Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms

TY - JOUR

T1 - Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms

AU - Borsini, Alessandra

AU - Merrick, Blair

AU - Edgeworth, Jonathan

AU - Mandal, Gargi

AU - Srivastava, Deepak

AU - Vernon, Anthony

AU - Nebbia, Gaia

AU - Thuret, Sandrine

AU - Pariante, Carmine

N1 - Funding Information: All authors are funded by the Rosetrees Trust (M970) for this study. Dr Alessandra Borsini and Professor Carmine M. Pariante are also funded by the UK Medical Research Council (grants MR/L014815/1, MR/J002739/1 and MR/N029488/1), the European Union’s Horizon 2020 research and innovation programme under Grant Agreement N 848158 (EARLYCAUSE), and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Professor Pariante is a NIHR Senior Investigator (2017-2025), and is also funded by the Kennedy Trust for research on COVID-19 and fatigue. Professor Deepak P. Srivastava and Dr Anthony C. Vernon are also funded by a Medical Research Council Centre Grant (MR/N026063/1) and by a NARSAD Independent Investigator Grant from the Brain & Beahvior Research Foundation (Grant No. 25957). Funding Information: AB, CMP and ST have received research funding from Johnson & Johnson for research on depression and inflammation which included cellular work (2012–2018), but this work is unrelated to that funding; moreover, less than 10% of Professor Pariante’s support in the last 10 years derives from commercial collaborations, including: a strategic award from the Wellcome Trust (Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, grant 104025), in partnership with Janssen, GlaxoSmithKline, Lundbeck and Pfizer; and consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and Värde Partners. ST received funding for a project on neural stem cell aging co-funded by the UK Medical Research Council and Merck Sharp & Dohme Corp. The work presented in this paper is unrelated to these awards. BM, JE, GM, DPS, ACV and GN have no conflicts of interest to declare. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

AB - Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

UR - http://www.scopus.com/inward/record.url?scp=85139398675&partnerID=8YFLogxK

U2 - 10.1038/s41380-022-01741-1

DO - 10.1038/s41380-022-01741-1

M3 - Article

SN - 1359-4184

VL - 27

SP - 5049

EP - 5061

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 12

ER -