bims-mevinf 2024-01-21 papers

Issue of 2024‒01‒21
three papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Cell Stress Chaperones. 2023 Nov;pii: S1355-8145(24)00021-X. [Epub ahead of print]28(6): 657-673

SARS-CoV-2 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway.

Rabab S Hamad, Hayder M Al-Kuraishy, Athanasios Alexiou, Marios Papadakis, Eman A Ahmed, Hebatallah M Saad, Gaber El-Saber Batiha.

Coronavirus disease 2019 (COVID-19) is a recent pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) leading to pulmonary and extra-pulmonary manifestations due to the development of oxidative stress (OS) and hyperinflammation. The underlying cause for OS and hyperinflammation in COVID-19 may be related to the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidative responses and cellular homeostasis. The Nrf2 pathway inhibits the expression of pro-inflammatory cytokines and the development of cytokine storm and OS in COVID-19. Nrf2 activators can attenuate endothelial dysfunction (ED), renin-angiotensin system (RAS) dysregulation, immune thrombosis, and coagulopathy. Hence, this review aimed to reveal the potential role of the Nrf2 pathway and its activators in the management of COVID-19. As well, we tried to revise the mechanistic role of the Nrf2 pathway in COVID-19.

Keywords: COVID-19; Nuclear factor erythroid 2-related factor 2; Oxidative stress; SARS-CoV-2

DOI: https://doi.org/10.1007/s12192-023-01379-0

J Virol. 2024 Jan 16. e0188023

Mitochondria-mediated ferroptosis contributes to the inflammatory responses of bovine viral diarrhea virus (BVDV) in vitro.

Zhijun Li, Bao Zhao, Ying Zhang, Wenqi Fan, Qinghong Xue, Xiwen Chen, Jingyu Wang, Xuefeng Qi.

IMPORTANCE: Bovine viral diarrhea virus (BVDV) threatens a wide range of domestic and wild cattle population worldwide. BVDV causes great economic loss in cattle industry through its immunosuppression and persistent infection. Despite extensive research, the mechanism underlying the pathogenesis of BVDV remains elusive. Our data provide the first direct evidence that mitochondria-mediated ferroptosis and mitophagy are involved in inflammatory responses in both biotypes of BVDV-infected cells. Importantly, we demonstrate that the different degrees of injury of mitochondria and inflammatory responses may attribute to different mitophagy pathways induced by biotypes of BVDV. Overall, our findings uncover the interaction between BVDV infection and mitochondria-mediated ferroptosis, which shed novel light on the physiological impacts of ferroptosis on the pathogenesis of BVDV infection, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution.

Keywords: BVDV; ferroptosis; inflammatory responses; mitochondria damage; mitophagy

DOI: https://doi.org/10.1128/jvi.01880-23

J Med Virol. 2024 Jan;96(1): e29372

Identification of dihydroorotate dehydrogenase inhibitor, vidofludimus, as a potent and novel inhibitor for influenza virus.

Jiazhou Li, Midori Takeda, Mikiko Imahatakenaka, Masanori Ikeda.

Influenza A virus (IAV) infection causes respiratory disease. Recently, infection of IAV H5N1 among mammals are reported in farmed mink. Therefore, to discover antivirals against IAV, we screened a compound library by using the RNA-dependent RNA polymerase (RdRp) assay system derived from H5N1 IAV including a drug-resistant PA mutant (I38T) and a viral polymerase activity enhancing PB2 mutant (T271A). Upon screening, we found vidofludimus can be served as a potential inhibitor for IAV. Vidofludimus an orally active inhibitor for dihydroorotate dehydrogenase (DHODH), a key enzyme for the cellular de novo pyrimidine biosynthesis pathway. We found that vidofludimus exerted antiviral activity against wild-type and drug-resistant mutant IAV, with effective concentrations (EC50 ) of 2.10 and 2.11 μM, respectively. The anti-IAV activity of vidofludimus was canceled by the treatment of uridine or cytidine through pyrimidine salvage synthesis pathway, or orotic acid through pyrimidine de novo synthesis pathway. This indicated that the main target of vidofludimus is DHODH in IAV RdRp expressing cells. We also produced recombinant seasonal IAV H1N1 virion and influenza B virus (IBV) RdRp assay system and confirmed vidofludimus also carried highly antiviral activity against seasonal IAV and IBV. Vidofludimus is a candidate drug for the future threat of IAV H5N1 infection among humans as well as seasonal influenza virus infection.

Keywords: H5N1; RdRp; baloxavir marboxil resistance; favipiravir; highly pathogenic; influenza virus; vidofludimus

DOI: https://doi.org/10.1002/jmv.29372