Generalist Malaria Parasites and Host Imprinting: Unveiling Transcriptional Memory.

Generalist parasites must adapt to diverse host environments to ensure their survival and transmission. These adaptations can involve fixed genetic responses, transcriptional plasticity, or epigenetic mechanisms. The avian malaria parasite Plasmodium homocircumflexum offers an ideal model for studying transcriptional variation across hosts. We experimentally inoculated P. homocircumflexum into different bird species, bypassing the vector, to assess whether gene expression remains stable across hosts, resets in response to new environments, or reflects epigenetic inheritance. We tested two alternative hypotheses: (i) universal gene expression profile ("one key fits all"), where parasite expression remains consistent across hosts. Our outcomes revealed that gene expression differed significantly depending on the host species and time postinfection, rejecting this hypothesis. (ii) Transcriptional plasticity, where gene expression is determined by the recipient host. Contrary to this hypothesis, we observed that gene expression was primarily influenced by the donor at 8 d postinfection (dpi), whereas gene expression was more aligned with the recipient host at 16 dpi. We also explored two mechanisms to explain these patterns: (i) epigenetic inheritance, whereby early transcription reflects the donor environment but adjusts over time, and (ii) genetic differentiation selecting for specific haplotypes. Our data support mechanism (i): 2,647 differentially expressed genes (DEGs) were associated with the donor at 8 dpi, while only 271 DEGs were linked to the recipient at 16 dpi. Single Nucleotide Polymorphism analyses revealed low genetic differentiation, rejecting mechanism (ii). These findings suggest that P. homocircumflexum undergoes a shift from donor-dependent to recipient-dependent gene expression, likely driven by epigenetic regulation and transcriptional plasticity.