Bacterial Infections and Mycoses Commons^™

The Streptococcus Pyogenes Hyaluronic Acid Capsule Prevents Neutrophil Clearance, And Greater Insights Into The Streptococcal M Protein As A Vaccine Candidate And Driver Of Heart Dysfunction, Jacklyn Hurst

Electronic Thesis and Dissertation Repository

Streptococcus pyogenes is a human-specific opportunistic pathogen that exploits an assortment of surface molecules to overcome host clearing mechanisms and cause a substantial burden of acute and chronic diseases worldwide. In the present work we utilize the M18 serotype S. pyogenes strain MGAS8232 to demonstrate that genomic deletion of thehyaluronic acid capsule significantly reduces bacterial densities in murine models of experimental nasopharyngeal and skin infections. We show that anti-Ly6G administration recovers the deteriorated burden by unencapsulated bacteria at both infection sites, indicating that capsule expression promotes resistance to neutrophil-mediated clearance during acute infections. We also evaluated the efficacy of serotype-specific …

Effects Of Annexin A5 On Endothelial Inflammation Induced By Lipopolysaccharide-Activated Platelets And Extracellular Vesicles, Brent Jeffrey Tschirhart

Electronic Thesis and Dissertation Repository

Sepsis is a dysregulated immune response to infection and the leading cause of mortality globally, accounting for 11 million deaths in 2017. To date, no therapeutics are available to treat the underlying septic response. Previous research from our laboratory has shown that annexin A5 (Anx5) treatment increased survival by 40% in mice with endotoxemia, a model of sepsis. During sepsis, activated platelets release membrane fragments called extracellular vesicles (EVs) with externalization of phosphatidylserine to which annexin A5 binds with a high affinity. We hypothesized that annexin A5 will block the pro-inflammatory response induced by activated platelets and EVs in vascular …

Synergistic Effects Of Non Contact Induction Heating & Antibiotics On Staphylococcus Aureus Biofilm, Rajeshwar Singh Sidhu

Electronic Thesis and Dissertation Repository

Staphylococcus aureus is a major cause of prosthetic joint infection (PJI) in which it forms adherent biofilms, thick aggregates of extracellular polymeric substances (EPS) produced by the bacteria. Biofilm associated infections are difficult to treat as they have increased resistance to various antimicrobial agents, which means infected implants often require multiple procedures and prolonged antibiotic therapy. However, a new and emerging method of treatment of PJI is non-contact induction heating (NCIH) of metal implants. We sought to investigate the feasibility and effectiveness of NCIH along with synergistic effects of antibiotics (Vancomycin) in reducing bacterial load within surface associated biofilms in …

The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer

Western Research Forum

Background:

Due to its complex branching structure, direct drug delivery to the remote areas of the lung is a major challenge. Consequently, most therapies, such as those treating pulmonary infection and inflammation, must utilize large systemic dosing, with the potential for adverse side effects. A novel alternative strategy is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle.

Objective:

Utilize an in vitro transferring system to assess exogenous surfactant (BLES) as a pulmonary delivery vehicle for different therapeutics.

Methods:

An in vitro technique was developed to simultaneously study surfactant delivery and …

The Epidemiology Of Infective Endocarditis Among People Who Inject Drugs In London, Ontario., Brian Hallam

Electronic Thesis and Dissertation Repository

Infective endocarditis is an infectious disease that affects the valves of the heart. Injection drug use is currently a leading risk factor among patients with endocarditis. We conducted a prospective study using data from hospital chart records among patients with endocarditis in London, Ontario, which has a relatively high prevalence of people who inject drugs to assess the severity of the issue and the major risk factors of mortality pertaining to this population. This study had a sample size of 353 and included a review of the incidence of admissions of endocarditis, as well as a survival analysis, using both …

Elucidating The Importance Of Hope And Its Potential Lewis Glycosylation In Helicobacter Pylori, Keertika Yogendirarajah

Electronic Thesis and Dissertation Repository

Helicobacter pylori colonizes 50% of the world’s population, whereby glycoproteins and Lewis Y-containing lipopolysaccharides contribute to its pathogenesis. We investigated whether the HopE porin is glycosylated, if the glycan is Lewis Y, and if this is mediated by the putative oligosaccharide transferase HP0946 or the O-antigen ligase WaaL. Western blotting was performed on outer membranes with anti-HopE antibodies, anti-Lewis Y antibodies and fucose-binding BambL lectin to ascertain HopE glycosylation. We discovered that HopE is likely glycosylated by a non-Lewis Y fucose-containing glycan and neither HP0946 nor WaaL are the transferase. Additionally, we investigated HopE’s role in antibiotic susceptibility via Etest …

Investigating The Pathogenesis Of Staphylococcus Aureus In Periprosthetic Joint Infections, Santiago L. Iglesias

Electronic Thesis and Dissertation Repository

The most challenging complication after total joint replacement is the periprosthetic joint infection (PJI). Staphylococcus aureus is a commensal bacterium and a human pathogen. It is responsible for more than half of the PJI. We demonstrated that synovial fluid has antimicrobial properties against S. aureus and the iron restriction is one of the mechanisms used for the host to prevent bacterial growth, and is even able to increase killing of S. aureus. We have shown a clear role of transferrin as a restrictive factor in synovial fluid that functions by iron starving the bacteria and sensitizing them to killing …

Contribution Of Enterococcus Faecalis To Urinary Tract Infection, Samantha Ann Whiteside

Electronic Thesis and Dissertation Repository

The purpose of this thesis was to increase understanding of enterococcal UTI, in particular, the response of Enterococcus to antibiotic prophylaxis in vitro and in vivo and enterococcal communication with the bladder.

We studied the in vitro effects of trimethoprim-sulfamethoxazole (TMP/SMX) and nitrofurantoin, two of the antibiotic treatments used most commonly in the management of both urinary tract infection (UTI) and recurrent UTI (RUTI), on Enterococcus faecalis attachment to urothelial cells. In doing so, we documented nitrofurantoin-induced increases in bacterial attachment at growth inhibitory concentrations of nitrofurantoin, but not TMP/SMX. This increased virulence did not correlate with increased expression of …

Developing Novel Therapeutics For Bacterial Lung Infections, Brandon J. Baer, Ruud Veldhuizen, Cory Yamashita

Western Research Forum

Background: Bacterial lung infections are leading causes of death worldwide. Unfortunately, increasing resistance to antibiotics and the inflammation often accompanying these infections are leading to poor outcomes despite antibiotic intervention. Complicating treatment further, the tree-like branching structure of the lung makes drug delivery to distal sites of infection difficult. Our research aims to address these challenges by developing new therapeutics and new tools to improve and assess drug delivery, bacterial killing and inflammation. Our therapy combines host defense peptides, which have been shown to kill antibiotic-resistant bacteria and down regulate inflammation, with a pulmonary vehicle, exogenous surfactant, that can improve …

Carbohydrates And Fungal Toxin Exposure Influence The Vaginal Microbiota, Metabolome, And Reproductive Health Of Women, Stephanie L. Collins

Electronic Thesis and Dissertation Repository

The reproductive health of women is influenced by microorganisms and their metabolites, namely those representing the vaginal microbiota and those producing toxins that are ingested. To manipulate the vaginal microbiota toward a health-associated, Lactobacillusdominant state, an approach adopting prebiotic lactulose was taken. Using batch culture, lactulose supported Lactobacillus maintenance and positively altered metabolites, while not disrupting indigenous L. crispatus epithelial adherence. The vagina also harbours abundant glycogen, but initial assumptions that lactobacilli utilize it were incorrect. I have now shown that glycogen selectively stimulates organisms associated with dysbiosis and L. iners in a self-limiting manner. Other compounds such as environmental …

Pulmonary Surfactant Fortified With Cath-2 As A Novel Therapy For Bacterial Pneumonia, Brandon J. Baer

Western Research Forum

Background: Bacterial pneumonia is a leading cause of death worldwide, with high mortality rates persisting even after antibiotic treatment. Current treatments for pneumonia involve administration of antibiotics, however after the bacteria are killed they release toxic substances that induce inflammation and lung dysfunction. Host defense peptides represent a potential solution to this problem through their ability to down regulate inflammation. However, effective delivery to the lung is difficult because of the complex branching structure of the airways. My study addresses this delivery problem by using exogenous surfactant, a pulmonary delivery vehicle capable of improving spreading of these peptides throughout the …

Characterization Of The Atsr/Atst Global Regulatory Pathway In Burkholderia Ceocepacia, Maryam Khodai-Kalaki

Electronic Thesis and Dissertation Repository

Phosphorylation cascades governed by two-component signal transduction systems provide key signalling mechanisms in bacteria, simple eukaryotes and higher plants, allowing them to translate signals into adaptive responses. These regulatory pathways consist of a transmembrane sensor protein that responds to an environmental cue leading to autophosphorylation, followed by the transfer of the phosphate to a cytoplasmic response regulator. Here, I study AtsR, a membrane-bound hybrid sensor kinase of Burkholderia cenocepacia, that negatively regulates quorum sensing related virulence factors such as biofilm, type 6-secretion and protease secretion. B. cenocepacia is a Gram-negative opportunistic pathogen which causes severe, chronic respiratory infections in …

Analysis Of Invariant Natural Killer T Cells In Intra-Abdominal Sepsis, Ram Venkatesh Anantha

Electronic Thesis and Dissertation Repository

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNKT) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of circulating iNKT cells in their peripheral blood, as compared to non-septic patients. We therefore investigated iNKT cells in mice with intra-abdominal sepsis (IAS). Our data show that iNKT cells are …

Effect Of Ascorbate On Coagulation And Fibrinolytic Factors In The Septic Microvasculature, Scott Swarbreck

Electronic Thesis and Dissertation Repository

Sepsis, a systemic inflammatory response to an infection, is a significant cause of morbidity and mortality worldwide. The microcirculation during sepsis fails, in part, due to microthrombosis and the resulting plugging of capillaries, precipitating organ failure. Intravenous injection of ascorbate has been shown to reduce capillary plugging, however the mechanism of this protective effect is unclear. We hypothesized that ascorbate-mediated destabilization of the microthrombi through promoting fibrinolysis could contribute to this protection.

We showed that streptokinase, a pro-fibrinolytic agent, reduced the capillary plugging to a similar degree as ascorbate. This similarity provided the impetus for studying the effect of ascorbate …

Systematic Assessment Of The Contribution Of Superantigens To Nasopharyngeal Colonization In A Mouse Model Of Streptococcal Infection, Katherine J. Kasper

Electronic Thesis and Dissertation Repository

Streptococcus pyogenes is adapted for persistence in humans. It typically colonizes the tonsils and skin, and humans are the only known reservoir. S. pyogenes can cause a wide range of mild to serious infections. Most streptococci-related deaths are due to complications of rheumatic fever and invasive infections. S. pyogenes produces virulence factors that contribute to the pathogen’s ability to colonize and cause disease, including streptococcal superantigens (SAgs), also known as streptococcal pyrogenic exotoxins (Spes). SAgs function by cross-linking T cells and antigen presenting cells (APC) which may cause a massive inflammatory response, and as such have been found to contribute …

Involvement Of Interleukin-33/St2 In Myocardial Dysfunction In Murine Model Of Sepsis, Yoonmi Choe

Electronic Thesis and Dissertation Repository

The disruption of myocardial extracellular matrix (ECM) has been implicated in myocardial dysfunction during sepsis. However, the underlying mechanism(s) are not clear. Interleukin-33 (IL-33) is a cytokine which regulates collagen synthesis in various cardiac pathologies. The purpose of the present study is to test whether IL-33 contributes to sepsis-induced myocardial dysfunction through regulation of matrix metalloproteinase-9 (MMP-9). The in vivo, feces-induced peritonitis (FIP) in mice and in vitro lipopolysaccharide (LPS) treatments to isolated cardiomyocytes were used. In FIP mice, myocardial IL-33 and MMP-9 expression were increased and myocardial contractility was decreased. Myocardial function in FIP mice was improved when treated …