The obligate intracellular pathogen, Anaplasma phagocytophilum, is the causative agent of life-threatening diseases in humans and animals. A. phagocytophilum is an emerging tick-borne pathogen in the United States, Europe, Africa and Asia, with increasing numbers of infected people and animals every year. It is increasingly recognized that intracellular pathogens modify host cell metabolic pathways to increase infection and transmission in both vertebrate and invertebrate hosts. Recent reports have shown that amino acids are central to the host-pathogen metabolic interaction. In this study, a genome-wide search for components of amino acid metabolic pathways was performed in Ixodes scapularis, the main tick vector of A. phagocytophilum in the United States, for which the genome was recently published. The enzymes involved in the synthesis and degradation pathways of the twenty amino acids were identified. Then, the available transcriptomics and proteomics data was used to characterize the mRNA and protein levels of I. scapularis amino acid metabolic pathway components in response to A. phagocytophilum infection of tick tissues and ISE6 tick cells. Our analysis was focused on the interplay between carbohydrate and amino acid metabolism during A. phagocytophilum infection in ISE6 cells. The results showed that tick cells increase the synthesis of phosphoenolpyruvate (PEP) from tyrosine to control A. phagocytophilum infection. Metabolic pathway analysis suggested that this is achieved by (i) increasing the transcript and protein levels of mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), (ii) shunting tyrosine into the tricarboxylic acid (TCA) cycle to increase fumarate and oxaloacetate which will be converted into PEP by PEPCK-M, and (iii) blocking all the pathways that use PEP downstream gluconeogenesis (i.e., de novo serine synthesis pathway (SSP), glyceroneogenesis and gluconeogenesis). While sequestering host PEP may be critical for this bacterium because it cannot actively carry out glycolysis to produce PEP, excess of this metabolite may be toxic for A. phagocytophilum. The present work provides a more comprehensive view of the major amino acid metabolic pathways involved in the response to pathogen infection in ticks, and provides the basis for further studies to develop novel strategies for the control of granulocytic anaplasmosis.

• Keywords
• Anaplasma phagocytophilum, Ixodes scapularis, glycerol- 3-phosphate, phosphoenolpyruvate, proteomics, transcriptomics,
• MeSH
• Amino Acids metabolism   MeSH
• Anaplasma phagocytophilum drug effects   genetics   metabolism   pathogenicity   MeSH
• Anaplasmosis MeSH
• Apoptosis MeSH
• Bacterial Proteins genetics   metabolism   MeSH
• Cell Line MeSH
• Citric Acid Cycle MeSH
• Phosphoenolpyruvate metabolism   pharmacology   MeSH
• Phosphoenolpyruvate Carboxykinase (ATP) metabolism   MeSH
• Genome, Bacterial MeSH
• Gluconeogenesis MeSH
• Glycolysis MeSH
• Host-Pathogen Interactions physiology   MeSH
• Ixodes microbiology   MeSH
• Oxaloacetic Acid metabolism   MeSH
• RNA, Messenger genetics   MeSH
• Metabolic Networks and Pathways genetics   MeSH
• Carbohydrate Metabolism MeSH
• Mitochondria metabolism   MeSH
• Proteomics methods   MeSH
• Serine metabolism   MeSH
• Transcriptome MeSH
• Tyrosine metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amino Acids MeSH
• Bacterial Proteins MeSH
• Phosphoenolpyruvate MeSH
• Phosphoenolpyruvate Carboxykinase (ATP) MeSH
• Oxaloacetic Acid MeSH
• RNA, Messenger MeSH
• Serine MeSH
• Tyrosine 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 tick Ixodes ricinus with 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 of I. ricinus, but remarkably Aves are super-spreaders of pathogens. The disparate contribution of Aves to the tick-host-pathogen networks revealed that I. ricinus evolved 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.

• Keywords
• communities, networks, tick-borne pathogens, ticks,
• 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.

• Keywords
• Anaplasma, Babesia, Borrelia, flavivirus, immunology, microbiome, tick, vaccine,
• 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
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH