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Identification of Amino Acid Residue...

Morrison, Clayton Russell.

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Identification of Amino Acid Residues Critical for TLR3 Inhibition by the Multifunctional West Nile Virus NS1 Protein.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Identification of Amino Acid Residues Critical for TLR3 Inhibition by the Multifunctional West Nile Virus NS1 Protein./
作者:	Morrison, Clayton Russell.
面頁冊數:	185 p.
附註:	Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
Contained By:	Dissertation Abstracts International74-07B(E).
標題:	Biology, Microbiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3538432
ISBN:	9781303012723

Identification of Amino Acid Residues Critical for TLR3 Inhibition by the Multifunctional West Nile Virus NS1 Protein.
Morrison, Clayton Russell.

Identification of Amino Acid Residues Critical for TLR3 Inhibition by the Multifunctional West Nile Virus NS1 Protein. - 185 p.

Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.

Thesis (Ph.D.)--North Carolina State University, 2013.

The flavivirus West Nile virus (WNV) is maintained in nature through an enzootic transmission cycle between mosquitoes and birds. However, epizootic transmission to humans and other animals can occur when an infected mosquito takes a blood meal. While the levels and duration of viremia in these animals are insufficient to maintain the transmission cycle, the virus is capable of causing febrile and encephalitic diseases in these dead end hosts, which can result in death. WNV was first isolated in 1937 in Uganda, Africa, and has since been found to be endemic to regions of Africa, Europe, and the Middle East. In 1999, WNV was first isolated in New York State in birds and humans and has since spread throughout the contiguous United States. WNV poses a major public health threat as no vaccine or antiviral strategies are currently available for humans.

ISBN: 9781303012723Subjects--Topical Terms:

1017734
Biology, Microbiology.

Identification of Amino Acid Residues Critical for TLR3 Inhibition by the Multifunctional West Nile Virus NS1 Protein.
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245 1 0 $a Identification of Amino Acid Residues Critical for TLR3 Inhibition by the Multifunctional West Nile Virus NS1 Protein.
300 $a 185 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
500 $a Adviser: Frank Scholle.
502 $a Thesis (Ph.D.)--North Carolina State University, 2013.
520 $a The flavivirus West Nile virus (WNV) is maintained in nature through an enzootic transmission cycle between mosquitoes and birds. However, epizootic transmission to humans and other animals can occur when an infected mosquito takes a blood meal. While the levels and duration of viremia in these animals are insufficient to maintain the transmission cycle, the virus is capable of causing febrile and encephalitic diseases in these dead end hosts, which can result in death. WNV was first isolated in 1937 in Uganda, Africa, and has since been found to be endemic to regions of Africa, Europe, and the Middle East. In 1999, WNV was first isolated in New York State in birds and humans and has since spread throughout the contiguous United States. WNV poses a major public health threat as no vaccine or antiviral strategies are currently available for humans.
520 $a Flaviviruses have evolved numerous mechanisms to both evade detection by the innate immune system and to actively suppress its activation, thereby promoting virus dissemination and transmission. The innate immune system is an evolutionarily conserved, first-line defense against invading microorganisms, and functions by detecting pathogen-associated molecular patterns (PAMPS) through pattern recognition receptors (PRR). Toll-like Receptor 3 (TLR3) is a PRR found in the endosomes of many cell types and recognizes dsRNA of many viruses. Activation of TLR3 triggers a highly coordinated signaling cascade that results in the production of pro-inflammatory cytokines and type I interferon. These cytokines synergistically induce an antiviral state in responsive cells and prime the adaptive immune response.
520 $a Recently, work by our laboratory has described a role for the WNV non-structural protein 1 (NS1) in inhibiting TLR3 signal transduction. TLR3 inhibition occurred in WNV infected cells, WNV replicon-bearing cells, cells ectopically expressing NS1, and naïve cells pretreated with the purified secreted form of NS1. The current study was designed to identify amino acids of the WNV NS1 protein that are important for TLR3 inhibition. Since the NS1 protein is also absolutely required for virus genome replication, a screening strategy was developed that would allow for the identification of random mutations in NS1 which relieve TLR3 inhibition, while still allowing virus genome replication. Fluorescence activated cell sorting (FACS) was used to isolate cells expressing mutant NS1 proteins of the desired phenotype. These cells were subsequently clonally expanded, and the sequences of their NS1 genes were determined.
520 $a Ultimately, three amino acid residues (G295, P320, and M333) located in the C-terminal half of NS1 were identified as being important for TLR3 inhibition. Changes at those positions were further characterized, both ectopically and in recombinant WNV. Each of the amino acid changes allowed genome replication and TLR3 signaling in cells infected with recombinant WNV.
520 $a Biochemical studies were designed to identify the defects of the NS1 mutants, which allow TLR3 signaling. The amino acid changes resulted in reduced protein stability, improper glycosylation, and inefficient cell surface expression and secretion. The cumulative result of these defects in NS1 processing prevents antagonism of TLR3 signaling by the mutant proteins.
520 $a Biochemical studies were designed to identify the defects of the NS1 mutants, which allow TLR3 signaling. The amino acid changes resulted in reduced protein stability, improper glycosylation, and inefficient cell surface expression and secretion. The cumulative result of these defects in NS1 processing prevents antagonism of TLR3 signaling by the mutant proteins.
590 $a School code: 0155.
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Virology. $3 1019068
650 4 $a Health Sciences, Immunology. $3 1017716
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710 2 $a North Carolina State University. $b Microbiology. $3 2091961
773 0 $t Dissertation Abstracts International $g 74-07B(E).
790 1 0 $a Scholle, Frank, $e advisor
790 1 0 $a Laster, Scott $e committee member
790 1 0 $a Sikes, Michael $e committee member
790 1 0 $a Yoder, Jeffrey $e committee member
790 $a 0155
791 $a Ph.D.
792 $a 2013
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3538432