Schwarz, Madeline May
(2023)
Lrp1 is an essential host factor for Rift Valley fever virus and other bunyaviruses.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Rift Valley fever virus (RVFV) is an emerging zoonotic arbovirus with pandemic potential. First isolated in 1931 from the Rift Valley of Kenya, it has caused widespread morbidity and mortality in humans and livestock for over 90 years. Previously confined to sub-Saharan Africa, RVFV has expanded to formerly naïve areas such as Egypt, Saudi Arabia, and Madagascar prompting devastating epidemics that have lasting effects on the local economy. The associated disease Rift Valley fever (RVF) is a significant burden to human health, yet there are no approved prophylactics or therapeutics to mitigate disease. This is due to much about the basic viral pathogenesis remaining unknown. In particular, host cell proteins that mediate cellular infection by RVFV are not well defined. To address this, we conducted an unbiased CRISPR/Cas9 survival screen to identify proviral factors for RVFV infection. We identified low-density lipoprotein receptor-related protein 1 (Lrp1) as a significant host factor in RVFV cellular infection. First, we validated the role of Lrp1 in RVFV infection using Lrp1 knockout cell lines, anti-Lrp1 antibodies, natural, high-affinity blocking ligands, and a proof-of-concept in vivo study. Second, we investigated the role of Lrp1 in lethal RVF hepatic disease using a mouse model with Lrp1 deleted in hepatocytes. Next, we determined if Lrp1 could be a multi-bunyaviral host factor for Oropouche, LaCrosse, Heartland, and Severe fever with thrombocytopenia syndrome virus (SFTSV). Finally, we briefly investigated the role of Lrp1 in RVFV infection of human ocular cells. Together, these studies conclude that Lrp1 (1) is essential for optimal RVFV infection, (2) is required for RVF hepatic disease in a mouse model, and (3) could serve as a host factor for other bunyaviruses that cause severe human morbidity and mortality in humans globally. The identification of the first highly conserved, multi-bunyaviral host factor can serve as the basis for development of multi-bunyaviral therapeutics to reduce the global burden of bunyaviral disease.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
9 May 2023 |
| Date Type: |
Publication |
| Defense Date: |
6 March 2023 |
| Approval Date: |
9 May 2023 |
| Submission Date: |
4 April 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
240 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Rift Valley fever virus, arbovirus, receptor, zoonoses, livestock, hemorrhagic fever, vaccines, antivirals |
| Date Deposited: |
10 May 2023 02:22 |
| Last Modified: |
10 May 2023 02:22 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44422 |
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