Virology Commons^™

The Role Of Adenovirus Serotype 5 E4 11k In The Relocalization Of The Cellular P Body Proteins, Kasey A. Karen, La`Quita Randolph, Kevin Neubrecht, Heather Vincent

Georgia Journal of Science

Human adenoviruses are a useful tool to understand basic cellular biology in addition to viral infections. Historically, cellular splicing was first discovered in adenovirus, but other cellular processes, such as double-strand break repair and aggresome formation, have been further elucidated through adenoviral infection. The adenovirus protein E4 11k has been shown to disrupt cytoplasmic processing bodies (p bodies), which are not well-understood but are involved in mRNA metabolism. Several p body proteins were found to be reorganized in the cytoplasm with adenovirus serotype 5 (Ad5) able to cause the colocalization of these p body proteins with aggresomes. The p body …

The Impact Of Processing Body Proteins On An Adenovirus Infection, La`Quita Randolph

Biology Theses

Adenovirus is a nonenveloped, double-stranded DNA virus that contains a 36 Kbp genome. The E4 ORF3 region of its genome consists of an E4 11k protein that can reorganize host cell components by relocalizing cellular proteins. One such cellular component is the cytoplasmic processing body, which consists of proteins involved in translational repression of mRNA and mRNA degradation. During an adenovirus infection, processing body proteins Ddx6 and Pat1b have been shown to colocalize and form aggresomes. Aggresomes induced by E4 11k are specific to the adenovirus serotype 5 (Ad 5). In this study, cytoplasmic Pat1b foci were observed and quantified …

Disruption Of Cellular P-Bodies During An Adenovirus Infection​, La`Quita Randolph, Kevin Neubrecht, Kasey A. Karen

Graduate Research Showcase

Adenovirus has made major contributions in medicine by serving as a model DNA virus to study other viruses, such as human papillomavirus (HPV). Adenoviruses are a diverse family of nonenveloped, double-stranded DNA viruses that are ubiquitous to animals and humans. There are over 67 serotypes of human adenoviruses that can cause a variety of illnesses including, gastroenteritis, conjunctivitis and respiratory infections. Adenovirus can cause these infections by invading host cells and producing an environment that is favorable for viral replication. During the early phases of infection, adenovirus expresses various viral proteins such as E4 11k, which has multiple functions. One …

Oncolytic Viruses: Cancer Treatment Going Viral, Rhianna N. Bronson

Chancellor’s Honors Program Projects

No abstract provided.

Longitudinal Quantification Of Adenovirus Neutralizing Responses In Zambian Mother-Infant Pairs: Impact Of Hiv-1 Infection And Its Treatment, Sara R. Privatt, Brianna L. Bullard, Eric A. Weaver, Charles Wood, John T. West

Nebraska Center for Virology: Faculty Publications

Vaccination offers the most cost-effective approach to limiting the adverse impact of infectious and neoplastic diseases that reduce the quality of life in sub-Saharan Africa (SSA). However, it is unclear what vaccine vectors would be most readily implementable in the setting and at what age they should be applied for maximal efficacy. Adenoviruses (Ad) and Ad-based vectors have been demonstrated to induce effective humoral and cellular immune responses in animal models and in humans. However, because immunity associated with Ad infection is lifelong, there exists a debate as to whether pre-existing immunity might decrease the efficacy of Ad vectored vaccines. …

A Single-Cycle Adenovirus Type 7 Vaccine For Prevention Of Acute Respiratory Disease, Brianna L. Bullard, Brigette N. Corder, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Adenovirus type 7 (Ad7) infection is associated with acute respiratory disease (ARD), especially in military recruits living in close quarters. Recently, several outbreaks of Ad7 infections have occurred in civilian populations, with some cases leading to death. However, the current Ad7 vaccine is licensed for use only in military recruits because it utilizes an orally delivered wild type virus which is shed in the stool for 28 days after immunization. This poses a safety risk due to the possibility of virus spread to vulnerable populations. To address the need for a safer Ad7 vaccine for use in civilian populations, we …

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 …

Effects Of Adenovirus Infection On The Localization Of Cellular Protein Pat1b, Emilee Friedman, Kasey A. Karen

Georgia Journal of Science

Adenoviruses are a diverse family of nonenveloped, double-stranded DNA viruses with a variety of vertebrate hosts including humans. Over 50 serotypes of human adenovirus have been identified, and cause a number of illnesses, including conjunctivitis, gastroenteritis, and respiratory infections. The life cycle of adenovirus is divided into immediate early, early, and late phases, with immediate early proteins controlling transcription and the cell cycle, early proteins being largely regulatory, and late proteins being structural. Early proteins such as E4 11k have been demonstrated to relocalize key cellular proteins, including proteins found within mRNA processing bodies (p-bodies). It is hypothesized that E4 …

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 …

Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses, Catherine M. Crosby, William E. Matchett, Stephanie S. Anguiano-Zarate, Christopher A. Parks, Eric A. Weaver, Larry R. Pease, Richard J. Webby, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Head-to-head comparisons of conventional influenza vaccines with ade- novirus (Ad) gene-based vaccines demonstrated that these viral vectors can mediate more potent protection against influenza virus infection in animal models. In most cases, Ad vaccines are engineered to be replication-defective (RD-Ad) vectors. In contrast, replication-competent Ad (RC-Ad) vaccines are markedly more potent but risk causing adenovirus diseases in vaccine recipients and health care workers. To harness antigen gene replication but avoid production of infectious virions, we de- veloped “single-cycle” adenovirus (SC-Ad) vectors. Previous work demonstrated that SC-Ads amplify transgene expression 100-fold and produce markedly stronger and more persistent immune responses than …

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 …

Vaccines Within Vaccines: The Use Of Adenovirus Types 4 And 7 As Influenza Vaccine Vectors, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Adenovirus Types 4 and 7 (Ad4 and Ad7) are associated with acute respiratory distress (ARD). In order to prevent widespread Ad-associated ARD (Ad-ARD) the United States military immunizes new recruits using a safe and effective lyophilized wildtype Ad4 and Ad7 delivered orally in an enteric-coated capsule. We cloned Ad4 and Ad7 and modified them to express either a GFP-Luciferase (GFPLuc) fusion gene or a centralized influenza H1 hemagglutinin (HA1-con). BALB/c mice were injected with GFPLuc expressing viruses intramuscularly (i.m.) and intranasally (i.n.). Ad4 induced significantly higher luciferase expression levels as compared with Ad7 by both routes. Ad7 transduction was restored …

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 …

Vaccines Within Vaccines: The Use Of Adenovirus Types 4 And 7 As Influenza Vaccine Vectors, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

adenovirus Types 4 and 7 (ad4 and ad7) are associated with acute respiratory distress (aRD). In order to prevent wide- spread ad-associated aRD (ad-aRD) the United states military immunizes new recruits using a safe and effective lyophi- lized wildtype ad4 and ad7 delivered orally in an enteric-coated capsule. We cloned ad4 and ad7 and modified them to express either a GFP-Luciferase (GFPLuc) fusion gene or a centralized influenza H1 hemagglutinin (Ha1-con). BaLB/c mice were injected with GFPLuc expressing viruses intramuscularly (i.m.) and intranasally (i.n.). ad4 induced significantly higher luciferase expression levels as compared with ad7 by both routes. ad7 transduction …

C-Jun N-Terminal Kinases Regulate Adenovirus-Mediated Autophagy And Antigen Presentation, Sarah R. Klein

Dissertations & Theses (Open Access)

Targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for oncolysis, but the molecular regulation of autophagy in infected cells remains under investigation. Our data suggested the canonical pathway regulating starvation-induced autophagy was not implemented in adenovirus-induced autophagy; however, adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) that was essential for autophagy. Adenoviral replication within the host cell elicited JNK pathway activation leading to B cell lymphoma-2 (Bcl-2) phosphorylation. JNK-dependent Bcl-2 phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy. Moreover, …

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 …

Mechanisms Of Adenovirus-Mediated Autophagy, Erin White

Dissertations & Theses (Open Access)

A patient diagnosed with a glioma, generally, has an average of 14 months year to live after implementation of conventional therapies such as surgery, chemotherapy, and radiation. Glioblastomas are highly lethal because of their aggressive nature and resistance to conventional therapies and apoptosis. Thus other avenues of cell death urgently need to be explored. Autophagy, which is also known as programmed cell death type II, has recently been identified as an alternative mechanism to kill apoptosis- resistant cancer cells. Traditionally, researchers have studied how cells undergo autophagy during viral infection as an immune response mechanism, but recently researchers have discovered …

Mechanisms Of Adenovirus-Mediated Autophagy, Erin White

Dissertations & Theses (Open Access)

A patient diagnosed with a glioma, generally, has an average of 14 months year to live after implementation of conventional therapies such as surgery, chemotherapy, and radiation. Glioblastomas are highly lethal because of their aggressive nature and resistance to conventional therapies and apoptosis. Thus other avenues of cell death urgently need to be explored. Autophagy, which is also known as programmed cell death type II, has recently been identified as an alternative mechanism to kill apoptosis- resistant cancer cells. Traditionally, researchers have studied how cells undergo autophagy during viral infection as an immune response mechanism, but recently researchers have discovered …

Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses, Catherine M. Crosby, William E. Matchett, Stephanie S. Anguiano-Zarate, Christopher A. Parks, Eric A. Weaver, Larry R. Pease, Richard J. Webby, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Head-to-head comparisons of conventional influenza vaccines with adenovirus (Ad) gene-based vaccines demonstrated that these viral vectors can mediate more potent protection against influenza virus infection in animal models. In most cases, Ad vaccines are engineered to be replication-defective (RD-Ad) vectors. In contrast, replication-competent Ad (RC-Ad) vaccines are markedly more potent but risk causing adenovirus diseases in vaccine recipients and health care workers. To harness antigen gene replication but avoid production of infectious virions, we developed “single-cycle” adenovirus (SC-Ad) vectors. Previous work demonstrated that SC-Ads amplify transgene expression 100-fold and produce markedly stronger and more persistent immune responses than RD-Ad vectors …