Cytomegalovirus (CMV) is the most common congenitally acquired infection. It is of major concern due to the long-term neurodevelopmental morbidity in both symptomatic and asymptomatic newborns. While CMV infection is less commonly diagnosed in infancy to adulthood, mostly due to its asymptomatic presentation, it is still an important differential to consider. A missed diagnosis could lead to visual impairments and neurological complications. Infants can acquire CMV by encountering bodily secretions from those who have an active infection. Symptoms of infection include fever, fatigue, pharyngitis, and hepatitis. Laboratory abnormalities include thrombocytopenia, elevated transaminases, and abnormal lymphocyte count. We investigated a clinical case of a previously healthy 5-month-old whose only symptoms were petechial rash and thrombocytopenia. They presented to the ED with a worsening petechial rash for 11 days. The patient’s mother had prenatal care and an uncomplicated pregnancy. In the ED IgM for CMV was positive and platelet count on admission was 35K. The patient was discharged without intervention because platelet count remained above 20K. Outpatient hematology workup ruled out other potential causes of thrombocytopenia. There is no family history of bleeding disorders. The patient was prescribed valganciclovir for 2 months and urine CMV PCR was ordered for the patient and the patient’s mother. The patient’s urine CMV was positive, but the mother’s urine CMV was negative. The patient’s petechiae and thrombocytopenia improved while on valganciclovir treatment. In this case, since the patient’s mother was negative for CMV, it is unlikely that the infection was maternally acquired. Our case illustrates that CMV infection in infancy can be acquired through horizontal transmission and its only presentation can be thrombocytopenia. Since the CMV infection was diagnosed early the patient did not have any neurological symptoms, such as sensorineural hearing loss or delayed developmental milestones.

Hemorrhagic enteritis is a disease of turkeys caused by virulent strains of Turkey Hemorrhagic Enteritis Virus (THEV) resulting in depression, splenomegaly, intestinal hemorrhage, immunosuppression, and mortality. Avirulent strains that do not produce intestinal lesions and mortality are used in live-virus vaccines that protect turkeys from virulent field challenge. The cause for the difference in phenotype between virulent and avirulent strains is unknown. The full-length genome of the Virginia Avirulent Strain (VAS) of THEV was sequenced and compared to the genome sequence of a virulent field isolate from Israel. Genetic differences were found in seven viral genes. Further sequencing narrowed the focus from seven genes to three: ORF1, E3, and Fiber. Consistent variation in these genes between strains of THEV with different phenotypes strongly indicates these genes as key factors affecting virulence. THEV is an officially recognized member of the viral family Adenoviridae, genus Siadenovirus. The genomes of the members of the genus, THEV and Frog Adenovirus 1, are not well-characterized. The genome sequences of both members were compared for the prediction of genetic and structural elements. Common features were found that distinguish this genus from all other adenoviruses, and differences were found that possibly contribute to host specificity of the members. The VAS is known to stimulate a life-long protective antibody response, though viral replication is only of short duration. Several studies were undertaken to determine changes in virus location and serology over time. Viral DNA was detected in various tissues through 15 weeks post-infection in the presence of high antibody titers. THEV infection was found to be similar to the non-lytic persistent infections seen with human adenoviruses. Regardless of the mechanism involved in the persistent stimulation of antibodies in infected turkeys, the VAS was shown to be an ideal vector for use in a recombinant live-virus vaccine. The next step in THEV research should be the creation of a full-length infectious DNA clone, which could be used in the creation of a recombinant vaccine. The infectious clone would also allow for the systematic testing of genes that are suspected to be involved in virulence. / Ph. D.

<p> Background: Vitamin D activity is important for the functioning of a broad range of body systems. Some of these, including the skeletal, immune, and cardiovascular systems, are particularly relevant in the management of HIV-infection; thus, and in consideration of evidence that factors associated with the scenario of HIV-infection can disrupt vitamin D metabolism, the assessment of vitamin D status in people living with HIV-infection may be particularly important. In this thesis, I address cardiovascular implications of vitamin D status in HIV-infection. More specifically, and based on a growing body of evidence implicating low vitamin D status in the development of cardiovascular disease (CVD), I hypothesized that in HIV-positive adults low 25-hydroxyvitamin D (25(0H)D) concentration would be associated with increased subclinical vascular disease as measured by carotid intima-medial thickness (IMT).</p> <p> Methods: Using regression analyses I cross-sectionally studied the relationship between 25(0H)D and carotid IMT in 283 participants of the Canadian HIV Vascular Study, a prospective study of CVD risk among HIV-positive Canadians.</p> <p> Results: The prevalence of vitamin D deficiency in the Canadian HIV Vascular study was surprisingly low. Plasma 25(0H)D by quartile was not associated with carotid IMT. However, in restricted cubic spline regression analyses designed to accommodate non-linearity there was evidence of an inverted U-shaped 25(0H)D-carotid IMT relationship. In exploratory regression models restricted to participants comprising the suboptimal range of vitamin D status, lower 25(0H)D concentration was statistically significantly associated with lower carotid IMT after adjustment for known CVD risk factors and other variables hypothesized to potentially confound a 25(0H)D-carotid IMT association.</p> <p> Main implication: While inference from these exploratory findings requires cautious interpretation, future investigations into the relationship between vitamin D status and vascular disease should consider the problem of non-linearity as a feature of primary analyses; otherwise, such studies might fail to detect a true association.</p> / Thesis / Master of Science (MSc)

Les prothèses intraosseuses transcutanées pour amputations (ITAP) représentent une alternative prometteuse par rapport aux prothèses orthopédiques actuellement utilisées en clinique puisqu’elles pourraient diminuer, entre autres, la douleur et l’inconfort chez les patients. Cependant, l’infection, surtout à l’interface implant /peau, reste une complication importante dans ce type de chirurgie orthopédique. Le but de ce projet de recherche est donc de limiter les infections sur une prothèse en alliage de titane (Ti6Al4V ELI).Deux approches ont été établies. La première consiste à promouvoir l’adhésion des cellules de la peau par les peptides d’adhésion KRGDS et KYIGSR, ce qui permettrait de sceller la partie de l’implant qui sort de l’os et ainsi limiter les infections et la deuxième à agir directement sur les bactéries en les éliminant, par le peptide antimicrobien, Magainine 2 (Mag 2).Pour ce travail de thèse, les deux peptides d’adhésion, soit KRGDS et KYIGSR et le peptide antimicrobien, Mag 2, ont été greffés de façon covalente et stable via les bras d’ancrage phosphonates et dopamine à la surface du matériau Ti6Al4V ELI. La caractérisation physico-chimique de ces surfaces a permis de valider le greffage covalent et stable de ces peptides. Des tests cellulaires et bactériens ont été effectués sur les surfaces Ti6Al4V ELI brutes et fonctionnalisées par les différents peptides. Pour les tests cellulaires, il y aune bonne adhésion et prolifération cellulaire des fibroblastes dermiques pour les 4types de matériaux Ti6Al4V ELI. Par contre, la viabilité cellulaire est améliorée pour les échantillons avec peptides greffés, surtout KRGDS et Mag 2. D’autant plus, l’attachement dermique est nettement meilleur sur les surfaces fonctionnalisées par Mag 2 également. Concernant les tests de microbiologie, les résultats obtenus avec les bactéries Staphylococcus epidermidis ATCC-12228 montrent un léger effet antibactérien de la Mag 2 greffée sur la surface Ti6Al4V ELI. Dans le cadre de ce projet, la fonctionnalisation de surface par le peptide antimicrobien Mag 2 est la meilleure alternative pour limiter les infections sur les matériaux Ti6Al4V ELI. / Intraosseous Transcutaneous Amputation Prostheses (ITAPs) represent apromising alternative to orthopedic prostheses currently used in the clinic since they could reduce, among other things, pain and discomfort in patients. However, infection, especially at the implant / skin interface, remains a significant complicationin this type of orthopedic surgery. The aim of this research project is therefore to limit infections on a titanium alloy prosthesis (Ti6Al4V ELI). Two approaches have been established. The first is to promote the adhesion of skin cells by using the KRGDS and KYIGSR peptides, which would seal the part of the implant that comes out of the bone and thus limit infections and the second to act directly on bacteria by eliminating them, by using the antimicrobial peptide, Mag 2. For this thesis work, the two adhesion peptides, either KRGDS or KYIGSR and the antimicrobial peptide, Mag 2, were covalently grafted via the phosphonate and dopamine anchor arms to the surface of the Ti6Al4V ELI material. The physico-chemical characterization of these surfaces made it possible to validate the covalent and stable grafting of these peptides. Cellular and bacterial tests were carried out on bare Ti6Al4V ELI surfaces and functionalized by the various peptides. For cellular assays, there is good celladhesion and proliferation of dermal fibroblasts on the 4 types of Ti6Al4V ELI samples. In contrast, cell viability is improved for samples with grafted peptides,especially KRGDS and Mag 2. Moreover, dermal attachment is significantly betteron surfaces functionalized by Mag 2 as well. Regarding microbiology tests, the results obtained with Staphylococcus epidermidis ATCC12228 bacteria show a slight antibacterial effect of Mag 2 grafted onto the Ti6Al4V ELI surface. Within the framework of this project, the surface functionalization by the antimicrobial peptide Mag 2 is the best alternative to limit infections on Ti6Al4V ELI materials

Infection & Immunity / Currently, there are 38 million people living with human immunodeficiency virus (HIV-1) worldwide and there were 680,000 HIV-related deaths in 2020 alone. The greatest cause of mortality in people living with HIV (PLHIV) is infection with opportunistic pathogens such as tuberculosis (TB), which accounts for one third of HIV-related deaths. PLHIV are 20 times more susceptible to TB and co-infection leads to significantly worsened outcomes in terms of both diseases. Humanized mouse (hu-mouse) models, which possess human immune cells for HIV to infect, have been useful for HIV research. Our aim is to create hu- mouse models of HIV, TB and co-infection to investigate disease progression, immune responses, therapeutics, prevention and vaccination. NOD-Rag1null-IL2rgnull (NRG) mice are highly immunocompromised mice that are traditionally used to generate hu-mouse models. We are also developing NRG mice that are transgenic for human HLA-DR4 and HLA-A2 (DRAG-A2) and similar mice have been reported to have improved immune responses. NRG and DRAG-A2 mice were humanized with hematopoietic stem cells obtained from human umbilical cord blood. DRAG-A2 mice had significantly higher engraftment success rates (defined as the percentage of mice with >10% hCD45+) as well as higher overall CD45+ leukocyte, CD4+ T cell, CD19+ B cell and CD14+ monocyte reconstitution in the blood compared to huNRGs. huNRG mice were permissive to infection with JR-CSF or NL4.3-Bal-Env HIV-1 intravaginally or systemically. huDRAG-A2 mice were also infected intravaginally with NL4.3-Bal-Env HIV-1. huDRAG-A2 mice, but not huNRGs, produced HIV-specific IgG, indicating improved immune responses. huNRG mice were infected intranasally with mCherry-Erdman, YFP-H37Rv or H37Rv Mtb. huDRAG-A2 mice were also infected with H37Rv. Human immune cell involvement and human-like granuloma formation was observed using flow cytometry and immunohistopathology. These findings show that the DRAG-A2 model may be optimal for investigating HIV, TB and co-infection, which continue to be serious global health concerns. / Thesis / Master of Science (MSc) / Human immunodeficiency virus (HIV) and tuberculosis (TB) are infectious diseases that affect millions of people worldwide every year. The greatest cause of death in people living with HIV is co-infection with TB and HIV-positive individuals are much more likely to get TB. Humanized mouse (hu-mouse) models possess human immune cells for HIV to infect and are useful for studying HIV. Our goal is to create hu-mouse models of HIV, TB and HIV/TB co-infection that will allow us to study how these diseases interact. We are currently developing a traditional hu-mouse model (known as NRG), as well as an improved next-generation model (known as DRAG-A2) with a more functional immune system. Both models have been successfully infected with HIV or TB. Only DRAG-A2 mice were able to make antibodies against HIV. The improved DRAG-A2 model will enable future studies on HIV, TB and co-infection, which continue to be understudied global problems.

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