The Good, the Bad and the Tick

Abstract

How tick-borne pathogens (TBPs) could help us understand cancer? The diversity of pathogens transmitted by ticks is higher than that of any other known arthropod vector and includes protozoa (e.g., Babesia spp. and Theileria spp.), bacteria (e.g., intracellular Rickettsia spp. and extracellular Borrelia spp.), viruses (e.g., Tick-borne encephalitis (TBE) and Crimean-Congo hemorrhagic fever (CCHF) virus), helminths (e.g., Cercopithifilaria) and, although less known, fungi (e.g., Dermatophilus) (Otranto et al., 2013; Brites-Neto et al., 2015; de la Fuente et al., 2017). TBPs have complex life cycles that involve vertebrate hosts and the ticks. Intracellular TBP infection triggers cellular and molecular responses that change host cell physiology in fundamental ways. Within vertebrate host cells, the apicomplexan parasites Theileria parva and Theileria annulata activate molecular pathways that result in increased production of reactive oxygen species (ROS), cell immortalization, cancer and host death. In contrast, infection by the rickettsia Anaplasma phagocytophilum inhibits apoptosis, block the production of ROS and results in a self-limiting infection that rarely is lethal for the host. Theileria spp. and A. phagocytophilum modulates host cell response by inducing transcriptional reprogramming of their vertebrate host cells, leukocytes. Transcriptional reprogramming is induced by pathogen-encoded effector proteins that modify host epigenetic pathways that affect not only gene transcription but also protein levels. The complexity of molecular pathways modulated by TBP infection in vertebrate host cells parallel that of cancer which offers a unique opportunity for comparative studies to understand complex health problems such as cancer. Identification of differences between the molecular pathways hijacked by Theileria spp. and A. phagocytophilum with those leading to non-infectious cancer will provide insights into proteins, pathways and biological processes (BP) associated with malignant transformation. This hypothesis is based in the following rationality: (i) Theileria spp. (Cheeseman and Weitzman, 2015), A. phagocytophilum (Sinclair et al., 2014) and oncogenic factors (GonzálezHerrero et al., 2018) behave as “epigenators” (Berger et al., 2009; Cheeseman and Weitzman, 2015) because they have the potential to trigger intracellular signaling pathways that lead to changes in chromatin status and gene expression, (ii) transcriptional reprograming and proteome modulation are hallmarks of infection by Theileria spp. (Kinnaird et al., 2013) and A. phagocytophilum (de la Fuente et al., 2005; Lee et al., 2008), and oncogenesis (González-Herrero et al., 2018), (iii) transcriptional reprograming and proteome modulation in Theileria spp. and A. phagocytophilum infections and oncogenesis are associated with similar molecular and cellular processes including apoptosis (Borjesson et al., 2005; Brown and Attardi, 2005; Hayashida et al., 2010; Ayllón et al., 2015), metabolic reprograming (Medjkane and Weitzman, 2013; Yu et al., 2018; Cabezas-Cruz et al., 2019; Masui et al., 2019), oxidative stress and ROS production (IJdo and Mueller, 2004; Medjkane et al., 2014; Takaki et al., 2019) among others. To compare the cell response to Theileria spp. and A. phagocytophilum infections and carcinogens we propose the combination of quantitative proteomics and network analysis (Figure 1). Networks of proteins and BPs clustered in Emerging Biological Pathways (i.e. network modules resulting from the clustering of proteins and BPs in response to different stimuli) can represent the topology of the specific cell response to Theileria spp. and A. phagocytophilum infection and exposure to carcinogens. The significance of proteins and processes can be then ranked and hierarchized by indexes representing the centrality of proteins and processes in the networks.