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Rational identification of novel drug targets and vaccine candidates against the cattle tick, Rhipicephalus microplus

ABSTRACT: Control of complex parasites via vaccination remains challenging, with the current combination of vaccines and small drugs remaining the choice of control strategy. The development of new vaccines against complex endo- and ectoparasites remains challenging and more studies are providing evidence that multicomponent vaccines will be needed for the development of protective vaccines against parasites. The development of multicomponent vaccines, require an in-depth understanding of parasite biology which remains insufficient for ticks. With the rapid development and spread of acaricide resistance in ticks, new targets for acaricide development also remains to be identified, along with novel targets that can be exploited for the design of lead compounds. In this study, we analysed the differential gene expression of Rhipicephalus microplus ticks that were fed on cattle vaccinated with a multi-component vaccine (Bm86 and 3 putative Bm86-binding proteins). The data was scrutinised for the identification of vaccine targets, small drug targets and novel pathways that can be evaluated in future studies. Limitations associated with targeting novel proteins for vaccine and/or drug design is also discussed and placed into the context of challenges arising when targeting large protein families and intracellular localised proteins. Lastly, this study provide insight into how Bm86-based vaccines may reduce successful uptake and digestion of the bloodmeal and overall tick fecundity.

ORGANISM(S): Rhipicephalus microplus

PROVIDER: GSE221646 | GEO | 2023/10/23

REPOSITORIES: GEO

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Project description:Anti-tick vaccines have proved to be an effective and sustainable method for the control of tick infestations and tick-borne diseases with clear advantages over the application of chemical acaricides (Šmit and Postma, 2016; de la Fuente, 2018; Ndawula and Tabor, 2020). Moreover, the efficacy of acaricide application against Ornithodoros ticks is seriously limited owing to their endophilic/nidicolous life style, which make these ticks less accessible to the chemical acaricides (Astigaraga et al., 1995). Success in tick vaccine development is largely dependent on identification of new and highly protective tick antigens. Searching of new candidate protective antigens is currently being approached among tick molecules that play important biological functions at the tick-host interface, and more precisely among the salivary and intestinal proteins involved in biological processes specifically evolved by ticks to adapt to haematophagy (de la Fuente et al., 2016; Oleaga et al., 2021; Pérez-Sánchez et al., 2021). Accordingly, next-generation sequencing (NGS) and high-throughput proteomics technologies are been used to explore the transcriptome and proteome of the salivary glands/saliva and midguts of an increasing number of tick species and obtain the corresponding sialomes and mialomes (Chmelař et al., 2016; Almeida-Martins et al., 2020; Mans et al., 2020; Oleaga et al., 2021). These studies have identified a wealth of tick molecules related to tick haematophagy, tick-host interplay and pathogen transmission, which can then be scrutinized and filtered in vaccinomics pipelines for selecting candidate protective antigens (Chmelař et al., 2016; Maruyama et al., 2017; Antunes et al., 2018; de la Fuente et al., 2018; Ren et al., 2019; Couto et al., 2021). Similarly, we were also interested in characterizing the O. erraticus sialome. As far as O. erraticus saliva must contain all the bioactive molecules that the tick need to successfully feed, decoding its composition will lead to the discovery of new antigen targets for developing vaccines for the control and prevention of O. erraticus infestations and the diseases it transmits. Accordingly, the objective of the present work was to obtain the proteome of the saliva of O. erraticus adult ticks. For this, we have used a proteomics informed by transcriptomics approach to analyse female and male saliva separately using two different mass spectrometry approaches: liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-dependent acquisition (DDA) mode, and Sequential Window Acquisition of all Theoretical fragment ion spectra Mass Spectrometry (SWATH MS). SWATH MS is a specific variant of data-independent acquisition (DIA) methods that combines deep proteome coverage capabilities with quantitative consistency and accuracy (Ludwig et al., 2018). Here we reported the identification of 387 non-redundant proteins in the saliva of O. erraticus adult ticks as well as a qualitative and quantitative comparison of the saliva protein composition between both sexes. The integration of O. erraticus sialoproteomic and sialotranscriptomic datasets facilitate a better understanding of the physiology of feeding in O. erraticus and will drive the discovery of new and more effective antigen targets for development of anti-tick vaccines.

Project description:Ticks are among the most economically important arthropod parasites due to the heavy infestations they provoke, affecting human and animal health and food production. Ticks are also important vectors of pathogens, mediating the dispersion of livestock and zoonotic diseases. Some examples of livestock diseases vectored by ticks include bovine babesiosis, anaplasmosis, theileriosis, and/or heartwater disease, all of which are enlisted by the World Organization for Animals as possible threats to animals and public health. The family Ixodidae (hard ticks) is of veterinary relevance, and many ixodid tick species within the genera Ixodes, Dermacentor, Amblyomma, Haemophysalis, Hyalomma, and Rhipicephalus, among others, impact farming production worldwide. However, there is no doubt that most pernicious tick species is Rhipicephalus microplus, commonly known as the southern cattle fever tick. This specie is not only the major economically important tick parasite for livestock production, but it is also the vector of Babesia bovis and B. bigemina, the causal agents of babesiosis, a severe disease that affects cattle from tropical and subtropical regions. Currently, global economic losses of the cattle industry attributable to R. microplus are estimated at around $18.7 US billion dollars per year. The economic impact is the leading reason to develop different strategies to constrains R. microplus and its vector-borne pathogens, including chemical, mechanical or environmental treatments, biological control, and/or genetic methods. Chemical, among other methods, are the most frequently applied, but the intense use worldwide, has led to the selection of acaricidal-resistant ticks populations. The molecular adaptations of ticks to overcome the effects of acaricides (e.g., deltamethrin, cypermethrin, amitraz, ivermectin) includes metabolic detoxiﬁcation mechanisms and/or the selection of mutated molecular targets. Recently, a couple of systematic reviews pointed out a significant increment in the number of studies intended to understand the acaricidal resistance in ticks. These reports highlighted the acaricide resistance observed in R. microplus and the wide geographical dispersion of this problem. Whereas many acaricide-resistant R. microplus populations have been reported in Brazil, India, and Mexico, the lack of strict regulatory policies on tick control, leaving the application of acaricides at discretion of farmers. Therefore, the correct implementation of existing strategies together with novel sustainable control methods may be crucial to safeguard livestock production in the context of growing population and global warming. However, until the implementation of such sanitary measures becomes the rule, the main control strategy will still rely on the use of chemical acaricides, such as ivermectin (IVM). Ivermectin is an antiparasitic macrocyclic lactone used to control the populations of R. microplus and other ticks in livestock farming. As occurs in other countries, in Mexico ivermectin is the primary synthetic antiparasitic drug, and its abuse during the last three decades represents an important selection pressure that boosted the development of ivermectin-resistant populations of R. microplus. Therefore, the understanding of the molecular basis of the R. microplus resistance to ivermectin, especially in those cases occurring in tropical and subtropical areas of developing countries, can help to underpin the development of novel strategies to tackle this problem. In this context, omics tools can provide helpful information for the discovery of the molecular mechanisms behind the ivermectin resistance in R. microplus and other related tick species. Previous studies identified the main proteomic components of ovaries of R. microplus, including proteins involved in protein synthesis, post-translational modification, nuclear regulation, cytoskeleton, proteasome, transcriptional regulation, energetic metabolism, detoxification metabolism, or energy storage. Recently, the vitellogenin receptor (VgR) was suggested as a target for tick control because of its essential role in egg formation and maturation. However, molecular information on tick ovaries currently available limits explores the feasibility of VgR or other reproduction-related molecules as promissory targets for tick control.

Project description:While dendritic cells (DCs) are known to play a major role in the process of vaccination, the mechanisms by which vaccines induce protective immunity in humans remain elusive. Herein, we used gene microarrays to characterize the transcriptional programs induced over time in human monocyte-derived DCs (moDCs) in vitro in response to influenza H1N1 Brisbane, Salmonella enterica and Staphylococcus aureus. We built a data-driven modular analytical framework focused on 204 pathogen-induced gene clusters. The expression of these modules was analyzed in response to 16 well-defined ligands, targeting TLRs, cytoplasmic PAMP receptors and cytokine receptors. This multi-dimensional framework covers the major biological functions of APC, including the IFN response, inflammation, DC maturation, T cell activation, antigen processing, cell motility and histone regulation. This framework was used to characterize the response of monocytes and moDCs to 14 commercially available vaccines. These vaccines displayed quantitatively and qualitatively distinct modular signatures in monocytes and DCs, in particular Fluzone and Pneumovax, highlighting the functional and phenotypic differences between APC subsets. This modular framework allows the application of systems immunology approaches to study early transcriptional changes in human APC subsets in response to pathogens and vaccines, which might guide the development of improved vaccines. 64 samples of IL4 DC, and 64 samples of monocytes stimulated by media (controls, designated 1 and 2 to indicate biological replicates), Menomune (Neisseiria meningitis vaccine, MGL), Fluzone 09-10 (Influenza vaccine, FZ), Havrix (Hepatitis A vaccine, HEPA), Ixiaro (Japanese encephalitis vaccine, JPE), ActHib (Haemophilus influenza vaccine, HIB) and Pneumovax (Pneumococcus vaccine, PVX), Engerix-B (Hepatitis B vaccine, HEPB), Zostavax (Herpes Zoster vaccine, HER), and Gardasil (Human Papilloma virus vaccine, HPV), LPS, Ipol (Polio vaccine, POL), Rabies vaccine (RAB), toxoid-based vaccine (TDAP), Varivax (Varicella vaccine, VAR)

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Rational identification of novel drug targets and vaccine candidates against the cattle tick, Rhipicephalus microplus

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