Interactions between Borrelia burgdorferi and ticks

Abstract

Borrelia burgdorferi is the causative agent of Lyme disease and is transmitted to vertebrate hosts by Ixodes spp. ticks. The spirochaete relies heavily on its arthropod host for basic metabolic functions and has developed complex interactions with ticks to successfully colonize, persist and, at the optimal time, exit the tick. For example, proteins shield spirochaetes from immune factors in the bloodmeal and facilitate the transition between vertebrate and arthropod environments. On infection, B. burgdorferi induces selected tick proteins that modulate the vector gut microbiota towards an environment that favours colonization by the spirochaete. Additionally, the recent sequencing of the Ixodes scapularis genome and characterization of tick immune defence pathways, such as the JAK-STAT, immune deficiency and cross-species interferon-γ pathways, have advanced our understanding of factors that are important for B. burgdorferi persistence in the tick. In this Review, we summarize interactions between B. burgdorferi and I. scapularis during infection, as well as interactions with tick gut and salivary gland proteins important for establishing infection and transmission to the vertebrate host.

Fig. 1. The life cycles of Ixodes scapularis and Borrelia burgdorferi.

Uninfected larvae hatch and seek a host to feed on, which is typically a small mammal or bird, but may include larger animals. Because Borrelia burgdorferi is not transmitted transovarially, this life stage is the primary opportunity for spirochaetes to infect ticks that feed on an infected host. After feeding, the six-legged larvae moult and emerge as eight-legged nymphs, which may be infected with spirochaetes acquired during their initial bloodmeal. Nymphs seek a second host, typically a small or medium-sized mammal, and this bloodmeal may offer a second opportunity for spirochaetes to infect ticks. Importantly, nymphs infected during the larval bloodmeal can transmit spirochaetes to hosts, including humans and domestic animals. After fed nymphs have moulted to the adult stage, newly emerged adult Ixodes scapularis ticks search for a large animal host, typically white-tailed deer, for mating and a final bloodmeal. Although deer are the preferred hosts, adult female ticks will also feed on humans and domestic animals, which can acquire B. burgdorferi, but are relatively unimportant to further perpetuation of infections. Because ticks cannot acquire B. burgdorferi from deer, these hosts are not effective reservoirs for B. burgdorferi, although they are important for perpetuation of tick populations. After mating, engorged females release themselves from hosts and eventually oviposit an egg mass, which may contain hundreds to thousands of eggs. I. scapularis ticks produce only a single clutch of eggs and then die. Solid arrows denote progression steps in the tick life cycle and dashed arrows denote host preferences for specific tick life stages.

Fig. 2. Acquisition of Borrelia burgdorferi.

a | When feeding on an infected host, the Ixodes scapularis tick takes up Borrelia burgdorferi with the bloodmeal. The tick injects the salivary protein SALP25D into the host skin to dampen inflammation at the feeding site. SALP25D quenches reactive oxygen species generated by activated neutrophils at the bite site. The activity of SALP25D enhances B. burgdorferi acquisition by the tick, possibly by increasing viability of the spirochaetes at the bite site. SALP12 functions as a chemoattractant for B. burgdorferi and increases the quantity of spirochetes entering the tick. Entry of B. burgdorferi into the tick induces upregulation of Hk1–Rrp1 and downregulation of RpoS, resulting in production of c-di-GMP, an important molecule regulating expression of outer surface proteins. b | Spirochaetes ingested in the bloodmeal adhere to the tick gut and remain in this organ until a subsequent tick feeding. B. burgdorferi expresses the outer surface proteins OspA and OspB, which protect spirochaetes from harmful components in host blood, including antibodies and complement, and enable them to adhere to and persist in the gut^,,. OspA interacts specifically with the tick receptor TROSPA, which is located on the luminal surface of gut epithelial cells and is upregulated when spirochaetes are ingested. tHRF, tick histamine release factor.

Fig. 3. Tick immune defences against Borrelia burgdorferi infection.

a | Infection with Borrelia burgdorferi activates the immune deficiency (IMD) pathway in Ixodes scapularis. On activation, p47 is polyubiquitylated by X-linked inhibitor of apoptosis (XIAP) in complex with the Bendless–Uev1a heterodimer. Downstream signalling through Kenny results in phosphorylation of Relish and transcription of antimicrobial peptides (AMPs). b | Uninfected I. scapularis can ingest mouse interferon-γ (IFNγ) along with the bloodmeal when feeding on B. burgdorferi infected mice. Mouse IFNγ signals in the tick gut through an unknown receptor, resulting in STAT-mediated activation of a Rho-like GTPase (IGTPase) and production of the AMP Dae2. c | Certain microbiota compositions enable activation of the JAK–STAT pathway by an unknown molecular signal and in turn induce the expression of peritrophin genes. Peritrophins are crucial for the formation of a structurally intact peritrophic matrix. B. burgdorferi uses the peritrophic matrix as a shield or barrier protecting it from toxic contents during colonization of the gut epithelium. STAT-induced immune effectors, as well as environmental changes, can alter the microbiota composition. Certain changes in the microbiota composition impair JAK–STAT signalling, and this results in decreased expression of peritrophins, leading to a thinner and compromised peritrophic matrix. A compromised peritrophic matrix no longer functions as a protective shield and thus impairs B. burgdorferi colonization of the gut epithelium.

Fig. 4. Transmission of Borrelia burgdorferi to a vertebrate host.

a | Several environmental changes that occur at the onset of tick feeding are cues for spirochaetes in the gut to transition to a form that is infectious for vertebrates and to initiate migration to the salivary glands. Outer surface proteins important for this process include BBA52, which is upregulated during the early stages of feeding, and BBE31, which interacts with the tick receptor TRE31 to enable the spirochaetes to exit the gut epithelial layer and migrate through the haemocoel to the salivary glands. Ixofin3D and ISDLP are other proteins expressed by epithelial cells that bind spirochaetes and are thought to assist in exit from the gut^,. Spirochaetes outside the gut express OspA and OspC, which promotes binding to tick salivary glands and early dissemination in the vertebrate host^,. b | Transmission of Borrelia burgdorferi to a mammalian host is enhanced by the activity of several tick salivary proteins. As the tick feeds, several proteins are secreted into the host to modulate the host environment and to obtain a complete bloodmeal. These proteins also assist B. burgdorferi transmission. Complement is an important immune defence mechanism that restricts B. burgdorferi, as well as tick feeding. The tick salivary proteins ISAC, SALP20 and TSLPI inhibit activation of complement and increase B. burgdorferi transmission^,,. Sialostatin L2 also modulates the immune response against the tick bite by impairing cytokine secretion by dendritic cells on exposure to B. burgdorferi. Tick histamine release factor (tHRF) is a salivary protein secreted during the late stage of tick feeding and triggers the release of histamine, presumably from mast cells or basophils. The best studied salivary protein is SALP15, which enhances B. burgdorferi transmission. B. burgdorferi expresses OspC on its surface during migration from the gut to the salivary glands. SALP15 binds OspC and can shield the spirochaete from antibody-mediated killing. Additionally, SALP15 suppresses CD4⁺ T cell function and IL-2 secretion.