AUTHOR=Chen Songqin , Hu Shanming , Zhou Yongzhi , Cao Jie , Zhang Houshuang , Wang Yanan , Zhou Jinlin 

TITLE=Tick HRF-dependent ferroptosis pathway to promote tick acquisition of Babesia microti

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1560152

DOI=10.3389/fcimb.2025.1560152

ISSN=2235-2988

ABSTRACT=B. microti is a tick-transmitted zoonotic erythrocytic intracellular parasite. Ferroptosis is an iron-dependent form of programmed cell death that affects pathogen replication in the host. Currently, there is limited research concerning the effect of tick ferroptosis on Babesia infection and the underlying mechanism of action. The present study used a B. microti -mouse- Haemaphysalis longicornis infection model in which nymphs fed on the blood of B. microti-infected mice. The midgut divalent iron (p<0.01) and reactive oxygen species (ROS) (p<0.05) levels were significantly elevated in infected ticks, and transmission electron microscopy (TEM) showed that mitochondrial ridges were absent or decreased in size. Downregulation of ferritin 1 and glutathione peroxidase 4 (GPX4) in ticks infected with B. microti suggests that these changes promote ferroptosis. In vivo studies demonstrated that the ferroptosis promoter Erastin increased B. microti load (p<0.05), while the inhibitor Ferrostatin-1 effectively decreased load (p<0.01). Tick histamine-releasing factor (HRF), a protein related to the antioxidant system, was downregulated in infected nymphs compared with uninfected nymphs (p<0.05), and interference with HRF promoted tick acquisition of B. microti (p<0.001). Transcriptomic analyses showed that HRF interference promotes tick ferroptosis by downregulating ferritin 1 and GPX4. Meanwhile, interference with tick HRF molecules showed increased divalent iron and ROS and decreased mitochondrial ridges compared with controls. These findings highlight the critical role of tick HRF molecules in regulating ferroptosis and acquisition of B. microti, thereby providing important insights for a deeper understanding of the tick-Babesia interaction.