Ghosh Riya, Joshi Garima, Shrimali Nishith M, Bhardwaj Kanchan, Chorol Tsewang, Thinlas Tashi, Koul Parvaiz A, Prchal Josef T, Guchhait Prasenjit
Manav Rachna International Institute of Research and Studies, Faridabad, India.
Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India.
PLoS Pathog. 2025 Jun 26;21(6):e1013296. doi: 10.1371/journal.ppat.1013296. eCollection 2025 Jun.
We previously reported that Tibetan-specific variant of prolyl-hydroxylase-2 (PHD2)D4E;C127S protects highlanders from hypoxia-triggered pathologies by destabilizing hypoxia-inducible factor (HIF)-1α. Others have reported that stabilized HIF1α negatively regulates interferon (IFN)-regulating factor (IRF)-3 under hypoxia. We examined the role of PHD2D4E;C127S variant in IFN synthesis in immune cells during viral infections. Primary monocytes and cells engineered to express the PHD2D4E;C127S variant displayed protection against dengue virus (DENV)-2 infection by suppressing HIF1α, in turn promoting IRF-3 and IFNα/β synthesis in hypoxia (3% O2) in vitro. However, under normoxia (21% O2), these mutant cells increased reactive oxygen species (ROS) generation following DENV2 infection. Increased ROS then suppressed PHD2D4E;C127S activity, reflected by reduced hydroxylation and concomitant stabilization of HIF1α, resulting in suppressed IFN synthesis and higher DENV2 replication. The PHD2WT cells demonstrated the opposite trend. Our data further confirmed the inverse correlation between HIF1α and IFN pathways. CAY10585, a HIF1α-inhibitor, decreased the DENV2 infection by increasing IFN-A/B and IRF-3/7/9 expression. HIF1α-depleted monocytes also showed a similar response to the infection. We extended our findings to COVID-19 infection. The CD4/CD8 T-cells collected from Tibetans with PHD2D4E;C127S variant and exposed to SARS-CoV-2 infection showed elevated expression of IFN-γ in response to exposure to SARS-CoV-2 receptor-binding domain (RBD) peptide under hypoxia, and a lesser expression under normoxia. The study thus highlights a unique crosstalk of PHD2D4E;C127S variant with HIF1α-IFN axis under environmental pO2 in protecting or predisposing Tibetans to viral infections.
我们之前报道过，脯氨酰羟化酶-2（PHD2）的藏族特异性变体D4E;C127S通过使缺氧诱导因子（HIF）-1α不稳定，保护高原居民免受缺氧引发的病理影响。其他人报道过，在缺氧条件下，稳定的HIF1α会对干扰素（IFN）调节因子（IRF）-3产生负调节作用。我们研究了PHD2D4E;C127S变体在病毒感染期间免疫细胞中IFN合成中的作用。原代单核细胞和经工程改造表达PHD2D4E;C127S变体的细胞通过抑制HIF1α，表现出对登革热病毒（DENV）-2感染的保护作用，进而在体外低氧（3%氧气）条件下促进IRF-3和IFNα/β的合成。然而，在常氧（21%氧气）条件下，这些突变细胞在DENV2感染后活性氧（ROS）生成增加。ROS增加随后抑制了PHD2D4E;C127S的活性，表现为HIF1α的羟基化减少和随之而来的稳定化，导致IFN合成受到抑制且DENV2复制增加。PHD2野生型细胞表现出相反的趋势。我们的数据进一步证实了HIF1α和IFN途径之间的负相关关系。CAY10585，一种HIF1α抑制剂，通过增加IFN-A/B和IRF-3/7/9的表达降低了DENV2感染。HIF1α缺失的单核细胞对感染也表现出类似的反应。我们将研究结果扩展到了新冠病毒感染。从携带PHD2D4E;C127S变体的藏族人身上采集的CD4/CD8 T细胞，在低氧条件下暴露于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染时，对SARS-CoV-2受体结合域（RBD）肽的暴露表现出IFN-γ表达升高，而在常氧条件下表达较低。因此，该研究突出了在环境氧分压下，PHD2D4E;C127S变体与HIF1α-IFN轴之间独特的相互作用，这在保护或使藏族人易患病毒感染方面发挥着作用。
