Elucidating the cellular and molecular mechanisms that govern filovirus pathogenesis within ferrets with emphasis on Marburg virus
| dc.contributor.author | Schiffman, Zachary | |
| dc.contributor.examiningcommittee | Kindrachuk, Jason (Medical Microbiology and Infectious Diseases) | |
| dc.contributor.examiningcommittee | Yao, Xiao-Jian (Medical Microbiology and Infectious Diseases) | |
| dc.contributor.examiningcommittee | Kung, Sam (Immunology) | |
| dc.contributor.examiningcommittee | Basler, Chrisopher F (Icahn School of Medicine at Mount Sinai) | |
| dc.contributor.supervisor | Strong, Jim | |
| dc.date.accessioned | 2025-01-15T16:57:10Z | |
| dc.date.available | 2025-01-15T16:57:10Z | |
| dc.date.issued | 2024-11-25 | |
| dc.date.submitted | 2025-01-03T19:27:40Z | en_US |
| dc.date.submitted | 2025-01-15T15:43:44Z | en_US |
| dc.degree.discipline | Medical Microbiology and Infectious Diseases | |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | |
| dc.description.abstract | Recently, the ferret has gained attention as a novel animal model for studying filoviruses. Ferrets are highly susceptible to several orthoebolaviruses, including Ebola virus (EBOV), yet refractory to infection with orthomarburgviruses, namely Marburg virus (MARV) and Ravn virus. The fact that ferrets are uniformly susceptible to infection with most orthoebolaviruses but not orthomarburgviruses suggests that these viruses differ fundamentally in their pathogenic mechanisms. This thesis explored two main hypotheses. Firstly, it was hypothesized that this lack of susceptibility by ferrets to lethal infection with orthomarburgviruses resulted from a block in glycoprotein (GP) mediated viral entry. The results demonstrate that while MARV-GP can mediate entry into ferret cells, the efficiency is lower than that of EBOV-GP, particularly during the early stages of infection. While MARV can replicate within ferret cells, replication is attenuated compared to EBOV. Lastly, rEBOV-mGP is uniformly lethal in ferrets. However, the onset of disease and viremia was delayed compared to EBOV. These data demonstrate that GP may represent one probable factor accounting for the lack of disease among MARV-challenged ferrets. Secondly, it was hypothesized that this lack of susceptibility by ferrets to lethal infection with orthomarburgviruses but not orthoebolaviruses is the result of mechanistic differences in the innate immune evasion tactics of these two viruses. The results demonstrated that inhibition of type I IFN production using drugs has a negligible impact on the replication of MARV within ferret cells. In contrast, inhibition of type I IFN signalling using drugs targeting the JAK/STAT pathway positively enhanced viral replication of MARV within ferret cells. Together, these data emphasize the potential contribution of MARV VP40 toward the viral replication of MARV within ferret cells. Challenge with guinea pig-adapted Marburg virus (GPA-MARV) resulted in uniform lethality among ferrets, whereas challenge with mouse-adapted (MA)-MARV resulted in only partial lethality. High levels of viral replication, a dysregulated immune response and hematological perturbations in biochemistry and blood counts were also observed among GPA-MARV-challenged ferrets. Lastly, several genome mutations appeared following challenge with GPA-MARV. This is the first report of a lethal orthomarburgvirus ferret model, and these data provide insight into the pathogenesis of orthomarburgviruses. | |
| dc.description.note | February 2025 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38817 | |
| dc.language.iso | eng | |
| dc.subject | Filovirus | |
| dc.subject | Ebola virus | |
| dc.subject | Marburg virus | |
| dc.subject | Ferret | |
| dc.subject | Animal model | |
| dc.title | Elucidating the cellular and molecular mechanisms that govern filovirus pathogenesis within ferrets with emphasis on Marburg virus | |
| local.subject.manitoba | no | |
| project.funder.name | Public Health Agency of Canada |