Transcriptomic reveals the ferroptosis features of host response in a mouse model of Zika virus infection

Abstract

Zika virus (ZIKV) is a neurotropic flavivirus. The outbreak of ZIKV in 2016 created a global health emergency. However, the underlying pathogenic mechanisms remain elusive. We investigated the host response features of in vivo replication in a mouse model of ZIKV infection, by performing a series of transcriptomic and bioinformatic analyses of ZIKV and mock‐infected brain tissue. Tissue damage, inflammatory cells infiltration and high viral replication were observed in the brain tissue of ZIKV infected mice. RNA‐Seq of the brain indicated the activation of ferroptosis pathways. Enrichment analysis of ferroptosis regulators revealed their involvement in pathways such as mineral absorption, fatty acid biosynthesis, fatty acid degradation, PPAR signaling pathway, peroxidase, and adipokinesine signalling pathway. We then identified 12 interacted hub ferroptosis regulators (CYBB, HMOX1, CP, SAT1, TF, SLC39A14, FTL, LPCAT3, FTH1, SLC3A2, TP53, and SLC40A1) that were related to the differential expression of CD8+ T cells, microglia and monocytes. CYBB, HMOX1, SALT, and SLAC40A1 were selected as potential biomarkers of ZIKV infection. Finally, we validated our results using RT‐qPCR and outside available datasets. For the first time, we proposed a possible mechanism of ferroptosis in brain tissue infected by ZIKV in mice and identified the four key ferroptosis regulators.

The mechanism of ferroptosis and its related diseases

“…These findings support the role of iron-induced death in Mtb-triggered necrosis. Further research revealed that the knockdown of heme oxygenase 1 (Hmox1) by siRNA resulted in a diminution of antioxidant factors GPX4 and FSP1 [ 32 ], along with an increased release of intracellular bacteria in Bacillus Calmette-Guérin (BCG)-infected macrophages [ 743 ]. These observations suggest that Mtb propagation occurs through ferroptosis, thereby inspiring us to search for promising strategies to manage pulmonary tuberculosis by focusing on ferroptosis-induced necrosis.…”

“…Due to involving various and complicated signaling, ferroptosis plays an important role in the occurrence and development of major chronic diseases and different roles in different disease contexts. A growing body of evidence suggests that the imbalance of ferroptosis affects, development and aging [ 13 , 14 ], and is closely related to the tumor [ 8 , 15 , 16 ], ischemic diseases [ 17 – 22 ], neurodegenerative disease [ 23 , 24 ], organ transplantation [ 25 , 26 ], cardiovascular disease [ 27 – 29 ], autoimmune functions [ 15 , 30 ], infection [ 31 , 32 ], iron-overload disease [ 33 ], and so on (Fig. 2 ).…”

Ferroptosis contributes to JEV-induced neuronal damage and neuroinflammation

“…Newcastle disease virus (NDV) induces GPX4-dependent ferroptosis by activating p53 ( Kan et al., 2021 ). Although a recent study using RNA-seq has demonstrated that ferroptosis-related pathways are significantly activated in ZIKV-infected mouse brains ( Yan et al., 2023 ), there is still no clear evidence on whether ferroptosis is involved in the pathogenesis of flaviviruses.…”

MNT inhibits lung adenocarcinoma ferroptosis and chemosensitivity by suppressing SAT1

“…More importantly, aberrantly expressed SAT1 is closely related to cancer development, including LUAD 10 , 12 . Recently, SAT1 was reported to be associated with the regulating process of ferroptosis in tumor cells 11 , 13 . However, the mechanism by which cancer regulates SAT1 to affect ferroptosis is still unidentified.…”