Transcriptomic analysis reveals reduced transcriptional activity in 1 the malaria parasite Plasmodium cynomolgi during progression into 2 dormancy 3

128 words) 24 Relapses of Plasmodium dormant liver hypnozoites compromise malaria eradication efforts. 25 New radical cure drugs are urgently needed, yet the vast gap in knowledge of hypnozoite biology 26 impedes drug discovery. We previously unraveled the transcriptome of 6 to 7 day-old P. 27 cynomolgi liver stages, highlighting pathways associated with hypnozoite dormancy (Voorberg28 van der Wel, 2017). We now extend these findings by transcriptome profiling of 9 to 10 day-old 29 liver stage parasites, thus revealing for the first time the maturation of the dormant stage over 30 time. Although progression of dormancy leads to a 10-fold decrease in transcription and 31 expression of only 840 genes, including genes associated with housekeeping functions, we show 32 that pathways involved in quiescence, energy metabolism and maintenance of genome integrity 33 remain the prevalent pathways active in mature hypnozoites. 34 35 Introduction (527 words) 36 Plasmodium vivax malaria puts 35% of the world’s population at risk of disease (WHO, 2015). A 37 large barrier to P. vivax eradication is afforded by the parasite’s ability to cause relapsing disease 38 weeks to months or even years after the primary mosquito-mediated infection [1]. This aspect of 39 P. vivax infection is caused by a dormant liver stage form of the parasite, named the hypnozoite. 40 Hypnozoites can reactivate through unknown mechanisms, continue development into liver 41 schizonts and cause renewed disease. While prophylactic drugs can prevent initial parasite 42 development in the liver [2], there is a need for new radical cure compounds targeting 43 established hypnozoites. There is a vast gap in knowledge surrounding hypnozoite biology that 44