Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression

Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi, afflicts one million people annually. Despite being a global health threat, little is known about O. tsutsugamushi pathogenesis. Here, we demonstrate that O. tsutsugamushi modulates the ER and ER-associated processe...

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Main Author: Rodino, Kyle G.
Format: Others
Published: VCU Scholars Compass 2018
Subjects:
Online Access:https://scholarscompass.vcu.edu/etd/5264
https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=6340&context=etd
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spelling ndltd-vcu.edu-oai-scholarscompass.vcu.edu-etd-63402019-10-20T22:04:29Z Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression Rodino, Kyle G. Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi, afflicts one million people annually. Despite being a global health threat, little is known about O. tsutsugamushi pathogenesis. Here, we demonstrate that O. tsutsugamushi modulates the ER and ER-associated processes as mechanisms of nutritional virulence and immune evasion. To obtain amino acids to fuel replication, O. tsutsugamushi simultaneously induces ER stress and the unfolded protein response (UPR) while inhibiting ER-associated degradation (ERAD) during early infection time points. During exponential growth, the bacterium releases the ER bottleneck, resulting in generation of ERAD-derived amino acids that it parasitized for replication. The O. tsutsugamushi effector, Ank4, is linked to this process, as it impedes ERAD when ectopically expressed. O. tsutsugamushi expression of ank4 peaks during the ERAD inhibition window, but is absent when the pathway is restored. These data reveal a novel mechanism of nutritional virulence, whereby an obligate intracellular pathogen coordinates the modulation of multiple ER-associated processes. Like other intracellular pathogens, O. tsutsugamushi inhibits expression of MHC-I, but it does so in a novel manner by degrading the master regulator of MHC-I, NLRC5. This impedes production of the MHC-I components, human leukocyte antigen A and Beta-2 microglobulin. The NLRC5-reduction mechanism recapitulates across diverse cell types, but the degree and duration of inhibition is cell type-specific. NLRC5 modulation and MHC-I inhibition are linked to another O. tsutsugamushi Ank, Ank5. NLRC5 is a putative interacting partner of Ank5. Moreover, NLRC5 and MHC-I levels are reduced in cells ectopically expressing Ank5. To our knowledge, these are the first examples of a pathogen modulating NLRC5 to negatively regulate MHC-I expression and of a bacterial effector interacting with NLRC5. As we learn more about the bacterium’s ability to regulate its host cell, a unifying theme has emerged: modulation of the ER and ER-associated pathways. These projects reveal two novel mechanisms of O. tsutsugamushi pathogenesis, strategies to acquire the amino acids needed for replication and to decrease MHC-I antigen presentation by the host cell. These insights help in understanding how O. tsutsugamushi and potentially other related pathogens co-opt host cell processes to cause disease. 2018-01-01T08:00:00Z text application/pdf https://scholarscompass.vcu.edu/etd/5264 https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=6340&context=etd © The Author Theses and Dissertations VCU Scholars Compass ER stress MHC-I Orientia RIckettsia ERAD Bacteriology Pathogenic Microbiology
collection NDLTD
format Others
sources NDLTD
topic ER stress
MHC-I
Orientia
RIckettsia
ERAD
Bacteriology
Pathogenic Microbiology
spellingShingle ER stress
MHC-I
Orientia
RIckettsia
ERAD
Bacteriology
Pathogenic Microbiology
Rodino, Kyle G.
Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression
description Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi, afflicts one million people annually. Despite being a global health threat, little is known about O. tsutsugamushi pathogenesis. Here, we demonstrate that O. tsutsugamushi modulates the ER and ER-associated processes as mechanisms of nutritional virulence and immune evasion. To obtain amino acids to fuel replication, O. tsutsugamushi simultaneously induces ER stress and the unfolded protein response (UPR) while inhibiting ER-associated degradation (ERAD) during early infection time points. During exponential growth, the bacterium releases the ER bottleneck, resulting in generation of ERAD-derived amino acids that it parasitized for replication. The O. tsutsugamushi effector, Ank4, is linked to this process, as it impedes ERAD when ectopically expressed. O. tsutsugamushi expression of ank4 peaks during the ERAD inhibition window, but is absent when the pathway is restored. These data reveal a novel mechanism of nutritional virulence, whereby an obligate intracellular pathogen coordinates the modulation of multiple ER-associated processes. Like other intracellular pathogens, O. tsutsugamushi inhibits expression of MHC-I, but it does so in a novel manner by degrading the master regulator of MHC-I, NLRC5. This impedes production of the MHC-I components, human leukocyte antigen A and Beta-2 microglobulin. The NLRC5-reduction mechanism recapitulates across diverse cell types, but the degree and duration of inhibition is cell type-specific. NLRC5 modulation and MHC-I inhibition are linked to another O. tsutsugamushi Ank, Ank5. NLRC5 is a putative interacting partner of Ank5. Moreover, NLRC5 and MHC-I levels are reduced in cells ectopically expressing Ank5. To our knowledge, these are the first examples of a pathogen modulating NLRC5 to negatively regulate MHC-I expression and of a bacterial effector interacting with NLRC5. As we learn more about the bacterium’s ability to regulate its host cell, a unifying theme has emerged: modulation of the ER and ER-associated pathways. These projects reveal two novel mechanisms of O. tsutsugamushi pathogenesis, strategies to acquire the amino acids needed for replication and to decrease MHC-I antigen presentation by the host cell. These insights help in understanding how O. tsutsugamushi and potentially other related pathogens co-opt host cell processes to cause disease.
author Rodino, Kyle G.
author_facet Rodino, Kyle G.
author_sort Rodino, Kyle G.
title Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression
title_short Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression
title_full Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression
title_fullStr Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression
title_full_unstemmed Orientia tsutsugamushi Modulates Endoplasmic Reticulum Stress to Benefit its Intracellular Growth and Targets NLRC5 to Inhibit Major Histocompatibility Complex I Expression
title_sort orientia tsutsugamushi modulates endoplasmic reticulum stress to benefit its intracellular growth and targets nlrc5 to inhibit major histocompatibility complex i expression
publisher VCU Scholars Compass
publishDate 2018
url https://scholarscompass.vcu.edu/etd/5264
https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=6340&context=etd
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