Tick Humoral Responses: Marching to the Beat of a Different Drummer

Abstract

Ticks transmit a variety of human pathogens, including Borrelia burgdorferi, the etiological agent of Lyme disease. Multiple pathogens that are transmitted simultaneously, termed "coinfections," are of increasing importance and can affect disease outcome in a host. Arthropod immunity is central to pathogen acquisition and transmission by the tick. Pattern recognition receptors recognize pathogen-associated molecular patterns and induce humoral responses through the Toll and Immune Deficiency (IMD) pathways. Comparative analyses between insects and ticks reveal that while the Toll pathway is conserved, the IMD network exhibits a high degree of variability. This indicates that major differences in humoral immunity exist between insects and ticks. While many variables can affect immunity, one of the major forces that shape immune outcomes is the microbiota. In light of this, we discuss how the presence of commensal bacteria, symbionts and/or coinfections can lead to altered immune responses in the tick that impact pathogen persistence and subsequent transmission. By investigating non-insect arthropod immunity, we will not only better comprehend tick biology, but also unravel the intricate effects that pathogen coinfections have on vector competence and tick-borne disease transmission.

Keywords: Lyme disease; humoral immunity; tick-borne diseases; ticks; vector.

FIGURE 1

The Immune Deficiency (IMD) and Toll pathways in Drosophila and ticks. (A) Activation of the IMD pathway in Drosophila is initiated by PGRP-LC binding to diaminopimelic acid (DAP)-type peptidoglycan. This leads to IMD, dFADD, and DREDD recruitment. IMD is cleaved by DREDD, exposing an ubiquitylation site and is polyubiquitylated by IAP2, Effete, Uev1a and Bendless in a K63-dependent manner. K-63 polyubiquitin chains are believed to serve as the recruiters for the proteins TAB2, TAK1, and IKK (IKKγ and IKKβ), which transfer a phosphate group to Relish. Relish is then cleaved by DREDD, removing the C-terminal ankyrin repeats. The N-terminal portion of Relish is translocated to the nucleus where it induces the transcription of AMPs (Vandenabeele and Bertrand, 2012). In ticks, transmembrane PGRPs, IMD, dFADD and possibly DREDD are missing (shaded gray). XIAP is suggested to regulate the IMD pathway in ticks through direct interaction with Bendless (Shaw et al., 2017). (B) In Drosophila, the Toll pathway is activated by PGRPs and GNBPs binding to Lysine-type peptidoglycan or β1-3-glucan, respectively. PAMP binding to PRRs leads to activation of ModSP (Modular Serine Protease) and Grass in the extracellular milieu. Spz is then cleaved and binds to Toll receptors. Following Spz binding, MyD88 dimers interface with the Toll receptor and recruit Tube, an adaptor molecule that interacts with the protein kinase Pelle. Cactus is then phosphorylated and degraded, which leads to translocation of Dif (Dorsal-related immunity factor) and/or Dorsal to the nucleus and AMP upregulation (Lindsay and Wasserman, 2014). The tick genome encodes all components of the Toll pathway, with the exception of GNBPs and dif.

FIGURE 2

The I. scapularis response to B. burgdorferi infection. Spirochetes (light yellow) enter the tick midgut (purple) during blood feeding. Spirochetes interact with gut tissues and trigger activation of the JAK/STAT pathway. Induction of JAK/STAT signaling and possibly other pathways leads to AMP production (Defensins and DAE2). Spirochete migration into the hemolymph elicits cellular and humoral immunity. Cellular responses include increased prevalence of hemocytes (green) and initiation of phagocytosis. Humoral immunity results in the secretion of Defensins (originating from hemocytes and the fat body) and Lysozyme (hemocytes) into the hemolymph (Johns et al., 2001b; Ceraul et al., 2003, 2007). Niche-specific immune responses, such as those originating from the salivary glands (light blue structures), remain elusive.