# Tick-Pathogen Interactions: Exploring the Intersection between Stress Responses and Immunity

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2024 · $502,787

## Abstract

Abstract
Arthropod-borne disease continues to be a significant source of morbidity and mortality worldwide. The ability of
an arthropod to harbor and transmit pathogens is termed “vector competency”. Many factors influence vector
competency, including how the arthropod immune system responds to the microbe. The intricacies of insect
immunity have been well-studied owing the model organism, Drosophila. In contrast, comparatively little is known
about tick immunity, representing a fundamental knowledge gap in vector biology. Arthropod immune processes
are now increasingly recognized as being divergent across species. For example, we identified a noncanonical
Immune Deficiency (IMD) pathway in ticks that limits colonization of two bacterial pathogens: Borrelia burgdorferi
(Lyme disease) and Anaplasma phagocytophilum (Human Granulocytic Anaplasmosis). Ticks lack genes
encoding upstream IMD pathway regulators. Therefore, the molecular and cellular events preceding the
noncanonical IMD pathway in ticks deviate from the classical paradigm defined in insects. We asked in our
previously funded R21 whether a specialized stress-response system termed the Unfolded Protein Response
(UPR) could impact vector competency through tick immunity. Infection imparts stress on the host and, for this
reason, cellular stress-responses are tightly intertwined with innate immunity. Our data shows that the UPR is
induced by tick-borne bacteria and initiates the noncanonical IMD pathway in ticks. Through RNAi knockdown
and pharmacological manipulation, we show that the IRE1α branch of the UPR signals through the adapter
molecule TRAF2 to restrict vector colonization by A. phagocytophilum and B. burgdorferi both in vitro and in vivo.
Collectively, our findings provide an explanation for how the core IMD pathway is activated independent of
canonical upstream regulators. Based on these findings, our central hypothesis is that the UPR functionally
regulates vector-microbe interactions through crosstalk with the IMD pathway. AIM 1 of this proposal will now
investigate the role of the I. scapularis UPR on microbial growth, migration kinetics through tick tissues and/or
transmission to a naïve host. AIM 2 will uncover the mechanistic linkage between the UPR and the noncanonical
IMD pathway using an unbiased approach to define and characterize the signalosome during infection. Since
microbial infections impart stress on host systems and cellular stress responses are well conserved across
eukaryotes, we expect that the findings from this R01 will uncover novel determinants of vector competence and
may have broad relevance to many arthropod-pathogen systems.

## Key facts

- **NIH application ID:** 10875621
- **Project number:** 5R01AI162819-03
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Dana Kathleen Shaw
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $502,787
- **Award type:** 5
- **Project period:** 2022-07-11 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875621

## Citation

> US National Institutes of Health, RePORTER application 10875621, Tick-Pathogen Interactions: Exploring the Intersection between Stress Responses and Immunity (5R01AI162819-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10875621. Licensed CC0.

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