Tick-Pathogen Interactions and Vector Competence: Identification of Molecular Drivers for Tick-Borne Diseases

Abstract

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.

Keywords: Anaplasma; Babesia; Borrelia; flavivirus; immunology; microbiome; tick; vaccine.

Figure 1

Model organisms: tick-borne pathogens that constitute a growing burden for human and animal health. The pathogens covered in this review include bacteria (A. phagocytophilum and B. burgdorferi), viruses (Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus), and protozoa (Babesia spp.) transmitted by hard ticks (Ixodidae). The most prevalent diseases caused by these pathogens, main tick vectors, and disease distribution worldwide is shown in the figure.

Figure 2

Tick-pathogen molecular interactions. (A) A. phagocytophilum (B) B. burgdorferi s.l., (C) TBEV, and (D) B. bovis/B. bigemina activate mechanisms (panel 1) and manipulate tick protective responses and other biological processes in order to facilitate infection (panel 2), while ticks respond to limit pathogen infection and preserve feeding fitness and vector competence for survival of both ticks and pathogens (panel 3). MG, midgut; HE, hemocyte; SG, salivary gland; MSPs, major surface proteins; HSPs, heat shock proteins; ER, endoplasmic reticulum.

Figure 3

Possible impact of tick microbiome on pathogen transmission. Tick microbiome may affect pathogen transmission either directly via nutrient competition or induced/reduced immunity, or indirectly by affecting tick populations (viability, reproduction) or fitness (affecting host-seeking success). MG, midgut; SG, salivary gland; OV, ovaries.

Figure 4

Pathogens inhibit vector cell apoptosis by different mechanisms. After infection of tick salivary glands, A. phagocytophilum inhibit apoptosis by decreasing the expression of the pro-apoptotic genes coding for proteins such as ASK1 and Porin. Porin down-regulation is associated with the inhibition of mitochondrial Cyt c release (Ayllón et al., 2015a). In contrast, A. phagocytophilum infection does not affect Bcl-2 levels, probably because this protein but not Porin is essential for tick feeding (Ayllón et al., 2015a). A. phagocytophilum also induces ER stress in tick cells which play a role in reducing the levels of MKK that inhibits apoptosis (Villar et al., 2015a). Another interesting mechanism of A. phagocytophilum to inhibit apoptosis is the manipulation of glucose metabolism by reducing the levels of PEPCK (Villar et al., 2015a). The capacity of A. phagocytophilum to downregulate gene expression in neutrophils was associated with HDAC1 recruitment to the promoters of target genes by the ankyrin repeat protein AnkA (Garcia-Garcia et al., ,; Rennoll-Bankert et al., 2015). Tick HDAC1 is overrepresented in A. phagocytophilum-infected salivary glands and chemical inhibition of this protein decreases A. phagocytophilum burden in tick cells (Cabezas-Cruz et al., 2016). Infection of tick cells with flaviviruses results in the up-regulation of genes such as hsp70 that inhibit apoptosis (Mansfield et al., 2017). N, Nucleus; M, Mitochondria; ER, Endoplasmic Reticulum; Cyt c, Cytochrome c; ASK1, Apoptosis signal-regulating kinase 1; MKK, Mitogen-activated Protein Kinase; HDAC1, Histone Deacetylase 1; AnkA, Ankyrin A; PEPCK, Phosphoenolpyruvate Carboxykinase; FOXO, Forkhead box O; Hid, Head involution defective; JNK, Jun amino-terminal kinases; Casp, caspases. The molecules and processes represented in green are up-regulated, while those represented in red are down-regulated in response to infection. The activity of the molecules represented in blue varies in response to infection.