Abstract
Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human granulocytic anaplasmosis. These intracellular bacteria establish infection by affecting cell function in both the vertebrate host and the tick vector, Ixodes scapularis. Previous studies have characterized the tick transcriptome and proteome in response to A. phagocytophilum infection. However, in the postgenomic era, the integration of omics datasets through a systems biology approach allows network-based analyses to describe the complexity and functionality of biological systems such as host-pathogen interactions and the discovery of new targets for prevention and control of infectious diseases. This study reports the first systems biology integration of metabolomics, transcriptomics, and proteomics data to characterize essential metabolic pathways involved in the tick response to A. phagocytophilum infection. The ISE6 tick cells used in this study constitute a model for hemocytes involved in pathogen infection and immune response. The results showed that infection affected protein processing in endoplasmic reticulum and glucose metabolic pathways in tick cells. These results supported tick-Anaplasma co-evolution by providing new evidence of how tick cells limit pathogen infection, while the pathogen benefits from the tick cell response to establish infection. Additionally, ticks benefit from A. phagocytophilum infection by increasing survival while pathogens guarantee transmission. The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection but requires protein degradation to prevent ER stress and cell apoptosis to survive in infected cells. Additionally, A. phagocytophilum may benefit from the tick cell's ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which also results in the inhibition of cell apoptosis that increases infection of tick cells. These results support the use of this experimental approach to systematically identify cell pathways and molecular mechanisms involved in tick-pathogen interactions. Data are available via ProteomeXchange with identifier PXD002181.
Highlights
The pathogen benefits from the tick cell response to establish infection
The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection but requires protein degradation to prevent endoplasmic reticulum (ER) stress and cell apoptosis to survive in infected cells
Our results showed that phosphoenolpyruvate carboxykinase (PEPCK) stimulation increases apoptosis in tick cells, suggesting again a coevolutionary mechanism by which A. phagocytophilum may benefit from the tick cell’s ability to limit rickettsial infection by inhibiting PEPCK and thereby decreasing glucose metabolism, which results in the inhibition of cell apoptosis that increases infection in ticks [8, 12]
Summary
The pathogen benefits from the tick cell response to establish infection. ticks benefit from A. phagocytophilum infection by increasing survival while pathogens guarantee transmission. A. phagocytophilum may benefit from the tick cell’s ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which results in the inhibition of cell apoptosis that increases infection of tick cells These results support the use of this experimental approach to systematically identify cell pathways and molecular mechanisms involved in tick–pathogen interactions. Our objective was that the integration of metabolomics, transcriptomics, and proteomics data to expand the understanding of tick–Anaplasma interactions with the discovery of tick metabolic pathways playing a critical role at the tick– pathogen interface To address this objective, a systems biology approach was developed to integrate metabolomics, transcriptomics, and proteomics data collected from uninfected and A. phagocytophilum-infected I. scapularis ISE6 cells, which constitute a model for hemocytes involved in pathogen infection and immune response [20]. The results showed that infection with A. phagocytophilum affected protein processing in endoplasmic reticulum (ER) and glucose metabolic pathways in tick cells and suggested new coevolved mechanisms involved in pathogen infection and the tick cell response to infection
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