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Innate Immune Responses in Zika Viru...

Yockey, Laura Jeannette.

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Innate Immune Responses in Zika Virus Control and Pathogenesis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Innate Immune Responses in Zika Virus Control and Pathogenesis./
作者:	Yockey, Laura Jeannette.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	200 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
Contained By:	Dissertations Abstracts International80-02B.
標題:	Obstetrics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10957215
ISBN:	9780438269569

Innate Immune Responses in Zika Virus Control and Pathogenesis.
Yockey, Laura Jeannette.

Innate Immune Responses in Zika Virus Control and Pathogenesis. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 200 p.

Source: Dissertations Abstracts International, Volume: 80-02, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item must not be added to any third party search indexes.

The female reproductive tract is an important site of viral exposure, in the case of sexually-transmitted infections. It must also protect and support normal pregnancy and development of the fetus, a process that requires complex immunological changes. The type I interferon (IFN) response is a critical innate immune signaling pathway that restricts viral infection in the female reproductive tract and throughout the body. Zika virus (ZIKV), an emerging primarily mosquito-borne flavivirus, is unique among closely related viruses for its ability to be sexually transmitted and to cause defects in the developing fetuses. The overall goal of this thesis is to investigate the components of the innate immune response that control ZIKV infection and contribute to its pathogenesis during pregnancy. First, we developed a mouse model of intravaginal ZIKV infection in order to investigate the innate immune control and pathogenesis of sexually-transmitted ZIKV. Epidemiological data demonstrate that ZIKV can be transmitted between sexual partners, most commonly from an infected male to his female partner. The impact of sexually-transmitted ZIKV during pregnancy is poorly understood. Using our mouse model, we show that the vagina was a susceptible route of ZIKV infection, and sexually-transmitted ZIKV led to fetal infection and demise. We also demonstrated that different components of the IFN pathway distinctly control local replication, systemic spread, and vertical transmission of ZIKV. Next, we investigate the in vivo role for one of the candidate entry receptors for ZIKV, Axl. Identifying the cellular entry receptor for ZIKV is a critical step towards understanding the unique pathogenesis and tropism of ZIKV as a teratogenic and sexually-transmitted pathogen. Multiple in vitro and coexpression studies highlight the Tyro-3, Axl, and Mertk (TAM) receptor, Axl, as a candidate entry receptor for ZIKV. We showed that TAM receptors were not required for ZIKV replication or spread after multiple routes of infection and using multiple mouse models. Finally, we investigated how the IFN response of the fetus and fetal-derived placenta contributes to ZIKV-mediated pathology. This question has important implications for understanding the underlying pathogenesis and shared presentation of many congenital infections, which include microcephaly and growth restriction. We show that, paradoxically, the IFN response is responsible for causing fetal demise and severe growth restriction after ZIKV infection. Specifically, IFN blocks development of the placenta, a critical organ for supporting fetal growth. Overall, we show that the same pathway, the IFN pathway, is critical for controlling local replication and systemic ZIKV spread after intravaginal infection, but is also a key mediator of fetal growth restriction and demise. These studies contribute to our understanding of ZIKV pathogenesis after sexual transmission and during pregnancy.

ISBN: 9780438269569Subjects--Topical Terms:

634501
Obstetrics.

Innate Immune Responses in Zika Virus Control and Pathogenesis.
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520 $a The female reproductive tract is an important site of viral exposure, in the case of sexually-transmitted infections. It must also protect and support normal pregnancy and development of the fetus, a process that requires complex immunological changes. The type I interferon (IFN) response is a critical innate immune signaling pathway that restricts viral infection in the female reproductive tract and throughout the body. Zika virus (ZIKV), an emerging primarily mosquito-borne flavivirus, is unique among closely related viruses for its ability to be sexually transmitted and to cause defects in the developing fetuses. The overall goal of this thesis is to investigate the components of the innate immune response that control ZIKV infection and contribute to its pathogenesis during pregnancy. First, we developed a mouse model of intravaginal ZIKV infection in order to investigate the innate immune control and pathogenesis of sexually-transmitted ZIKV. Epidemiological data demonstrate that ZIKV can be transmitted between sexual partners, most commonly from an infected male to his female partner. The impact of sexually-transmitted ZIKV during pregnancy is poorly understood. Using our mouse model, we show that the vagina was a susceptible route of ZIKV infection, and sexually-transmitted ZIKV led to fetal infection and demise. We also demonstrated that different components of the IFN pathway distinctly control local replication, systemic spread, and vertical transmission of ZIKV. Next, we investigate the in vivo role for one of the candidate entry receptors for ZIKV, Axl. Identifying the cellular entry receptor for ZIKV is a critical step towards understanding the unique pathogenesis and tropism of ZIKV as a teratogenic and sexually-transmitted pathogen. Multiple in vitro and coexpression studies highlight the Tyro-3, Axl, and Mertk (TAM) receptor, Axl, as a candidate entry receptor for ZIKV. We showed that TAM receptors were not required for ZIKV replication or spread after multiple routes of infection and using multiple mouse models. Finally, we investigated how the IFN response of the fetus and fetal-derived placenta contributes to ZIKV-mediated pathology. This question has important implications for understanding the underlying pathogenesis and shared presentation of many congenital infections, which include microcephaly and growth restriction. We show that, paradoxically, the IFN response is responsible for causing fetal demise and severe growth restriction after ZIKV infection. Specifically, IFN blocks development of the placenta, a critical organ for supporting fetal growth. Overall, we show that the same pathway, the IFN pathway, is critical for controlling local replication and systemic ZIKV spread after intravaginal infection, but is also a key mediator of fetal growth restriction and demise. These studies contribute to our understanding of ZIKV pathogenesis after sexual transmission and during pregnancy.
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