Identifier

etd-04032017-094905

Degree

Master of Science (MS)

Department

Veterinary Medical Sciences - Pathobiological Sciences

Document Type

Thesis

Abstract

After the emergence of Zika virus (ZIKV) in the Americas in 2015, ZIKV infection was associated for the first time since its discovery with severe symptoms in both adults and congenital cases, including neurological, ocular, and developmental manifestations. Previous ZIKV circulation in Africa and Southeast Asia has been characterized by mild symptoms and small-scale case-counts. It is unclear whether the unprecedented size and severity of the ZIKV outbreak in the Americas are the consequence of a change in the virus, different background flaviviral immunity in the population, or a reporting issue. In addition, ZIKV has been shown to be transmitted through sexual contact, and the shedding of ZIKV from various bodily fluids in both humans and in vivo models suggests that other potential routes of transmission exist. We present here two mouse models that can be used to further investigate ZIKV pathogenesis, transmission, and immune response. Mice lacking interferon regulatory factors 3 and 7 (IRF 3/7 DKO) supported robust infection with the prototype MR766 strain from Uganda, while maintaining a 72% survival rate, and recapitulated symptoms and tissue lesions associated to infection with American ZIKV isolates in humans and other in vivo models. The MR766 strain was capable of causing retinal lesions and viral RNA shedding from the conjunctival fluid, hitherto unreported to be caused by an African strain. Further, ZIKV was visualized in the seminal fluid co-localized with infected epithelial epididymal cells, suggesting a possible cellular component of sexual transmission. Immunocompetent C57BL/6 mice, although not susceptible to ZIKV, were capable of mounting a robust antibody response that strongly neutralized ZIKV and was also able to cross-neutralize DENV2. We further report that homologous re-exposure with ZIKV in C57BL/6 mice reduced the DENV2 cross-neutralizing capability of the antibody population, while at the same time increasing enhancement of DENV2 infection. We conclude that ZIKV strains of the African and Asian lineages share a similar pathogenesis, suggesting that the increased severity of symptoms is unlikely to be due to a change in the virus. We also show that re-exposure to ZIKV can alter the antibody response to increase the risk of heterologous infection.

Date

2017

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Christofferson, Rebecca

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