Immunomic Investigation of Holocyclotoxins to Produce the First Protective Anti-Venom Vaccine Against the Australian Paralysis Tick, Ixodes holocyclus.

Manuel Rodriguez-Valle,Mitchell Booth,Kim Agnew,Sonia Mcalister,Claudia Ellenberger,Matthew I Bellgard,Ala E Tabor,Paula M Moolhuijzen,Aleta G Knowles,Kathleen Vanhoff

doi:10.3389/fimmu.2021.744795

Abstract

Venom producing animals are ubiquitously disseminated among vertebrates and invertebrates such as fish, snakes, scorpions, spiders, and ticks. Of the ~890 tick species worldwide, 27 have been confirmed to cause paralysis in mammalian hosts. The Australian paralysis tick (Ixodes holocyclus) is the most potent paralyzing tick species known. It is an indigenous three host tick species that secretes potent neurotoxins known as holocyclotoxins (HTs). Holocyclotoxins cause a severe and harmful toxicosis leading to a rapid flaccid paralysis which can result in death of susceptible hosts such as dogs. Antivenins are generally polyclonal antibody treatments developed in sheep, horses or camels to administer following bites from venomous creatures. Currently, the methods to prevent or treat tick paralysis relies upon chemical acaricide preventative treatments or prompt removal of all ticks attached to the host followed by the administration of a commercial tick-antiserum (TAS) respectively. However, these methods have several drawbacks such as poor efficacies, non-standardized dosages, adverse effects and are expensive to administer. Recently the I. holocyclus tick transcriptome from salivary glands and viscera reported a large family of 19 holocyclotoxins at 38-99% peptide sequence identities. A pilot trial demonstrated that correct folding of holocyclotoxins is needed to induce protection from paralysis. The immunogenicity of the holocyclotoxins were measured using commercial tick antiserum selecting HT2, HT4, HT8 and HT11 for inclusion into the novel cocktail vaccine. A further 4 HTs (HT1, HT12, HT14 and HT17) were added to the cocktail vaccine to ensure that the sequence variation among the HT protein family was encompassed in the formulation. A second trial comparing the cocktail of 8 HTs to a placebo group demonstrated complete protection from tick challenge. Here we report the first successful anti-venom vaccine protecting dogs from tick paralysis.

Highlights

Venom producing animals are ubiquitously distributed among vertebrates and invertebrates like fish, snakes, scorpions, spiders, and ticks [1, 2]
The Australian paralysis tick (I. holocyclus) is the most important tick species associated with paralysis in Australia distributed along the eastern coast from North Queensland to the Lakes Entrance in the southern state of Victoria [6]
Using the holocyclotoxin 1 (HT1) sequence (AAV34602) identified in the 1990s, our study identified a further 18 HT homologues (HT2-HT19) from the I. holocyclus internal organ transcriptome data11

Summary

Introduction

Venom producing animals are ubiquitously distributed among vertebrates and invertebrates like fish, snakes, scorpions, spiders, and ticks [1, 2]. Due to its incidence and human impact, the World Health Organization recently recognized snakebite as a neglected tropical disease that affects ∼ 2.7 million per annum [3] Hematophagous invertebrates such as ticks are not as well recognized as venomous animals [1]. The Australian paralysis tick (I. holocyclus) is the most important tick species associated with paralysis in Australia distributed along the eastern coast from North Queensland to the Lakes Entrance in the southern state of Victoria [6]. It has been reported from an unpublished survey to cause tick paralysis in approximately 10,000 to 100,000 animals annually with a death rate of around 5% [7]. In Australia, there is no formal reporting system of paralysis tick cases with incidence data only available from focused geographical or specific annual survey reports [14, 15]

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Conclusion