Characterization of innate immune signaling pathways in the tick Ixodes scapularis

Ticks are vectors of Lyme and other established and emerging diseases of increasing health relevance in the United States and Europe. Prevention of tick-borne illnesses would be significantly aided by improving our understanding of immune signaling in ticks. Ixodes scapularis is an arthropod vector of the Lyme disease spirochete Borrelia burgdorferi, the rickettsial pathogen Anaplasma phagocytophilum, and other pathogens. Comparison of genes encoded by the I. scapularis genome with genes in Dipteran insects reveals some conservation of immune signaling pathway components, including JAK/STAT, IMD/JNK, and STING pathway components. However, it is also becoming abundantly clear that immune signaling in I. scapularis and other ticks is significantly different, such that there is a need for direct study. The long lifecycle of the tick, the uniqueness of pathogens they transmit, the state of tick gene annotations, and a relative lack of molecular genetic tools have previously been barriers to systematically studying arthropod-microbe interactions. Recent work by our group and others has begun to fill these gaps. For example, our laboratories have developed molecular genetic methods for tick cell studies and applied single-cell RNAseq to tick immune cells (hemocytes). These advancements facilitate application in the tick system of systematic strategies that take advantage of a cell culture system and ‘omics technologies for relatively rapid discovery, including unbiased identification of potential new innate immune pathway components, followed by functional validation by observing the effects of perturbing the new candidate pathway genes on pathway activity. Altogether, we will combine cell cultured-based methods with in vivo assays in I. scapularis, performed in the presence of B. burgdorferi or A. phagocytophilum, to identify signaling factors and test their relevance in microbe-arthropod interactions. Notably, the project will both interrogate conserved factors and identify new factors via functional-based approaches. This project will result in a significantly expanded understanding of innate immune signaling in ticks, paving the way for further study of this health-relevant topic and development of new interventions for the prevention of tick-borne diseases. Project Number: 1R01AI186279-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: NORBERT PERRIMON (+2 co-PIs) | Institution: HARVARD MEDICAL SCHOOL, BOSTON, MA | Award Amount: $831,622 | Activity Code: R01 | Study Section: Transmission of Vector-Borne and Zoonotic Diseases Study Section [TVZ] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18627901A1