Studying the biology of, and developing countermeasures to, a tick-transmitted hemorrhagic fever virus
Rodriguez, Sergio Enrique
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Crimean-Congo hemorrhagic fever (CCHF) is one of the world’s most medically relevant tick-borne viral diseases. The CCHF virus (CCHFV) is transmitted in seasonal cycles among ticks and animals and is endemic to the Eastern hemisphere. Severe disease may develop with outbreak case fatality rates up to 30%. Pathogenesis studies have focused on the later stages of disease, whereas little is known about the influence of the tick-vector in disease outcome. Herein, the role of tick-transmission of CCHFV was investigated to examine the biology and early pathogenesis of CCHF. Concurrently, there are no licensed prevention or treatment options for CCHF and work with live CCHFV is restricted to biosafety level 4 (BSL-4) laboratories. This measure, while preserving biosafety, has hampered progress towards developing medical countermeasures. Recombinant vesicular stomatitis viruses (rVSV) expressing foreign glycoproteins have shown promise as both experimental vaccines and as a surrogate model at a lower biosafety level (BSL-2), called pseudotypes, for several viral pathogens. Herein, rVSV pseudotypes expressing the CCHFV glycoprotein precursor (GPC) were developed, which encodes CCHFV structural glycoproteins (GP). Two distinct recombinant viruses were generated: one infectious but replication deficient, and the other replication competent. Both constructs drive strong expression of CCHFV-GP in tissue cultures, with the replication competent vector possessing CCHFV-GP on the virion surface of rVSV. This permitted studies for the biology of the CCHFV-GPC and the application to a serological detection and characterization means for CCHFV antibodies. The replication-competent pseudotype also demonstrated its use in a screening of antiviral compounds targeting the GPC. Both rVSV constructs were further evaluated as vaccines for CCHF. Varying degrees of efficacy were observed depending on the construct and experimental conditions, with up to a 100% efficacy observed using the replication-competent pseudotype for the vaccination in a lethal CCHFV animal model. This dissertation offers insight into the biology of CCHFV and its tick vector and highlights the utility of pseudotyped rVSV as a tool to further medical countermeasure developments for this deadly human pathogen and global public health concern.
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