Vector-borne diseases constitute 17% of all infectious diseases in the world; among the blood-feeding arthropods, ticks transmit the highest number of pathogens. Understanding the interactions between the tick vector, the mammalian host and the pathogens circulating between them is the basis for the successful development of vaccines against ticks or the tick-transmitted pathogens as well as for the development of specific treatments against tick-borne infections. A lot of effort has been put into transcriptomic and proteomic analyses; however, the protein-carbohydrate interactions and the overall glycobiology of ticks and tick-borne pathogens has not been given the importance or priority deserved. Novel (bio)analytical techniques and their availability have immensely increased the possibilities in glycobiology research and thus novel information in the glycobiology of ticks and tick-borne pathogens is being generated at a faster pace each year. This review brings a comprehensive summary of the knowledge on both the glycosylated proteins and the glycan-binding proteins of the ticks as well as the tick-transmitted pathogens, with emphasis on the interactions allowing the infection of both the ticks and the hosts by various bacteria and tick-borne encephalitis virus.

• MeSH
• Anaplasma pathogenicity   MeSH
• Borrelia pathogenicity   MeSH
• Glycomics methods   MeSH
• Glycosylation MeSH
• Host-Pathogen Interactions physiology   MeSH
• Ixodes microbiology   physiology   virology   MeSH
• Lectins metabolism   MeSH
• Tick-Borne Diseases physiopathology   MeSH
• Polysaccharides metabolism   MeSH
• Proteomics MeSH
• Carbohydrates physiology   MeSH
• Encephalitis Viruses, Tick-Borne pathogenicity   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Ticks infest a variety of animal species and transmit pathogens causing disease in both humans and animals worldwide. Tick-host-pathogen interactions have evolved through dynamic processes that accommodated the genetic traits of the hosts, pathogens transmitted and the vector tick species that mediate their development and survival. New approaches for tick control are dependent on defining molecular interactions between hosts, ticks and pathogens to allow for discovery of key molecules that could be tested in vaccines or new generation therapeutics for intervention of tick-pathogen cycles. Currently, tick vaccines constitute an effective and environmentally sound approach for the control of ticks and the transmission of the associated tick-borne diseases. New candidate protective antigens will most likely be identified by focusing on proteins with relevant biological function in the feeding, reproduction, development, immune response, subversion of host immunity of the tick vector and/or molecules vital for pathogen infection and transmission. This review addresses different approaches and strategies used for the discovery of protective antigens, including focusing on relevant tick biological functions and proteins, reverse genetics, vaccinomics and tick protein evolution and interactomics. New and improved tick vaccines will most likely contain multiple antigens to control tick infestations and pathogen infection and transmission.

• MeSH
• Antigens immunology   MeSH
• Tick Infestations parasitology   prevention & control   MeSH
• Host-Pathogen Interactions MeSH
• Ticks immunology   MeSH
• Humans MeSH
• Tick-Borne Diseases parasitology   prevention & control   MeSH
• Vaccines immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Ticks are vectors of pathogens affecting human and animal health worldwide. Nevertheless, the ecological and evolutionary interactions between ticks, hosts, and pathogens are largely unknown. Here, we integrated a framework to evaluate the associations of the tickIxodes ricinuswith its hosts and environmental niches that impact pathogen circulation. The analysis of tick-hosts association suggested that mammals and lizards were the ancestral hosts of this tick species, and that a leap to Aves occurred around 120 M years ago. The signature of the environmental variables over the host's phylogeny revealed the existence of two clades of vertebrates diverging along a temperature and vegetation split. This is a robust proof that the tick probably experienced a colonization of new niches by adapting to a large set of new hosts, Aves. Interestingly, the colonization of Aves as hosts did not increase significantly the ecological niche ofI. ricinus, but remarkably Aves are super-spreaders of pathogens. The disparate contribution of Aves to the tick-host-pathogen networks revealed thatI. ricinusevolved to maximize habitat overlap with some hosts that are super-spreaders of pathogens. These results supported the hypothesis that large host networks are not a requirement of tick survival but pathogen circulation. The biological cost of tick adaptation to non-optimal environmental conditions might be balanced by molecular mechanisms triggered by the pathogens that we have only begun to understand.

• MeSH
• Adaptation, Biological MeSH
• Species Specificity MeSH
• Ecology methods   MeSH
• Host-Pathogen Interactions MeSH
• Lizards parasitology   MeSH
• Ticks microbiology   parasitology   physiology   MeSH
• Ixodes classification   parasitology   physiology   MeSH
• Humans MeSH
• Tick-Borne Diseases parasitology   transmission   MeSH
• Vertebrates classification   parasitology   MeSH
• Birds classification   parasitology   MeSH
• Mammals classification   parasitology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Ticks and the pathogens they transmit constitute a growing burden for human and animal health worldwide. Vector competence is a component of vectorial capacity and depends on genetic determinants affecting the ability of a vector to transmit a pathogen. These determinants affect traits such as tick-host-pathogen and susceptibility to pathogen infection. Therefore, the elucidation of the mechanisms involved in tick-pathogen interactions that affect vector competence is essential for the identification of molecular drivers for tick-borne diseases. In this review, we provide a comprehensive overview of tick-pathogen molecular interactions for bacteria, viruses, and protozoa affecting human and animal health. Additionally, the impact of tick microbiome on these interactions was considered. Results show that different pathogens evolved similar strategies such as manipulation of the immune response to infect vectors and facilitate multiplication and transmission. Furthermore, some of these strategies may be used by pathogens to infect both tick and mammalian hosts. Identification of interactions that promote tick survival, spread, and pathogen transmission provides the opportunity to disrupt these interactions and lead to a reduction in tick burden and the prevalence of tick-borne diseases. Targeting some of the similar mechanisms used by the pathogens for infection and transmission by ticks may assist in development of preventative strategies against multiple tick-borne diseases.

• MeSH
• Arachnid Vectors microbiology   parasitology   virology   MeSH
• Host-Pathogen Interactions * MeSH
• Ticks microbiology   parasitology   physiology   virology   MeSH
• Humans MeSH
• Tick-Borne Diseases epidemiology   MeSH
• Disease Transmission, Infectious * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Ticks must durably suppress vertebrate host responses (hemostasis, inflammation, immunity) to avoid rejection and act as vectors of many pathogenic microorganisms that cause disease in humans and animals. Transcriptomics and proteomics studies have been used to study tick-host-pathogen interactions and have facilitated the systematic characterization of salivary composition and molecular dynamics throughout tick feeding. Tick saliva contains a complement of protease inhibitors that are differentially produced during feeding, many of which inhibit blood coagulation, platelet aggregation, vasodilation, and immunity. Here we focus on two major groups of protease inhibitors, the small molecular weight Kunitz inhibitors and cystatins. We discuss their role in tick-host-pathogen interactions, how they mediate the interaction between ticks and their hosts, and how they might be exploited both by pathogens to invade hosts and as candidates for the treatment of various human pathologies.

• MeSH
• Aprotinin chemistry   metabolism   MeSH
• Cystatins chemistry   metabolism   MeSH
• Protease Inhibitors metabolism   MeSH
• Host-Parasite Interactions * MeSH
• Ticks MeSH
• Proteomics MeSH
• Salivary Glands metabolism   MeSH
• Saliva metabolism   MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The publication of the first tick sialome (salivary gland transcriptome) heralded a new era of research of tick protease inhibitors, which represent important constituents of the proteins secreted via tick saliva into the host. Three major groups of protease inhibitors are secreted into saliva: Kunitz inhibitors, serpins, and cystatins. Kunitz inhibitors are anti-hemostatic agents and tens of proteins with one or more Kunitz domains are known to block host coagulation and/or platelet aggregation. Serpins and cystatins are also anti-hemostatic effectors, but intriguingly, from the translational perspective, also act as pluripotent modulators of the host immune system. Here we focus especially on this latter aspect of protease inhibition by ticks and describe the current knowledge and data on secreted salivary serpins and cystatins and their role in tick-host-pathogen interaction triad. We also discuss the potential therapeutic use of tick protease inhibitors.

• MeSH
• Cystatins physiology   therapeutic use   MeSH
• Immunomodulation MeSH
• Protease Inhibitors classification   metabolism   therapeutic use   MeSH
• Serine Proteinase Inhibitors physiology   therapeutic use   MeSH
• Host-Parasite Interactions MeSH
• Ticks metabolism   MeSH
• Humans MeSH
• Serpins physiology   therapeutic use   MeSH
• Saliva enzymology   metabolism   MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Anaplasma phagocytophilum MeSH
• Adaptation, Biological genetics   physiology   MeSH
• Biological Evolution MeSH
• Ecology * MeSH
• Transcription, Genetic genetics   MeSH
• Host-Pathogen Interactions genetics   MeSH
• Ticks microbiology   MeSH
• Ixodes microbiology   MeSH
• Evolution, Molecular MeSH
• Gene Expression Regulation genetics   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Ticks and the pathogens they transmit constitute a growing burden for human and animal health worldwide. Traditionally, tick-borne pathogen detection has been carried out using PCR-based methods that rely in known sequences for specific primers design. This approach matches with the view of a 'single-pathogen' epidemiology. Recent results, however, have stressed the importance of coinfections in pathogen ecology and evolution with impact in pathogen transmission and disease severity. New approaches, including high-throughput technologies, were then used to detect multiple pathogens, but they all need a priori information on the pathogens to search. Thus, those approaches are biased, limited and conceal the complexity of pathogen ecology. Currently, next generation sequencing (NGS) is applied to tick-borne pathogen detection as well as to study the interactions between pathogenic and non-pathogenic microorganisms associated to ticks, the pathobiome. The use of NGS technologies have surfaced two major points: (i) ticks are associated to complex microbial communities and (ii) the relation between pathogens and microbiota is bidirectional. Notably, a new challenge emerges from NGS experiments, data analysis. Discovering associations among a high number of microorganisms is not trivial and therefore most current NGS studies report lists of microorganisms without further insights. An alternative to this is the combination of NGS with analytical tools such as network analysis to unravel the structure of microbial communities associated to ticks in different ecosystems.

• MeSH
• Bacteria isolation & purification   MeSH
• Host-Pathogen Interactions MeSH
• Ticks microbiology   MeSH
• Coinfection microbiology   MeSH
• Humans MeSH
• Microbial Interactions MeSH
• Microbiota * MeSH
• Tick-Borne Diseases diagnosis   microbiology   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Tick-borne encephalitis virus (TBEV) is a member of the genus Flavivirus. It can cause serious infections in humans that may result in encephalitis/meningoencephalitis. Although several studies have described the involvement of specific genes in the host response to TBEV infection in the central nervous system (CNS), the overall network remains poorly characterized. Therefore, we investigated the response of DAOY cells (human medulloblastoma cells derived from cerebellar neurons) to TBEV (Neudoerfl strain, Western subtype) infection to characterize differentially expressed genes by transcriptome analysis. Our results revealed a wide panel of interferon-stimulated genes (ISGs) and pro-inflammatory cytokines, including type III but not type I (or II) interferons (IFNs), which are activated upon TBEV infection, as well as a number of non-coding RNAs, including long non-coding RNAs. To obtain a broader view of the pathways responsible for eliciting an antiviral state in DAOY cells we examined the effect of type I and III IFNs and found that only type I IFN pre-treatment inhibited TBEV production. The cellular response to TBEV showed only partial overlap with gene expression changes induced by IFN-β treatment - suggesting a virus-specific signature - and we identified a group of ISGs that were highly up-regulated following IFN-β treatment. Moreover, a high rate of down-regulation was observed for a wide panel of pro-inflammatory cytokines upon IFN-β treatment. These data can serve as the basis for further studies of host-TBEV interactions and the identification of ISGs and/or lncRNAs with potent antiviral effects in cases of TBEV infection in human neuronal cells.

• MeSH
• Transcriptional Activation MeSH
• Cytokines genetics   immunology   MeSH
• Host-Pathogen Interactions MeSH
• Interferons genetics   immunology   MeSH
• Encephalitis, Tick-Borne genetics   immunology   virology   MeSH
• Humans MeSH
• Neurons immunology   virology   MeSH
• Encephalitis Viruses, Tick-Borne genetics   physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The life cycle of enveloped viruses is closely linked to host-cell lipids. However, changes in lipid metabolism during infections with the tick-borne encephalitis virus (TBEV) have not been described. TBEV is a medically important orthoflavivirus, which is endemic to many parts of Europe and Asia. In the present study, we performed targeted lipidomics with HPLC-MS/MS to evaluate changes in phospholipid and sphingolipid concentrations in TBEV-infected human neuronal SK-N-SH cells. TBEV infections significantly increased phosphatidylcholine, phosphatidylinositol, and phosphatidylserine levels within 48 h post-infection (hpi). Sphingolipids were slightly increased in dihydroceramides within 24 hpi. Later, at 48 hpi, the contents of sphinganine, dihydroceramides, ceramides, glucosylceramides, and ganglioside GD3 were elevated. On the other hand, sphingosine-1-phosphate content was slightly reduced in TBEV-infected cells. Changes in sphingolipid concentrations were accompanied by suppressed expression of a majority of the genes linked to sphingolipid and glycosphingolipid metabolism. Furthermore, we found that a pharmacological inhibitor of sphingolipid synthesis, fenretinide (4-HPR), inhibited TBEV infections in SK-N-SH cells. Taken together, our results suggested that both structural and signaling functions of lipids could be affected during TBEV infections. These changes might be connected to virus propagation and/or host-cell defense.

• MeSH
• Cell Line MeSH
• Phospholipids * metabolism   MeSH
• Host-Pathogen Interactions MeSH
• Humans MeSH
• Lipidomics MeSH
• Lipid Metabolism MeSH
• Neurons * virology   metabolism   MeSH
• Sphingolipids * metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Encephalitis Viruses, Tick-Borne * physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH