SARS-CoV-2 infection in hiPSC-derived neurons is cathepsin-dependent and causes differential accumulation of HIF1ɑ and phosphorylated tau

Pinja Kettunen; Janika Ruuska; Tania Quirin; Ravi Ojha; Saber H. Saber; Julian D.J. Sng; Sean Morrison; Bahaa Al-Mhanawi; Mohammed R. Shaker; Simon De Neck; Anja Kipar; Lassi Paavolainen; Ernst Wolvetang; Merja Joensuu; Jari Koistinaho; Taisia Rolova; Giuseppe Balistreri

Pinja Kettunen, Janika Ruuska, Tania Quirin, Ravi Ojha, Saber H Saber, Julian D J Sng, Sean Morrison, Bahaa Al-Mhanawi, Mohammed R Shaker, Simon De Neck, Anja Kipar, Lassi Paavolainen, Ernst Wolvetang, Merja Joensuu, Jari Koistinaho, Taisia Rolova, Giuseppe Balistreri

Molecular Therapy Nucleic Acids, doi:10.1016/j.omtn.2025.102726

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to infect areas of the human brain and a subset of neurons in vitro. We have previously demonstrated that the virus enters human induced pluripotent stem cell (hiPSC)-derived neurons via an endosomallysosomal pathway. Here, we show that neuronal infection with both SARS-CoV-2 Wuhan and Omicron XBB.1.5 variants is dependent on cathepsins and can be blocked by an inhibitor of cathepsin B. The result was reproducible in non-transgenic hiPSC-derived cortical organoids. We further show that SARS-CoV-2 can replicate in neuron cultures, but the infectivity of the newly produced virions declined at 24 h post-infection despite a further increase in released viral RNA at later time points. The number of infected neurons decreased within five days, suggesting virus-induced neuronal cell death. The infection also caused the accumulation of the hypoxia-inducible stress factor HIF1-α in infected neurons under normoxia. Finally, expanding previous findings, in SARS-CoV-2 infected neurons, the microtubule-associated protein tau was hyperphosphorylated at multiple loci, including S202/T205, and mislocalized to the soma of infected 2D-neuronal cultures, but not in 3D-organotypic models. Hence, the neurodegenerative potential of SARS-CoV-2 infection should be carefully considered in different infection models.

AUTHOR CONTRIBUTIONS P.K.: design, data collection and analysis (2D cultures), interpretation, drafting of the article; J.R.: design, data collection and analysis (2D cultures), drafting of the article; T.Q.: data collection and analysis (2D cultures); R.O.: data collection (2D cultures); S. H.S.: data collection (organoids); S.M.: data collection (organoids); S.M.; image analysis (organoids); L.P.: image analysis of microglial cells; S.D.N.: analysis and data collection of organoid immunohistochemistry; A.K.: guided the work for immunohistochemistry of organoids, provided infrastructures and funding; E.W.: guided the work, provided infrastructures and provided funding (organoids); M.J.: guided the work, provided infrastructures and provided funding (organoids); J.K.: design, interpretation, drafting and commenting of the article, guided the work, provided infrastructures and provided funding; T.R.: design, data collection and analysis (2D cultures), interpretation, drafting and commenting of the article, guided the work; G.B.: design, analysis, interpretation, drafting and commenting of the article, guided the work, provided infrastructures and provided funding. DECLARATION OF INTERESTS We declare no competing interests. SUPPLEMENTAL INFORMATION Supplemental information can be found online at https://doi.org/10.1016/j.omtn.2025. 102726 .

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