Resistance In Katahdin Sheep, Kelsey Lynne Bentley

Graduate Theses, Dissertations, and Problem Reports

Our understanding of the complex connection between selection for parasite resistance and the overall health outcomes in livestock is unclear. This study investigates the impact of post-weaning fecal egg count (PFEC) estimated breeding values (EBV) on health outcomes and immune responses in Katahdin sheep. Selection for PFEC, favoring Low-PFEC lambs, not only affects survivability to weaning but also suggests broader implications for immunity beyond parasite resistance. The effect of PFEC EBV on antibody production in response to vaccination against Clostridium perfringens type C&D and tetanus toxoid (CD&T) revealed a stepwise decrease in immunoglobin (IgG) from Low-PFEC to High-PFEC groups upon …

Cluster Homolog Of Immunoglobulin-Like Receptor Genes In Chicken Immune Responses, Brandi A. Sparling

Graduate Theses, Dissertations, and Problem Reports

This dissertation explores the identity and role of immunoglobulin-like (Ig-like) receptors in chickens, with focus on their implications in disease and disease progression. These receptors, wisely expressed across immune cells, interact with the major histocompatibility complex (MHC) class I molecules to modulate immune responses in mammals. Due to the insufficient representation of chicken Ig-like receptors in online databases, this study systematically annotates the chicken Cluster Homolog of Immunoglobulin-like Receptors (CHIR) genes using advanced bioinformatic techniques, aligning with the release of the 7th edition of the chicken genome assembly that comprises builds for a broiler and layer chicken. The analysis identifies …

The Development Of A New Pertussis Booster Formulation Via The Implementation Of New Adjuvants And Utilization Of Alternate Routes Of Administration, Megan Ashley Dejong

Graduate Theses, Dissertations, and Problem Reports

Pertussis (whooping cough) is a respiratory disease caused by airborne transmission of the Gram-negative bacterium, Bordetella pertussis. Prior to the development of the first pertussis vaccines (whole cell (wP) vaccines), the incidence of pertussis was in the hundreds of thousands of cases per year, which led to the death of many children, as the infection is most severe in younger populations. Thankfully, the wP formulation resulted in a dramatic decrease in the number of annual pertussis cases, nearly eradicating the disease. However, as wP contained the whole B. pertussis bacterium (and its lipooligosaccharide (LOS)), reactogenicity issues became apparent, leading …

Utilizing The K18-Hace2 Mouse Model To Develop Protective Covid-19 Vaccines, Ting Y. Wong

Graduate Theses, Dissertations, and Problem Reports

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the respiratory virus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Similar to other respiratory viruses, SARS-CoV-2 is transmitted through inhalation of respiratory droplets and aerosols from infected individuals. Once inhaled, SARS-CoV-2 utilizes the receptor binding domain (RBD) on the spike protein to bind to human Angiotensin Converting Enzyme 2 (hACE2) receptor to gain entrance into host cells to begin viral replication. SARS-CoV-2 infection can result in mild to severe cases of COVID-19 ranging from asymptomatic infections, cold or flu like symptoms to respiratory failure. The onset of the pandemic in …

Tetramerization Of Stat5 Has Opposing Roles In Governing Autoimmune Pathogenesis, Kelly Lynn Monaghan

Graduate Theses, Dissertations, and Problem Reports

Signal transducers and activators of transcription 5 (STAT5A and STAT5B) are members of the STAT protein family. STAT5 plays a critical role in mediating cellular responses following cytokine stimulation. Critical STAT5 signaling is achieved following functional dimerization, which occurs via SH2 domain interactions. The binding of two STAT5 dimers to tandemly linked TTCN₃GAA γ-interferon-activated sequence (GAS) motifs and N-terminal domain interactions, facilitates functional tetramerization. The biological role of STAT5 tetramers has been investigated using the Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, in which STAT5 tetramers cannot be formed due to substitutions in critical amino acid …

Investigating The Interplay Of The Immune System, Skin Barrier, And Microbiome Following Dermal Exposure To Triclosan, Rachel Baur

Graduate Theses, Dissertations, and Problem Reports

Triclosan is an antimicrobial chemical used in healthcare products that are applied to the skin. However, exposure to triclosan has been positively associated with food allergy, aeroallergy, and asthma severity in humans. In mice, dermal triclosan exposure, although not directly sensitizing, has been shown to augment the allergic response in a model of asthma. Furthermore, exposure to triclosan on mouse skin has been demonstrated to be immunomodulatory through the activity of thymic stromal lymphopoietin and S100 calcium-binding protein A8. The skin barrier and microbiome are known to interact with the immune system and disruptions in barrier integrity and the microbiome …

A Survey Of Anthelmintic Resistance In Angus Bulls Participating In Centralized Performance Tests In Appalachia, Roger Tyler Rohrbaugh

Graduate Theses, Dissertations, and Problem Reports

Resistance to anthelmintics, more commonly referred to as “de-wormers,” has been on the rise in parasites that affect cattle. Parasite infection can have severe impacts on calf productivity resulting in reduced profitability. Therefore, we sought to better understand anthelmintic resistance in Appalachia by surveying Angus bulls entering performance tests in VA and WV. During a four-year period, over 1050 Angus bulls were tested at bull development facilities in Wardensville, WV, Culpeper, VA and Wytheville, VA. Fecal samples were collected at arrival and 14-21 days later for determination of fecal egg count (FEC) reduction. Upon arrival, all bulls received either fenbendazole …

The Effects Of Genetic Differences In An Innate Immune Receptor On Immune Responses To Haemonchus Contortus In Sheep, Denzel Deshawn Middleton

Graduate Theses, Dissertations, and Problem Reports

Little is known about differences observed in early immunological signaling events that result in cellular infiltration and Th2 cytokine production that mediate parasite expulsion. Parasite resistant St. Croix (STC) sheep have been used as model for full host protective immunity as they present the ability to respond to larval stages of H. contortus. RNA sequencing analysis of peripheral blood mononuclear cells (PBMC) stimulated with H. contortus larval antigen (HcLA) revealed significant upregulation in NLRP3 and its pathway component TLR4. Predicted protein structural software identified distinct differences in NLRP3 protein structure in STC and parasite susceptible Suffolk (SUF) sheep. NLRP3 …

Pseudomonas Aeruginosa Vaccine Development Using Dual-Species Whole Cell And Subunit Vaccines, Catherine Bell Blackwood

Graduate Theses, Dissertations, and Problem Reports

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen which can cause severe, recurrent, and chronic infections. The pathogen is highly adaptable, and pneumonia caused by it is associated with high morbidity and mortality, especially in individuals with the genetic disorder cystic fibrosis. Antibiotic resistance amongst clinical isolates of P. aeruginosa is steadily increasing, and multi-drug resistant strains are prevalent. There is currently no vaccine available for commercial use against P. aeruginosa. For these reasons, we sought to understand the immunity to P. aeruginosa induced by whole cell vaccination and identify antigens for development of future subunit vaccines. In this dissertation, …

Targeting The Cerebrovasculature In Sepsis: A Focus On The Brain Microvascular Endothelium, Divine C. Nwafor

Graduate Theses, Dissertations, and Problem Reports

The blood-brain barrier (BBB) is a critical interface between the systemic circulation and the brain. It is a specialized multicellular unit composed of brain microvascular endothelial cells (BMECs), pericytes, a basement membrane, and astrocytic end foot processes. BMECs are a principal component of the BBB that provide the structural framework needed for the stringent transport of molecules into the brain. BMEC dysfunction permits the trafficking of neurotoxins from systemic circulation into the brain, which ultimately exacerbates BBB dysfunction and neuroinflammation. Studies have shown that BBB dysfunction is a key determinant of cognitive decline in sepsis. However, there are critical knowledge …

Pulmonary Immune Responses To Respirable Elongate Mineral Particles Of Asbestiform And Non-Asbestiform Morphologies, Timur Khaliullin

Graduate Theses, Dissertations, and Problem Reports

Inhalation exposure to asbestiform elongate mineral particles (EMPs) may cause pulmonary fibrosis, lung and pleural cancer. At the same time, epidemiological evidence for non-asbestiform EMP pathogenicity is scarce, with little if any risk of cancer, but consistent findings of pneumoconiosis and increased mortality. Globally, conditions caused by asbestos exposures contribute most to the occupational cancer burden and are responsible for the increasing mortality for occupational respiratory diseases. Immunological components of the fiber-induced lesions are extremely understudied, partly due to the lack of comparable test articles. In this study I utilized respirable preparations of asbestiform and non-asbestiform riebeckite and tremolite to …

Haemonchus Contortus Antigen Identification And Use Of Tropomyosin In Ovine Vaccine Development, Brynnan P. Russ

Graduate Theses, Dissertations, and Problem Reports

Globally, the small ruminant industry loses hundreds of millions of dollars due to parasitism by the gastrointestinal nematode Haemonchus contortus. This parasite feeds on blood in the host’s abomasum leading to disease including anemia, hypoproteinemia, lethargy, and death. There have been exhaustive efforts to manage this parasite including different management applications, anthelmintic treatment, and now integration of resistance genetics into a flock. Like antibiotics, overuse of anthelmintics has led to resistance of H. contortus to these drugs. Therefore, other methods of control are the main focuses of many research initiatives. St. Croix are a resistant breed of sheep that mount …

Characterization Of Ovine Monocytes In Response To Haemonchus Contortus Larvae In Vitro And A Novel Role Of Interleukin-13 Inducing Larval Paralysis, Elizabeth Shepherd

Graduate Theses, Dissertations, and Problem Reports

Haemonchus contortus is a hematophagous, gastrointestinal parasite affecting small ruminants. Parasitism by H. contortus is the greatest concern of sheep producers in the United States and accounts for billions of dollars in economic loss worldwide. However, different breeds of sheep display differences n natural resistance to H. contortus. St. Croix hair sheep have a remarkable ability to clear H. contortus without the aid of anthelmintics and develop a robust T helper type 2 (Th2) immune response, preventing establishment of infective stage 3 larvae (L3), when compared to susceptible Suffolk sheep. However, the mechanism of development of immune response and …

Induction Of Cerebral Hyperexcitability By Peripheral Viral Challenge: Role Of Cxcl10 Chemokine, Tiffany J. Petrisko

Graduate Theses, Dissertations, and Problem Reports

Peripheral viral infections are po­tent comorbid factors that exacerbate neuro­degene­ration. Although the under­lying mecha­nisms have not been defined, neuronal hyperexcitability has been established as an underlying feature. Our lab has developed a preclinical model in which a viral mimetic, poly­inosinic-poly­cytidylic acid (PIC) is injected in­tra­peritoneally to induce an anti-viral acute phase response (APR). APR in turn elicits robust neuronal hyperexcitability. The present study was undertaken to characterize molecular mechanisms that mediate the development of hyperexcitability in response to PIC challenge. The analysis of brain tissue after PIC challenge revealed a robust elevation of CXCL10 chemokine, indicating its putative role in …

The Microvascular And Systemic Effects Of Titanium Dioxide Nanoparticle Exposure: A Physiological Perspective, Alaeddin Bashir Abukabda

Graduate Theses, Dissertations, and Problem Reports

Titanium dioxide nanoparticles (nano-TiO₂) are one of the most widely used engineered nanomaterials (ENM). Their ubiquitous inclusion warrants a more thorough understanding of their toxicity, particularly in sensitive populations such as pregnant women and the developing fetus.

The aim of the first study was to determine the most sensitive segments of the vasculature to pulmonary ENM exposure. Macrovascular function was investigated in the thoracic aorta, common femoral artery and 3^rd order mesenteric arterioles using wire myography. Microvascular function was assessed in 4^th and 5^th order mesenteric arterioles via pressure myography. Nano-TiO₂ exposure induced impairments …