center for viral pathogenesis research symposium november

Center for Viral Pathogenesis Research Symposium November 29, 2017 University of Kansas Medical Center PRESENTATION ABSTRACTS Kevin Ault, MD University of Kansas Medical Center Nicholas Wallace, PhD Kansas State University High Risk

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  1. Center for Viral Pathogenesis Research Symposium November 29, 2017 – University of Kansas Medical Center PRESENTATION ABSTRACTS Kevin Ault, MD – University of Kansas Medical Center Nicholas Wallace, PhD – Kansas State University High Risk α -Papillomavirus Oncogenes Induce Aberrant Translesion Synthesis High risk α - papillomaviruses (HR α -HPV) cause anogenital and oropharyngeal tumors. These malignancies are dependent on HR α - HPV E6 and E7 and associated with destabilized genomes. Because HR α -HPV E6 and E7 are known to alter cellular signaling pathways, we hypothesize that the genomic instability in HR α -HPV+ cancers could be attributable to aberrant responses to DNA damage. To evaluate our hypothesis, we analyzed gene expression in 86 cervical carcinomas and 58 control samples. We found a significant upregulation of genes involved in replication in the tumors and predicted increased replication would require an enhance ability to tolerate damage during S- phase. The translesion synthesis (TLS) pathway prevents deleterious replication fork collapse by allowing the fork to bypass any DNA lesion that it encounters. Consistent with this hypothesis TLS gene transcripts were more abundant in cervical cancers with the notable exception of the TLS- specific polymerase (Pol η) that is required for lesion bypass. We have confirmed these results and shown that they are drive n by HR α -HPV E6 and E7. Further, our data demonstrate that HR α - HPV E6 and E7 prevent the induction of pol η in response to crosslinked DNA and sensitize cells to DNA crosslinking agents. We speculate that inhibition of TLS by HPV oncogenes may explain the observation that HPV-associated malignancies are acutely sensitive to DNA crosslinking drugs. Rollie Clem, PhD – Kansas State University Unraveling the Arbovirus Midgut Escape Barrier in Mosquito Vectors When an arbovirus is acquired by a mosquito in a blood meal, available evidence indicates that the first tissue that is infected is the midgut. Subsequently, in order to for transmission to occur, the arbovirus must replicate in the midgut epithelium and then escape from the midgut, presumably by crossing the midgut basal lamina. Disseminated infection is required for transmission because the virus must eventually replicate in salivary glands in order to be injected along with saliva in a subsequent blood meal. However, there are known arbovirus/vector combinations where the virus is able to infect and replicate in the midgut epithelium, but is not able to efficiently disseminate to the rest of the mosquito. This has led to the concept of the midgut escape barrier, but there is almost nothing known about the molecular basis for this barrier. I will discuss our recent work on trying to understand the mechanisms by which the alphavirus Sindbis virus escapes from the midgut of the mosquito Aedes aegypti. A. Sally Davis, DVM, PhD – Kansas State University Viral Pathogenesis through the Lens of an Investigative Veterinary Pathologist Investigative or experimental veterinary pathology is defined as a branch of veterinary medicine dealing with the essential nature of disease, especially changes in animal tissues and organs that cause or are caused by disease. Add to this a focus on infectious diseases and you have a unique perspective from which to look at host-pathogen interactions, a core component of viral pathogenesis. The laboratory of investigative pathology currently focuses on emerging and zoonotic viral diseases such as Rift Valley fever and influenza from a primary hypothesis driven research point of view with a small focus area in Pneumocystis research. However, equally important is our focus on investigative pathology techniques development. We work closely with the K-State Veterinary Diagnostic Laboratory's (VDL) Histology Lab to identify assays of mutual interest and co-develop, validate and optimize these for use in our laboratory and as a service by the VDL. Examples of recent project-based work in histochemistry, immunohistochemistry, immunofluorescence, digital microscopy and molecular diagnostic assays using formalin- fixed, paraffin-embedded tissues as their starting point will be shared. Additionally, we are actively involved in the development of new biosample handling techniques running the spectrum from biosample acquisition through fixation, inactivation, decalcification and further preparation of samples for optimal use in downstream assays. This focus leads us to tackle issues related to visualization of markers in tissue, improved tissue treatments for better molecular biology endpoints and maximizing archival materials for retrospective studies.

  2. Brandon DeKosky, PhD – University of Kansas - Lawrence High-Throughput Characterization of Anti-Viral Human Antibody Responses Antibodies are a critical feature of our adaptive immune system for viral protection, and each antibody is comprised of a unique heavy and a light chain peptide sequence that is encoded by a single B cell. The DeKosky laboratory applies a custom-developed technology to characterize the repertoire of paired antibody heavy and light chain sequences from over one million single B cells at a time. This suite of technologies includes RT-PCR-based DNA molecular engineering, massively parallel emulsion droplet reactions, Next Generation DNA sequencing, and high- throughput computational analysis. We are applying this unique workflow to characterize the response to vaccines and diseases in human patients to better understand the mechanisms and features of adaptive immune protection against viral pathogens. Navneet Dhillon, PhD – University of Kansas Medical Center HIV-1, Illicit Drugs and Pulmonary Vascular Remodeling The prolonged survival of human immuno-deficiency virus (HIV-1)-infected patients with the use of antiretroviral therapy has resulted in an increase in the incidence of non-infectious cardio-pulmonary complications including HIV-related pulmonary arterial hypertension (HRPAH). Given that intravenous drug use (IVDU) has been found to be one of the most common risk factor of HRPAH, the research focus of the talk will be on how HIV-1 and drugs of abuse interact and contribute to this enhanced pulmonary vascular remodeling. Ying Fang, PhD – Kansas State University A Naturally Occurring Cross Order Recombinant of Enterovirus and Torovirus Enteroviruses comprise a highly diversified group of viruses, which are implicated in a wide range of diseases in human and animals. Genetic recombination has been considered as a driving force for viral evolution; however, recombination between viruses from two different orders is a rare event. In this study, we identified a special case of cross-order recombination between enterovirus G (order picornavirales) and Torovirus (order Nidovirales). This naturally occurring recombinant event may have broad implications for other picornaviral and/or nidoviral species. Importantly, we demonstrated that the exogenous ToV-PLP gene that inserted into the EVG genome encodes a deubiquitinase/deISGylase and potentially suppresses host cellular innate immune responses. Our results provide insights on how gain of function through genetic recombination, in particular cross-order recombination, may improve the ability of a virus to evade host immunity. William Groutas, PhD – Wichita State University Drug Discovery and Development of Antiviral Therapeutics Viruses belonging to the Picornaviridae, Caliciviridae and Coronaviridae families include several medically- important pathogens. These include the causative agents of outbreaks of acute gastroenteritis (noroviruses), high- mortality systemic diseases (SARS-CoV and MERS-CoV) and hand, foot, and mouth disease (enteroviruses). There are currently no effective vaccines or antiviral agents against these viruses. The aforementioned viruses possess 3C or 3C-like proteases that are essential for virus replication, consequently, agents that inhibit these proteases are of potential therapeutic value. Using a structure-guided approach, the design of an array of novel inhibitors of norovirus with in vivo efficacy was accomplished. We have furthermore demonstrated for the first time in clinical trials that inhibition of feline infectious peritonitis virus (FIPV) 3CL protease reverses the progression of fatal infectious peritonitis (FIP). Since FIP disease progression is quite rapid and its pathogenesis primarily immune-mediated, features shared by MERS-CoV and SARS-CoV, we hypothesize that judiciously-designed 3CL protease inhibitors may reverse the pathogenesis of MERS-CoV in affected hosts. An overview of the scope and current status of our drug discovery program will be presented. Ferdaus Hassan, PhD – Children’s Mercy Hospital Host-Response to Enterovirus-D68 infection in Children: From Bench-to-Bed Side Enterovirus-D68 (EV-D68) is a relatively unknown virus. In the summer of 2014, EV-D68 caused a nationwide outbreak, effecting mainly school-aged children and Kansas City was one the most effected regions. During that summer, among all the children that were tested, almost 60% were positive for EV-D68 infection. Many of them required hospitalization and intensive care. To understand the mechanism of pathogenesis, EV-D68 was isolated, infected in lung epithelial cell A-549 and RNA-seq was done to determine the pattern of gene expression and further analyzed by Ingenuity pathway. In addition, clinical respiratory samples were obtained from children with or without

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