Abstract
Coxiella burnetii (Cb), the causative agent of Q fever, replicates within host macrophages by modulating immune responses through poorly understood mechanisms. Long non-coding RNAs (lncRNAs) are crucial yet underexplored regulators of inflammation, particularly in Cb pathogenesis. Employing a comparative transcriptomic analysis of THP-1 macrophages infected with 16 different microbes, we dissect a core set of immune-responsive lncRNAs such as MAILR, LINC01215, PACER, and MROCKI-common to human anti-pathogen responses, and distinguish them from lncRNAs specifically altered at early (1 h) time points in individual infections. In particular, our approach identifies lncRNA CYP1B1-AS1 as specifically upregulated in a spatiotemporal manner along with CYP1B1 in cis during Cb infection. Promoter assays confirm their co-regulation via a shared bidirectional promoter, while aryl hydrocarbon receptor (AHR)-lucia luciferase and nuclear translocation assays demonstrate that Cb infection activates AHR, driving their transcription. Knockdown of CYP1B1-AS1 or CYP1B1 alone disrupts mitochondrial homeostasis, increases ROS and mitochondrial dysfunction, and exacerbates apoptosis during infection. These findings position the CYP1B1-AS1/CYP1B1 axis as a key regulator of mitochondrial homeostasis under AHR signaling, supporting an intracellular environment that benefits Cb replication. Our results highlight the critical roles of lncRNAs in immune regulation and provide a valuable resource for future lncRNA research.