Ixodes Immune Responses Against Lyme Disease Pathogens

Abstract

Although Ixodes scapularis and other related tick species are considered prolific vectors for a number of important human diseases, many aspects of their biology, microbial interactions, and immunity are largely unknown; in particular, how these ancient vectors recognize invading pathogens like Borrelia burgdorferi and influence their persistence. The analysis of the Ixodes genome and a limited set of transcriptomic data have established that ticks encode many components of classical immune pathways; yet at the same time, they lack many key orthologs of these recognition networks. Therefore, whether a given immune pathway is active in Ixodes ticks and how precisely they exert its microbicidal functions are only incompletely delineated. A few recent studies have suggested that classical pathways like the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) as well as immunodeficiency (IMD) pathways are fully functional in I. scapularis, and upon challenge with microbes, generate potent microbicidal responses against diverse tick-borne pathogens including B. burgdorferi. These studies also highlight novel concepts of vector immunity that include both a direct and an indirect mode of recognition of pathogens, as well as the influence of the gut microbiome, which ultimately dictates the outcome of a robust microbicidal response. Further understanding of how Ixodes ticks recognize and suppress invading microbes like B. burgdorferi will enrich our fundamental knowledge of vector immunobiology, thereby contributing to the development of future interventions to better control the tick-borne pathogen.

Keywords: Borrelia burgdorferi; Ixodes ticks; immunity; lyme disease; microbial recognition.

Figure 1

Diagram highlighting representative examples of Ixodes immune components that impact persistence of Lyme disease agents. During tick engorgement on a mammalian host, B. burgdorferi (Bb, white color) from an infected host dermis are acquired in ticks (Bb in tick gut indicated in blue color). Ixodes ticks can recognize the presence of pathogens in the incoming blood using multiple immune surveillance mechanisms, including an indirect cross-species signaling mechanism that involves sensing mammalian cytokines like IFNγ (indicated by green dots). Ingested cytokine in the tick initiate microbicidal responses involving a tick STAT, an immune GTPase (IGTPase) and an antimicrobial protein (AMP) like Dae2. In addition, a direct recognition mechanism, such as involving an atypical IMD pathway, is also operative in ticks that limits spirochete levels in the vector. The other classical components of innate immune cascades like Toll and JAK-STAT signaling pathways, which are although represented in Ixodes genome, their roles in direct recognition of B. burgdorferi in Ixodes ticks remain unknown. Additional factors in the gut, such as a feeding induced molecular barrier (di-tyrosine network) and the gut microbiome also impact the persistence of spirochetes. During a subsequent blood meal, Bb (red color) exit the tick gut and disseminate to salivary gland (SG) via hemocoel (H), which contains hemocytes that can also impact microbial survival in the vector.