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Identifying host factors important f...

Petersen, Josiah E.

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Identifying host factors important for hantavirus entry.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Identifying host factors important for hantavirus entry./
Author:	Petersen, Josiah E.
Description:	150 p.
Notes:	Source: Dissertation Abstracts International, Volume: 75-07(E), Section: B.
Contained By:	Dissertation Abstracts International75-07B(E).
Subject:	Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3614142
ISBN:	9781303790836

Identifying host factors important for hantavirus entry.
Petersen, Josiah E.

Identifying host factors important for hantavirus entry. - 150 p.

Source: Dissertation Abstracts International, Volume: 75-07(E), Section: B.

Thesis (Ph.D.)--University of Pennsylvania, 2013.

This item is not available from ProQuest Dissertations & Theses.

Hantaviruses are a genus of rodent-borne viruses within the family Bunyaviridae. Humans are a dead end host, wherein Hantavirus infection can cause severe, potentially fatal clinical disease. The specific mechanisms of Hantavirus infection are poorly understood. In particular, the host proteins and entry pathways that mediate Hantavirus entry are not yet known. We set out to identify these factors using two separate, but potentially complementary methods, focusing our efforts on a representative Hantavirus - Andes Virus (ANDV). First, using a high-throughput, luciferase-based assay with ANDV pseudotypes, we screened a siRNA library of ~9000 genes to identify host factors involved in ANDV infection. We ultimately identified 9 genes important for Hantavirus entry including SREBF2, a transcriptional regulator of cholesterol uptake. At the same time, a separate genetic screen performed by a collaborator independently identified SREBF2 and other members of the same cholesterol regulatory pathway (SCAP, S1P, S2P). Further experiments using siRNAs and small molecule inhibitors with both pseudotypes and live ANDV, identified an important role for cholesterol in ANDV internalization. Second, we attempted to use the highly characterized NCI-60 panel of cell lines to identify genes whose expression is correlated with ANDV entry. We infected a panel of 32 cell lines with ANDV pseudovirions in a FACS-based assay to measure relative permissiveness and then correlated permissiveness with gene expression using cDNA microarray data for these cell lines. Using this analysis we identified a list of 33 genes that potentially play a role in ANDV entry. Although initial follow-up experiments have failed to validate a subset of these genes, further experiments will be needed to fully test the entire list of candidate genes. Further analysis and experiments combining this list of genes with the cholesterol-dependence of ANDV entry may lead to further identification of specific pathways and factors utilized by Hantaviruses for infection and possibly potential targets for therapy.

ISBN: 9781303790836Subjects--Topical Terms:

536250
Microbiology.

Identifying host factors important for hantavirus entry.
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020 $a 9781303790836
035 $a (MiAaPQ)AAI3614142
035 $a AAI3614142
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100 1 $a Petersen, Josiah E. $3 3173940
245 1 0 $a Identifying host factors important for hantavirus entry.
300 $a 150 p.
500 $a Source: Dissertation Abstracts International, Volume: 75-07(E), Section: B.
500 $a Adviser: Robert W. Doms.
502 $a Thesis (Ph.D.)--University of Pennsylvania, 2013.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a Hantaviruses are a genus of rodent-borne viruses within the family Bunyaviridae. Humans are a dead end host, wherein Hantavirus infection can cause severe, potentially fatal clinical disease. The specific mechanisms of Hantavirus infection are poorly understood. In particular, the host proteins and entry pathways that mediate Hantavirus entry are not yet known. We set out to identify these factors using two separate, but potentially complementary methods, focusing our efforts on a representative Hantavirus - Andes Virus (ANDV). First, using a high-throughput, luciferase-based assay with ANDV pseudotypes, we screened a siRNA library of ~9000 genes to identify host factors involved in ANDV infection. We ultimately identified 9 genes important for Hantavirus entry including SREBF2, a transcriptional regulator of cholesterol uptake. At the same time, a separate genetic screen performed by a collaborator independently identified SREBF2 and other members of the same cholesterol regulatory pathway (SCAP, S1P, S2P). Further experiments using siRNAs and small molecule inhibitors with both pseudotypes and live ANDV, identified an important role for cholesterol in ANDV internalization. Second, we attempted to use the highly characterized NCI-60 panel of cell lines to identify genes whose expression is correlated with ANDV entry. We infected a panel of 32 cell lines with ANDV pseudovirions in a FACS-based assay to measure relative permissiveness and then correlated permissiveness with gene expression using cDNA microarray data for these cell lines. Using this analysis we identified a list of 33 genes that potentially play a role in ANDV entry. Although initial follow-up experiments have failed to validate a subset of these genes, further experiments will be needed to fully test the entire list of candidate genes. Further analysis and experiments combining this list of genes with the cholesterol-dependence of ANDV entry may lead to further identification of specific pathways and factors utilized by Hantaviruses for infection and possibly potential targets for therapy.
590 $a School code: 0175.
650 4 $a Microbiology. $3 536250
650 4 $a Virology. $3 642304
690 $a 0410
690 $a 0720
710 2 $a University of Pennsylvania. $b Cell and Molecular Biology. $3 2101694
773 0 $t Dissertation Abstracts International $g 75-07B(E).
790 $a 0175
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3614142