Adaptation of Anaplasma phagocytophilum to the tick vector is controlled by the transcriptional regulator Tr1

ABSTRACT Rickettsial pathogens are strictly dependent on the cellular biology of their hosts for survival and replication. Predominantly transmitted by blood-feeding arthropods, these vector-borne pathogens are forced to adapt between the disparate environments of their mammalian host and arthropod vector. To achieve this, the Rickettsial bacteria Anaplasma phagocytophilum undergo extensive transcriptional reprogramming, with over 41% of its genes differentially transcribed between mammals and Ixodes scapularis ticks. How the bacterium orchestrates this dramatic transcriptional reprogramming is not understood. The gene tr1 encodes a Helix-Turn-Helix DNA-binding protein that is exclusively expressed during tick infection. Herein, we show that tr1 is essential for A. phagocytophilum survival in ticks and regulates the transcription of other genes necessary to adapt to the arthropod vector. We demonstrate that Tr1 is a DNA-binding protein that recognizes promoters of tick-specific genes in A. phagocytophilum , including secreted effector ateA , alternate components of the type IV secretion system (T4SS), and membrane proteins. Our findings demonstrate that Tr1 is a master regulator of genes critical for A. phagocytophilum adaptation to the tick. IMPORTANCE Tick-borne pathogens are a persistent threat to human and animal health worldwide. These pathogens must be capable of surviving in both the arthropod vector and the mammalian hosts to successfully complete their lifecycle. To achieve this, these pathogens reciprocally regulate genes that are specific for either mammalian or tick infection. The mechanism orchestrating this switch remains undefined. In this study, we identify a transcriptional regulator controlling how the tick-borne agent for granulocytic anaplasmosis, Anaplasma phagocytophilum , adapts to life in the tick. Disabling this transcriptional switch and the genes it controls renders the bacteria unable to survive in the arthropod vector. Understanding how this central regulator and the genes under its control impact tick infection could lead to interventions that disrupt the cycle of transmission, thereby preventing disease.