Tick holocyclotoxins trigger host paralysis by presynaptic inhibition

Abstract

Ticks are important vectors of pathogens and secreted neurotoxins with approximately 69 out of 692 tick species having the ability to induce severe toxicoses in their hosts. The Australian paralysis tick (Ixodes holocyclus) is known to be one of the most virulent tick species producing a flaccid paralysis and fatalities caused by a family of neurotoxins known as holocyclotoxins (HTs). The paralysis mechanism of these toxins is temperature dependent and is thought to involve inhibition of acetylcholine levels at the neuromuscular junction. However, the target and mechanism of this inhibition remain uncharacterised. Here, we report that three members of the holocyclotoxin family; HT-1 (GenBank AY766147), HT-3 (GenBank KP096303) and HT-12 (GenBank KP963967) induce muscle paralysis by inhibiting the dependence of transmitter release on extracellular calcium. Previous study was conducted using extracts from tick salivary glands, while the present study is the first to use pure toxins from I. holocyclus. Our findings provide greater insight into the mechanisms by which these toxins act to induce paralysis.

Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43 Q331K transgenic mouse model of amyotrophic lateral sclerosis

“…As our functional findings indicate presynaptic deficits, we next investigated short‐term plasticity at Q331K NMJs by using facilitation studies, which allowed better assessment of intracellular calcium handling, vesicle dynamics at the active zone, and the relationship to release probability. Whereas Q331K NMJs displayed a degree of facilitation, it was significantly lower than both NTg and WT NMJs, which is suggestive of alterations in short‐term plasticity of the NMJ and, possibly, defective recycling of synaptic vesicles and/or calcium handling (36). Our functional studies showed no change in calcium sensitivity or dependence at Q331K NMJs compared with NTg NMJs at age 10 mo.…”

Transcriptome and toxin family analysis of the paralysis tick, Ixodes holocyclus

“…A proteomics study confirmed that these toxins are secreted in extensor digitorum longus (EDL) muscles showed that these toxins are functionally similar. The study also showed that HT1, HT3 and HT12 induced muscle paralysis by inhibiting neurotransmitter release through a calcium-dependent mechanism; however, the molecular target of these toxins is currently unknown (Chand et al, 2016).…”

Loss of laminin‐a4 results in pre‐ and postsynaptic modifications at the neuromuscular junction

“…The innervating nerve was stimulated with square wave pulses of 15 to 20 V intensity, 0.8 to 0.10 ms duration, and 0.2 to 0.5 Hz frequency using a Grass Instrument stimulator coupled to a Grass Instrument stimulus isolator (Grass Instrument, West Warwick, RI, USA). Electro‐physiological recordings of evoked and spontaneous release using intracellular and extracellular techniques were conducted as previously reported (9, 10, 15). Stimulus‐induced muscle contractions at elevated [Ca 2+ ] O were prevented by the use of the sodium channel blocker μ‐conotoxin GIIIB (0.5–2 μM; Alomone Labs, Jerusalem, Israel).…”