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035 a| (Sirsi) o1257305443;

035 a| (OCoLC)1257305443;

049 a| EREE;

100 1 a| Garrigues, Ryan,e| author.?| UNAUTHORIZED;

245 10 a| Borrelia burgdorferi ErpB and ErpQ inhibit C1 complex of the classical pathway of complement through a novel mechanism /c| by Ryan Garrigues.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2021.;

300 a| 1 online resource (83 pages) :b| illustrations (some color).;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text file;

347 b| PDF;

347 c| 2.232 MB;

490 1 a| ECU Brody School of Medicine thesis;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| M.S.c| East Carolina Universityd| 2021;

500 a| Presented to the faculty of the Biomedical Sciences Program.;

500 a| Advisor: Brandon L. Garcia;

500 a| Title from PDF t.p. (viewed February 18, 2022).;

520 3 a| The complement system is an organized proteolytic cascade of dozens of proteins that functions in the recognition, opsonization, and lysis of pathogenic and altered-host cells. Bloodborne pathogens like the etiologic agent of Lyme disease, Borrelia burgdorferi, encounter complement during their bloodmeal and in their dissemination through the body. Therefore, to avoid complement mediated destruction, these pathogens have developed mechanisms that aid in complement evasion and defense. The spirochete B. burgdorferi, has nearly a dozen known complement recruiting or inhibiting surface exposed lipoproteins. Here, we uncover a novel inhibitory mechanism for two surface exposed lipoproteins, ErpB and ErpQ, that were recently identified using a lipoprotein gain of function library. Using surface plasmon resonance, ErpB and ErpQ were found to bind C1 complex proteases C1r and C1s with high affinity. Gel-based biochemical assays showed that ErpB and ErpQ specifically inhibit C1s-mediated cleavage of both C2 and C4 making them the only known bacterial inhibitors of C1s. Furthermore, they were shown to block C1s outside of the active site indicating that they function by a novel mechanism. Additional site-directed mutagenesis of C1s exosites revealed determinants for high affinity inhibitor interactions that have been shown to be important for C1s recognition of C4 outside of the active site. The discovery of a novel mechanism of complement inhibition by a medically-relevant human pathogen expands our knowledge of host pathogens interactions and contributes to previously unknown pathophysiological immune evasion by B. burgdorferi. Mechanistic studies on ErpB and ErpQ also support further understanding of molecular interactions between complement proteases and their substrates, which provides alternative means for the development of specific complement therapeutics toward complement-mediated diseases.;

504 a| Includes bibliographical references.;

650 2 a| Borrelia burgdorferi.=| ^A965952;

650 2 a| Lyme Disease.=| ^A925335;

653 a| Complement;

653 a| Protease inhibitors;

653 a| Immune evasion;

655 7 a| Academic theses.2| fast0| (OCoLC)fst01726453;

655 7 a| Academic theses.2| lcgft;

700 1 a| Garcia, Brandon L.,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Microbiology and Immunology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 u| http://hdl.handle.net/10342/9112z| Access via ScholarShip;

949 o| wjh;

994 a| C0b| ERE;

096 a| QW 155;

596 a| 1 4;

998 a| 5636991;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5636991-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 6/22/2021x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5636991-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 6/22/2021x| ETDz| HERESOURCE;

Borrelia burgdorferi ErpB and ErpQ inhibit C1 complex of the classical pathway of complement through a novel mechanism / by Ryan Garrigues.

Author/creator	Garrigues, Ryan author.
Other author	Garcia, Brandon L., degree supervisor.
Other author	East Carolina University. Department of Microbiology and Immunology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2021.
Description	1 online resource (83 pages) : illustrations (some color).
Supplemental Content	Access via ScholarShip
Subjects	Borrelia burgdorferi. Lyme Disease.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
Summary	The complement system is an organized proteolytic cascade of dozens of proteins that functions in the recognition, opsonization, and lysis of pathogenic and altered-host cells. Bloodborne pathogens like the etiologic agent of Lyme disease, Borrelia burgdorferi, encounter complement during their bloodmeal and in their dissemination through the body. Therefore, to avoid complement mediated destruction, these pathogens have developed mechanisms that aid in complement evasion and defense. The spirochete B. burgdorferi, has nearly a dozen known complement recruiting or inhibiting surface exposed lipoproteins. Here, we uncover a novel inhibitory mechanism for two surface exposed lipoproteins, ErpB and ErpQ, that were recently identified using a lipoprotein gain of function library. Using surface plasmon resonance, ErpB and ErpQ were found to bind C1 complex proteases C1r and C1s with high affinity. Gel-based biochemical assays showed that ErpB and ErpQ specifically inhibit C1s-mediated cleavage of both C2 and C4 making them the only known bacterial inhibitors of C1s. Furthermore, they were shown to block C1s outside of the active site indicating that they function by a novel mechanism. Additional site-directed mutagenesis of C1s exosites revealed determinants for high affinity inhibitor interactions that have been shown to be important for C1s recognition of C4 outside of the active site. The discovery of a novel mechanism of complement inhibition by a medically-relevant human pathogen expands our knowledge of host pathogens interactions and contributes to previously unknown pathophysiological immune evasion by B. burgdorferi. Mechanistic studies on ErpB and ErpQ also support further understanding of molecular interactions between complement proteases and their substrates, which provides alternative means for the development of specific complement therapeutics toward complement-mediated diseases.
General note	Presented to the faculty of the Biomedical Sciences Program.
General note	Advisor: Brandon L. Garcia
General note	Title from PDF t.p. (viewed February 18, 2022).
Dissertation note	M.S. East Carolina University 2021
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.
Genre/form	Academic theses.
Genre/form	Academic theses.

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Borrelia burgdorferi ErpB and ErpQ inhibit C1 complex of the classical pathway of complement through a novel mechanism / by Ryan Garrigues.

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