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Uncovering The Mechanisms Underlying The Immunogenicity Of Adenovirus Vaccine Vectors, Natalie Nidetz

Dissertations

Vaccination is historically the most effective tool for preventing infectious disease but current vaccine strategies fail to generate robust immunity to major infectious diseases such as HIV and malaria. Therefore, newer vaccine approaches are needed. Vaccines generated from viral, adenovirus based, vectors (AdVs) have proven highly immunogenic in multiple disease models. However, the clinical use of many AdVs is limited by the presence of pre-existing antibodies in human populations, which prevent expression of antigenic genes during immunization with AdVs based on common adenovirus (Ad) serotypes, such as HAdV-5C. Immunization with rare serotype based AdVs, such as HAdV-28D, are not affected …

Adenovirus Evasion Of Cell-Intrinsic Immunity, Andrew Michael Burrage

Dissertations

Virus cell entry represents one of the earliest opportunities for a host to respond to infection. Understanding the processes of pathogen detection and restriction employed by the host, as well as strategies utilized by the virus itself to evade such processes, is critical in developing therapeutics to counter pathogenesis. Adenovirus (Ad) infections are self-limiting in healthy populations, but can be devastating to individuals with compromised immune systems. Currently, no specific antiviral treatments exist to combat Ad infections in susceptible populations. However, because Ad infections are not severe in healthy individuals, employing replication-defective Ads as vaccine vectors is generally regarded as …

The Role Of Pidd Protein In Adenoviral Induction Of Apoptosis, Iris Teresa Figueroa

Master's Theses

The Adenovirus E1A gene sensitizes cells to genetic insults and apoptosis, most notably in response to cytotoxic factors from innate immune cells. The mechanisms by which E1A sensitizes cells to apoptotic stressors have not been fully elucidated, however E1A actively represses NF-κB anti-apoptotic defenses, thereby sensitizing cells to alternative apoptotic cascades. Recent studies alternatively indicate that E1A also actively induces Caspase-2 activation and mitochondrial injury in the presence of certain cytotoxic injuries.

Caspase-2 is cleaved and activated in a large complex consisting of p53-inducible protein with a death domain (PIDD), an adaptor protein RAIDD, and pro-caspase 2. PIDD auto-proteolyzes into …

Malaria Transmission Blocking Vaccines, Lukasz Jacek Sewera

Master's Theses

Malaria affects 198 million people and kills 584,000 each year, predominantly in Sub-Saharan Africa (WHO). The most severe form of malaria is caused by the protozoan parasite Plasmodium falciparum. Development of a vaccine against P. falciparum has been hindered by its complex life cycle with multiple antigenically distinct human and mosquito stages. To effectively prevent disease and reduce the parasite burden in populations, a vaccine will need to target multiple stages, including blocking transmission at the mosquito stage.

Antibodies generated against P. falciparum mosquito stage antigen Pfs25 can prevent parasite transmission from humans to mosquitoes. However, Pfs25 is poorly immunogenic …

Adenovirus Vectors As Potent Adjuvants In Vaccine Development, Kathleen Ann Mcguire

Dissertations

Due to their ability to activate the immune system, replication-defective Adenoviruses (Ad) are potential vaccine vectors for several pathogens. The proinflammatory response to Ad contributes to the response to vaccine antigens. We found that reactive oxygen species (ROS) are an important signal in the proinflammatory response to Ad. We identified that serotype 5 adenovirus (Ad5) elicits ROS by inducing mitochondrial membrane damage, a process that is dependent on endosomal membrane rupture and Cathepsin release. This mitochondrial dysfunction contributes to NLRP3 inflammasome- and NFκB-dependent innate immune activation. The ROS-dependent inflammatory response likely contributes to the adaptive immune response by supporting DC …

Evading Innate And Adaptive Immunity During Adenovirus Cell Entry, Shauna Marvin

Dissertations

Adenovirus (Ad), a non-enveloped, dsDNA virus, enters cells via clathrin-mediated endocytosis. For viral genome delivery to the nucleus, Ad must penetrate endosomal membranes to create defects sufficient for the passage of the 90 nm diameter capsid across cell membranes. Recent observations suggest that adenovirus type 5 (Ad5) capsid uncoating occurs at the cell surface upon binding to both the coxsackievirus and adenovirus receptor and α_v integrins. This uncoating event leads to the exposure of the capsid membrane lytic protein VI. Using the cytosolic protein galectin-3 (gal3) as a marker of membrane rupture, we demonstrate that Ad5 membrane rupture occurs …