Date of Award:

12-2010

Document Type:

Thesis

Degree Name:

Master of Science (MS)

Department:

Animal, Dairy, and Veterinary Sciences

Advisor/Chair:

Brian B. Gowen

Abstract

Hantaviruses are members of the Bunyaviridae family of viruses. Pathogenic hantaviruses are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS), a disease principally endemic in the Old World, and hantavirus pulmonary syndrome (HPS), a disease primarily restricted to the Americas. Maporal virus (MPRLV), a recently isolated hantavirus, has been found to cause disease in hamsters that resembles HPS in humans. However, the virus has not been linked to human cases of HPS. Considerable evidence suggests that β-integrin usage mediating infection may serve to distinguish hantaviruses pathogenic to humans from nonpathogenic, but this receptor usage pattern information is not yet available for MPRLV. Although ribavirin has been shown to be effective in treating HFRS, it lacks specificity and has toxicity. Moreover, there are no effective antivirals for the treatment of HPS. Considering the above, we have investigated MPRLV 1) β-integrin-mediated mechanism of entry, 2) genetic determinants of pathogenicity, and 3) susceptibility to the promising antiviral, favipiravir (T-705). Using antibodies targeting specific integrin chains, we found infection of Vero E6 cells with MPRLV to be dependent on β3-integrins, similar to that reported for other pathogenic hantaviruses such as Dobrava virus (DOBV) included in our studies. β1-integrin chain-specific antibodies and fibronectin did not block MPRLV or DOBV infectivity as observed with the nonpathogenic Prospect Hill Virus (PHV). Phylogenic analysis of characteristic degron sequences and ITAM motifs in the G1 cytoplasmic tails of MPRLV and other hantaviruses emphasizes the close genetic proximity of MPRLV to other HPS-causing hantaviruses. Favipiravir, a pyrazine derivative reported to be active against related bunyaviruses, was found to be active against MPRLV, DOBV, and PHV (EC50 = 65 - 93 µM) with therapeutic indexes of 74, 52, and 58, respectively. The data presented suggests that MPRLV may be pathogenic to humans and that it and other hantaviruses tested are sensitive to favipiravir in cell culture.

Comments

This work made publicly available electronically on December 23, 2010.

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