A Dityrosine Network Mediated by Dual Oxidase and Peroxidase Influences the Persistence of Lyme Disease Pathogens within the Vector

Yang, Xiuli; Smith, Alexis A.; Williams, Mark S.; Pal, Utpal

doi:10.1074/jbc.m113.538272

Cited by 43 publications

(75 citation statements)

References 45 publications

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“…During the acquisition and transmission blood meals, B. burgdorferi, an extreme auxotroph, must adapt physiologically to the fed midgut milieu, particularly with respect to the use of alternate carbon sources (12)(13)(14). Spirochetes also must cross physical barriers (i.e., peritrophic and basement membranes) and evade the tick's innate immune defenses, which includes antimicrobial peptides and defensins, lysozyme, agglutinins/lectins, complement-related molecules, and reactive oxygen species (ROS) (4,(7)(8)(9)(10)(11). In order to migrate into and out of the vector, Borrelia must sense and respond to chemotactic signals encountered within the bite site and midgut, respectively (113,114).…”

Section: Discussionmentioning

confidence: 99%

“…Successful colonization of the vector requires B. burgdorferi to establish an intimate association with rapidly differentiating, highly endocytic midgut epithelial cells (4)(5)(6). In order to accomplish this feat, spirochetes must resist deleterious substances within the midgut lumen, such as host-and tick-derived innate immune effector molecules, reactive oxygen species (ROS), and salivary enzymes imbibed from the feeding site (4,(7)(8)(9)(10)(11). At the same time, B. burgdorferi also must alter its metabolic machinery to exploit the availability of alternative carbon sources (e.g., glycerol, N-acetylglucosamine [GlcNAc], chitobiose) as the supply of ingested glucose diminishes (12)(13)(14)(15).…”

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confidence: 99%

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Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

et al. 2015

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e Borrelia burgdorferi, the Lyme disease spirochete, couples environmental sensing and gene regulation primarily via the Hk1/ Rrp1 two-component system (TCS) and Rrp2/RpoN/RpoS pathways. Beginning with acquisition, we reevaluated the contribution of these pathways to spirochete survival and gene regulation throughout the enzootic cycle. Live imaging of B. burgdorferi caught in the act of being acquired revealed that the absence of RpoS and the consequent derepression of tick-phase genes impart a Stay signal required for midgut colonization. In addition to the behavioral changes brought on by the RpoS-off state, acquisition requires activation of cyclic di-GMP (c-di-GMP) synthesis by the Hk1/Rrp1 TCS; B. burgdorferi lacking either component is destroyed during the blood meal. Prior studies attributed this dramatic phenotype to a metabolic lesion stemming from reduced glycerol uptake and utilization. In a head-to-head comparison, however, the B. burgdorferi ⌬glp mutant had a markedly greater capacity to survive tick feeding than B. burgdorferi ⌬hk1 or ⌬rrp1 mutants, establishing unequivocally that glycerol metabolism is only one component of the protection afforded by c-di-GMP. Data presented herein suggest that the protective response mediated by c-di-GMP is multifactorial, involving chemotactic responses, utilization of alternate substrates for energy generation and intermediary metabolism, and remodeling of the cell envelope as a means of defending spirochetes against threats engendered during the blood meal. Expression profiling of c-di-GMP-regulated genes through the enzootic cycle supports our contention that the Hk1/Rrp1 TCS functions primarily, if not exclusively, in ticks. These data also raise the possibility that c-di-GMP enhances the expression of a subset of RpoS-dependent genes during nymphal transmission. Borrelia burgdorferi, the causative agent of Lyme disease, is maintained in nature within an enzootic cycle that involves an arthropod vector and vertebrate reservoir hosts, typically, small rodents and birds (1). In the northeastern United States, the primary vector for B. burgdorferi is the black-legged deer tick, Ixodes scapularis (2, 3). Because B. burgdorferi cannot be passaged transovarially, naive larvae acquire spirochetes by feeding on infected reservoir hosts. Successful colonization of the vector requires B. burgdorferi to establish an intimate association with rapidly differentiating, highly endocytic midgut epithelial cells (4-6). In order to accomplish this feat, spirochetes must resist deleterious substances within the midgut lumen, such as host-and tick-derived innate immune effector molecules, reactive oxygen species (ROS), and salivary enzymes imbibed from the feeding site (4, 7-11). At the same time, B. burgdorferi also must alter its metabolic machinery to exploit the availability of alternative carbon sources (e.g., glycerol, N-acetylglucosamine [GlcNAc], chitobiose) as the supply of ingested glucose diminishes (12-15). During nymphal transmission, spirochetes are almost certai...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

et al. 2015

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“…The B. burgdorferi B31 isolate A3 was grown in Barbour-Stoenner-Kelly H (BSK-H) media (Yang et al, 2014). Four- to-six-week-old female C3H/HeN or B6 mice deficient for IFN-γ or IFN-γ receptor were purchased from the National Institutes of Health, Charles River Laboratories, or the Jackson Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Cross-Species Interferon Signaling Boosts Microbicidal Activity within the Tick Vector

Smith

Navasa

Yang

et al. 2016

Cell Host & Microbe

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SUMMARY Evolution of hematophagy in blood-sucking parasites likely involves communication with their hosts. We find that Ixodes ticks are responsive to IFNγ acquired in a blood meal from mice infected with the Lyme disease-causing bacteria Borrelia burgdorferi, leading to induction of antimicrobial responses. Ixodes ticks parasitizing B. burgdorferi-infected mice up-regulated an I. scapularis Rho-like GTPase (IGTPase). IGTPase knockdown enhanced B. burgdorferi levels in post-fed ticks, suggesting this protein controls spirochete survival. Notably, IGTPase was only induced during pathogen acquisition from mice and not upon transmission to naïve hosts. Microinjection of ticks with IFNγ induced IGTPase, and ticks parasitizing IFNγ knockout mice failed to upregulate IGTPase. Additionally, ticks lacking the transcription factor STAT, which signals downstream of IFNγ, did not induce IGTPase. IGTPase expression induced antimicrobial peptides, including Dae2, previously shown to inhibit B. burgdorferi. These results identify an interspecies signaling cascade allowing ticks to detect invading bacteria and mount microbicidal responses.

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“…Meanwhile, JAK-STAT pathway was shown to be important in Anaplasma phagocytophilum infection in ticks after its knockdown increased the infection in the salivary glands of nymphs that fed on infected mice [135]. A dual oxidase and a peroxidase, ISCW017368, which together forms a dityrosine network, were separately silenced in I. scapularis, both resulting to reduced Borrelia burgdorferi persistence in ticks [136].…”

Section: Rnai Studies On Tick Protective Antigens and Immunitymentioning

confidence: 99%

“…The function of some components of immunity, such as α2-macroglobulin proteins [132,133], antimicrobial peptides [131], Janus kinase (JAK)-signaling transducer activator of transcription (STAT) pathway [135], dityrosine network [136], and cysteine protease inhibitor in the hemocytes [140] have been analyzed using RNAi. The α2-macroglobulin proteins of I. ricinus, related to vertebrate complement system, were shown to be involved in the phagocytic activity of hemocytes against Gram-negative bacteria [132,133].…”

Section: Rnai Studies On Tick Protective Antigens and Immunitymentioning

confidence: 99%

RNA Interference – A Powerful Functional Analysis Tool for Studying Tick Biology and its Control

Galay¹,

Umemiya‐Shirafuji²,

MasamiMochizuki³

et al. 2016

RNA Interference

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Ticks (Acari: Ixodida) are blood-sucking arthropods globally recognized as vectors of numerous diseases. They are primarily responsible for the transmission of various pathogens, including viruses, rickettsiae, and blood parasites of animals. Ticks are second to mosquitoes in terms of disease transmission to humans. The continuous emergence of tick-borne diseases and acaricide resistance of ticks necessitates the development of new and more effective control agents and strategies; therefore, understanding of different aspects of tick biology and their interaction with pathogens is very crucial in developing effective control strategies. RNA interference (RNAi) has been widely used in the area of tick research as a versatile reverse genetic tool to elucidate the functions of various tick proteins. During the past decade, numerous studies on ticks utilized RNAi to evaluate potentially key tick proteins involved in blood feeding, reproduction, evasion of host immune response, interaction with pathogens, and pathogen transmission that may be targeted for tick and pathogen control. This chapter reviewed the application of RNAi in tick research over the past decade, focusing on the impact of this technique in the advancement of knowledge on tick and pathogen biology.

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A Dityrosine Network Mediated by Dual Oxidase and Peroxidase Influences the Persistence of Lyme Disease Pathogens within the Vector

Cited by 43 publications

References 45 publications

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

Cross-Species Interferon Signaling Boosts Microbicidal Activity within the Tick Vector

RNA Interference – A Powerful Functional Analysis Tool for Studying Tick Biology and its Control

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