SARS-CoV-2 infection impacts carbon metabolism and depends on glutamine for replication in Syrian hamster astrocytes.
COVID-19
SARS-CoV2
glutamine
neuropathology
proteomics
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
10
07
2022
received:
20
12
2021
accepted:
12
07
2022
pubmed:
27
7
2022
medline:
20
10
2022
entrez:
26
7
2022
Statut:
ppublish
Résumé
COVID-19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID-19. Here, we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS-CoV-2 infected Syrian hamsters. We show that SARS-CoV-2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real-time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro. SARS-CoV-2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID-19, as memory loss, confusion, and cognitive impairment.
Identifiants
pubmed: 35880385
doi: 10.1111/jnc.15679
pmc: PMC9350388
doi:
Substances chimiques
Ketoglutaric Acids
0
Pyruvates
0
Glutamine
0RH81L854J
Carbon
7440-44-0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113-132Informations de copyright
© 2022 International Society for Neurochemistry.
Références
Ahlmann-Eltze, C., & Huber, W. (2020). glmGamPoi: Fitting gamma-Poisson generalized linear models on single cell count data. Bioinformatics, 36, 5701-5702.
Al-Mufti, F., et al. (2021). Acute cerebrovascular disorders and vasculopathies associated with significant mortality in SARS-CoV-2 patients admitted to the intensive care unit in the New York epicenter. Journal of Stroke and Cerebrovascular Diseases, 30, 105429.
Andersen, J. V., Christensen, S. K., Westi, E. W., Diaz-delCastillo, M., Tanila, H., Schousboe, A., Aldana, B. I., & Waagepetersen, H. S. (2021). Deficient astrocyte metabolism impairs glutamine synthesis and neurotransmitter homeostasis in a mouse model of Alzheimer’s disease. Neurobiology of Disease, 148, 105198. https://doi.org/10.1016/j.nbd.2020.105198
Andersen, J. V., Markussen, K. H., Jakobsen, E., Schousboe, A., Waagepetersen, H. S., Rosenberg, P. A., & Aldana, B. I. (2021). Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology, 196, 108719. https://doi.org/10.1016/j.neuropharm.2021.108719
Araujo, D. B., Machado, R. R. G., Amgarten, D. E., Malta, F. M., de Araujo, G. G., Monteiro, C. O., Candido, E. D., Soares, C. P., de Menezes, F. G., Pires, A. C. C., Santana, R. A. F., de Viana, A. O., Dorlass, E., Thomazelli, L., de Ferreira, L. C. S., Botosso, V. F., Carvalho, C. R. G., Oliveira, D. B. L., Pinho, J. R. R., & Durigon, E. L. (2020). SARS-CoV-2 isolation from the first reported patients in Brazil and establishment of a coordinated task network. Memórias Do Instituto Oswaldo Cruz, 115, e200342. https://doi.org/10.1590/0074-02760200342
Audi, A., AlIbrahim, M., Kaddoura, M., Hijazi, G., Yassine, H. M., & Zaraket, H. (2020). Seasonality of respiratory viral infections: Will COVID-19 follow suit? Frontiers in Public Health, 8, 1-8.
Awogbindin, I. O., Ben-Azu, B., Olusola, B. A., Akinluyi, E. T., Adeniyi, P. A., Di Paolo, T., & Tremblay, M.-È. (2021). Microglial implications in SARS-CoV-2 infection and COVID-19: Lessons from viral RNA neurotropism and possible relevance to Parkinson’s disease. Frontiers in Cellular Neuroscience, 15, 670298. https://doi.org/10.3389/fncel.2021.670298
Barton, L. M., Duval, E. J., Stroberg, E., Ghosh, S., & Mukhopadhyay, S. (2020). COVID-19 Autopsies, Oklahoma, USA. American Journal of Clinical Pathology, 1-9, 725-733. https://doi.org/10.1093/ajcp/aqaa062
Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., Hoffmann, H.-H., Zhang, Y., Dorgham, K., Philippot, Q., Rosain, J., Béziat, V., Manry, J., Shaw, E., Haljasmägi, L., Peterson, P., Lorenzo, L., Bizien, L., Trouillet-Assant, S., Dobbs, K., de Jesus, A. A., … Casanova, J.-L. (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science, 370(6515), eabd4585. https://doi.org/10.1126/science.abd4585
Bharadwaj, S., Singh, M., Kirtipal, N., & Kang, S. G. (2021). SARS-CoV-2 and glutamine: SARS-CoV-2 triggered pathogenesis via metabolic reprograming of glutamine in host cells. Frontiers in Molecular Biosciences, 7, 1-14.
Centonze, D., Muzio, L., Rossi, S., Furlan, R., Bernardi, G., & Martino, G. (2010). The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death and Differentiation, 17, 1083-1091.
Chambers, J. W., Maguire, T. G., & Alwine, J. C. (2010). Glutamine metabolism is essential for human cytomegalovirus infection. Journal of Virology, 84, 1867-1873.
Chen, R., Wang, K., Yu, J., Howard, D., French, L., Chen, Z., Wen, C., & Xu, Z. (2021). The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in the human and mouse brains. Frontiers in Neurology, 11, 1-12.
Chu, H., Hu, B., Huang, X., Chai, Y., Zhou, D., Wang, Y., Shuai, H., Yang, D., Hou, Y., Zhang, X., Yuen, T. T. T., Cai, J. P., Zhang, A. J., Zhou, J., Yuan, S., To, K. K. W., Chan, I. H. Y., Sit, K. Y., Foo, D. C. C., … Yuen, K. Y. (2021). Host and viral determinants for efficient SARS-CoV-2 infection of the human lung. Nature Communications, 12, 1-15.
Codo, A. C., Davanzo, G. G., Monteiro, L. B., de Souza, G. F., Muraro, S. P., Virgilio-da-Silva, J. V., Prodonoff, J. S., Carregari, V. C., de Biagi Junior, C. A. O., Crunfli, F., Jimenez Restrepo, J. L., Vendramini, P. H., Reis-de-Oliveira, G., Bispo dos Santos, K., Toledo-Teixeira, D. A., Parise, P. L., Martini, M. C., Marques, R. E., Carmo, H. R., … Moraes-Vieira, P. M. (2020). Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent Axis. Cell Metabolism, 32, 437-446.e5.
Crunfli, F., Carregari, V. C., Veras, F. P., Vendramini, P. H., Valença, A. G. F., Antunes, A. S. L. M., Brandão-Teles, C., da Silva Zuccoli, G., Reis-de-Oliveira, G., Silva-Costa, L. C., Saia-Cereda, V. M., Smith, B. J., Codo, A. C., de Souza, G. F., Muraro, S. P., Parise, P. L., Toledo-Teixeira, D. A., de Castro, Í. M. S., Melo, B. M. S., … Martins-de-Souza, D. (2020). Morphological, cellular and molecular basis of brain infection in COVID-19 patients. https://doi.org/10.1101/2020.10.09.20207464
Del Brutto, O. H., et al. (2021). Cognitive decline among individuals with history of mild symptomatic SARS-CoV-2 infection: A longitudinal prospective study nested to a population cohort. European Journal of Neurology, 1-9, 3245-3253. https://doi.org/10.1111/ene.14775
de Matos, A. M. B., Dahy, F. E., de Moura, J. V. L., Marcusso, R. M. N., Gomes, A. B. F., Carvalho, F. M. M., Fernandes, G. B. P., Felix, A. C., Smid, J., Vidal, J. E., Frota, N. A. F., Casseb, J., Easton, A., Solomon, T., Witkin, S. S., Malta Romano, C., & de Oliveira, A. C. P. (2021). Subacute cognitive impairment in individuals with mild and moderate COVID-19: A case series. Frontiers in Neurology, 12, 678924. https://doi.org/10.3389/fneur.2021.678924
Distler, U., Kuharev, J., Navarro, P., & Tenzer, S. (2016). Label-free quantification in ion mobility-enhanced data-independent acquisition proteomics. Nature Protocols, 11(4), 795-812. https://doi.org/10.1038/nprot.2016.042
Eskandar, E. N., Altschul, D. J., de la Garza Ramos, R., Cezayirli, P., Unda, S. R., Benton, J., Dardick, J., Toma, A., Patel, N., Malaviya, A., Flomenbaum, D., Fernandez-Torres, J., Lu, J., Holland, R., Burchi, E., Zampolin, R., Hsu, K., McClelland, A., Burns, J., … Mehler, M. F. (2021). Neurologic syndromes predict higher in-hospital mortality in COVID-19. Neurology, 96, e1527-e1538.
Eymieux, S., Rouillé, Y., Terrier, O., Seron, K., Blanchard, E., Rosa-Calatrava, M., Dubuisson, J., Belouzard, S., & Roingeard, P. (2021). Ultrastructural modifications induced by SARS-CoV-2 in Vero cells: A kinetic analysis of viral factory formation, viral particle morphogenesis and virion release. Cellular and Molecular Life Sciences, 78, 3565-3576.
Fernandes, A., Mendes, N. D., Almeida, G. M., Nogueira, G. O., de Machado, C. M., de Horta-Junior, J. A. C., Assirati Junior, J. A., Garcia-Cairasco, N., Neder, L., & Sebollela, A. (2019). Short-term free-floating slice cultures from the adult human brain. Journal of Visualized Experiments, (153). https://doi.org/10.3791/59845
Finak, G., McDavid, A., Yajima, M., Deng, J., Gersuk, V., Shalek, A. K., Slichter, C. K., Miller, H. W., McElrath, M. J., Prlic, M., Linsley, P. S., & Gottardo, R. (2015). MAST: A flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biology, 16, 1-13.
Finkel, Y., Mizrahi, O., Nachshon, A., Weingarten-Gabbay, S., Morgenstern, D., Yahalom-Ronen, Y., Tamir, H., Achdout, H., Stein, D., Israeli, O., Beth-Din, A., Melamed, S., Weiss, S., Israely, T., Paran, N., Schwartz, M., & Stern-Ginossar, N. (2021). The coding capacity of SARS-CoV-2. Nature, 589, 125-130.
Fontaine, K. A., Camarda, R., & Lagunoff, M. (2014). Vaccinia virus requires glutamine but not glucose for efficient replication. Journal of Virology, 88, 4366-4374.
Fragiel, M., Miró, Ò., Llorens, P., Jiménez, S., Piñera, P., Burillo, G., Martín, A., Martín-Sánchez, F. J., García-Lamberechts, E. J., Jacob, J., Alquézar-Arbé, A., Juárez, R., Jiménez, B., del Rio, R., Mateo Roca, M., García, A. H., López Laguna, N., Lopez Diez, M. P., Pedraza García, J., … SIESTA (Spanish Investigators in Emergency Situations Team) network. (2021). Incidence, clinical, risk factors and outcomes of Guillain-Barré in Covid-19. Annals of Neurology, 89, 598-603.
Gerkin, R. C., Ohla, K., Veldhuizen, M. G., Joseph, P. V., Kelly, C. E., Bakke, A. J., Steele, K. E., Farruggia, M. C., Pellegrino, R., Pepino, M. Y., Bouysset, C., Soler, G. M., Pereda-Loth, V., Dibattista, M., Cooper, K. W., Croijmans, I., di Pizio, A., Ozdener, M. H., Fjaeldstad, A. W., … Baguma, M. (2021). Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms. Chemical Senses, 46, 1-12.
Gkini, V., & Namba, T. (2022). Glutaminolysis and the control of neural progenitors in neocortical development and evolution. The Neuroscientist, 107385842110690. https://doi.org/10.1177/10738584211069060
Guan, W.-J., Ni, Z. Y., Hu, Y., Liang, W. H., Ou, C. Q., He, J. X., Liu, L., Shan, H., Lei, C. L., Hui, D. S. C., du, B., Li, L. J., Zeng, G., Yuen, K. Y., Chen, R. C., Tang, C. L., Wang, T., Chen, P. Y., Xiang, J., … China Medical Treatment Expert Group for Covid-19. (2020). Clinical characteristics of coronavirus disease 2019 in China. The New England Journal of Medicine, 1-13, 1708-1720. https://doi.org/10.1056/NEJMoa2002032
Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., Bikdeli, B., Ahluwalia, N., Ausiello, J. C., Wan, E. Y., Freedberg, D. E., Kirtane, A. J., Parikh, S. A., Maurer, M. S., Nordvig, A. S., Accili, D., Bathon, J. M., Mohan, S., Bauer, K. A., … Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. Nature Medicine, 26, 1017-1032.
Hafemeister, C., & Satija, R. (2019). Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biology, 20(1), 296. https://doi.org/10.1186/s13059-019-1874-1
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., III, Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zager, M., Hoffman, P., Stoeckius, M., Papalexi, E., Mimitou, E. P., Jain, J., Srivastava, A., Stuart, T., Fleming, L. M., Yeung, B., … Satija, R. (2021). Integrated analysis of multimodal single-cell data. Cell, 184, 3573-3587.e29.
Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven article SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. 271-280 (2020) https://doi.org/10.1016/j.cell.2020.02.052.
Imai, M., Iwatsuki-Horimoto, K., Hatta, M., Loeber, S., Halfmann, P. J., Nakajima, N., Watanabe, T., Ujie, M., Takahashi, K., Ito, M., Yamada, S., Fan, S., Chiba, S., Kuroda, M., Guan, L., Takada, K., Armbrust, T., Balogh, A., Furusawa, Y., … Kawaoka, Y. (2020). Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proceedings of the National Academy of Sciences of the United States of America, 117, 16587-16595.
Jiang, J., Wang, C., Qi, R., Fu, H., & Ma, Q. (2020). scREAD: A single-cell RNA-seq database for Alzheimer's disease. iScience, 23, 101769.
Krishnan, S., Nordqvist, H., Ambikan, A. T., Gupta, S., Sperk, M., Svensson-Akusjärvi, S., Mikaeloff, F., Benfeitas, R., Saccon, E., Ponnan, S. M., Rodriguez, J. E., Nikouyan, N., Odeh, A., Ahlén, G., Asghar, M., Sällberg, M., Vesterbacka, J., Nowak, P., Végvári, Á., … Neogi, U. (2021). Metabolic perturbation associated with COVID-19 disease severity and SARS-CoV-2 replication. Molecular & Cellular Proteomics, 20, 100159. https://doi.org/10.1016/j.mcpro.2021.100159
Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi, Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., … Tan, W. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. The Lancet, 395(10224), 565-574. https://doi.org/10.1016/s0140-6736(20)30251-8
Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Miao, X., Li, Y., & Hu, B. (2020). Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology, 77, 683-690.
Marinescu, I., Marinescu, D., Mogoantă, L., Efrem, I. C., & Stovicek, P. O. (2020). Sars-cov-2 infection in patients with serious mental illness and possible benefits of prophylaxis with memantine and amantadine. Romanian Journal of Morphology and Embryology, 61, 1007-1022.
Meinhardt, J., Radke, J., Dittmayer, C., Franz, J., Thomas, C., Mothes, R., Laue, M., Schneider, J., Brünink, S., Greuel, S., Lehmann, M., Hassan, O., Aschman, T., Schumann, E., Chua, R. L., Conrad, C., Eils, R., Stenzel, W., Windgassen, M., … Heppner, F. L. (2021). Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nature Neuroscience, 24, 168-175.
Mendes, N. D., Fernandes, A., Almeida, G. M., Santos, L. E., Selles, M. C., Lyra e Silva, N. M., Machado, C. M., Horta-Júnior, J. A. C., Louzada, P. R., De Felice, F. G., Alves-Leon, S., Marcondes, J., Assirati, J. A., Matias, C. M., Klein, W. L., Garcia-Cairasco, N., Ferreira, S. T., Neder, L., & Sebollela, A. (2018). Free-floating adult human brain-derived slice cultures as a model to study the neuronal impact of Alzheimer’s disease-associated Aβ oligomers. Journal of Neuroscience Methods, 307, 203-209. https://doi.org/10.1016/j.jneumeth.2018.05.021
Merad, M., Blish, C. A., Sallusto, F., & Iwasaki, A. (2022). The immunology and immunopathology of COVID-19. Science, 375(6585), 1122-1127. https://doi.org/10.1126/science.abm8108
Mi, H., Muruganujan, A., Huang, X., Ebert, D., Mills, C., Guo, X., & Thomas, P. D. (2019). Protocol update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0). Nature Protocols, 14, 703-721.
Mullen, P. J., Garcia, G., Purkayastha, A., Matulionis, N., Schmid, E. W., Momcilovic, M., Sen, C., Langerman, J., Ramaiah, A., Shackelford, D. B., Damoiseaux, R., French, S. W., Plath, K., Gomperts, B. N., Arumugaswami, V., & Christofk, H. R. (2021). SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-22166-4
Nagu, P., Parashar, A., Behl, T., & Mehta, V. (2021). CNS implications of COVID-19: A comprehensive review. Reviews in the Neurosciences, 32, 219-234.
Nasirudeen, A. M. A., Wong, H. H., Thien, P., Xu, S., Lam, K. P., & Liu, D. X. (2011). RIG-i, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS Neglected Tropical Diseases, 5, e926.
Pinto, B. G. G., Oliveira, A. E. R., Singh, Y., Jimenez, L., Gonçalves, A. N. A., Ogava, R. L. T., Creighton, R., Schatzmann Peron, J. P., & Nakaya, H. I. (2020). ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. The Journal of Infectious Diseases, 222, 556-563.
Piras, I. S., Haapanen, L., Napolioni, V., Sacco, R., van de Water, J., & Persico, A. M. (2014). Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with autism Spectrum disorder. Brain, Behavior, and Immunity, 38, 91-99.
Rehmani, R., Segan, S., Maddika, S. R., Lei, Y. W., & Broka, A. (2021). Spectrum of neurologic & neuroimaging manifestation in COVID-19. Brain, Behavior, and Immunity-Health, 13, 100238.
Remsik, J., Wilcox, J. A., Babady, N. E., McMillen, T. A., Vachha, B. A., Halpern, N. A., Dhawan, V., Rosenblum, M., Iacobuzio-Donahue, C. A., Avila, E. K., Santomasso, B., & Boire, A. (2021). Inflammatory leptomeningeal cytokines mediate COVID-19 neurologic symptoms in cancer patients. Cancer Cell, 39, 276-283.e3.
Rhea, E. M., Logsdon, A. F., Hansen, K. M., Williams, L. M., Reed, M. J., Baumann, K. K., Holden, S. J., Raber, J., Banks, W. A., & Erickson, M. A. (2021). The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nature Neuroscience, 24(3), 368-378. https://doi.org/10.1038/s41593-020-00771-8
Song, E., Bartley, C. M., Chow, R. D., Ngo, T. T., Jiang, R., Zamecnik, C. R., Dandekar, R., Loudermilk, R. P., Dai, Y., Liu, F., Sunshine, S., Liu, J., Wu, W., Hawes, I. A., Alvarenga, B. D., Huynh, T., McAlpine, L., Rahman, N.-T., Geng, B., … Farhadian, S. F. (2021). Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms. Cell Reports Medicine, 2(5), 100288. https://doi.org/10.1016/j.xcrm.2021.100288
Song, E., Zhang, C., Israelow, B., Lu-Culligan, A., Prado, A. V., Skriabine, S., Lu, P., Weizman, O.-E., Liu, F., Dai, Y., Szigeti-Buck, K., Yasumoto, Y., Wang, G., Castaldi, C., Heltke, J., Ng, E., Wheeler, J., Alfajaro, M. M., Levavasseur, E., … Iwasaki, A. (2021). Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal of Experimental Medicine, 218(3), e20202135. https://doi.org/10.1084/jem.20202135
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., & Ng, L. F. P. (2020). The trinity of COVID-19: Immunity, inflammation and intervention. Nature Reviews Immunology, 20, 363-374.
Thai, M., Thaker, S. K., Feng, J., du, Y., Hu, H., Ting Wu, T., Graeber, T. G., Braas, D., & Christofk, H. R. (2015). MYC-induced reprogramming of glutamine catabolism supports optimal virus replication. Nature Communications, 6, 1-9.
Veras, F. P., Pontelli, M. C., Silva, C. M., Toller-Kawahisa, J. E., de Lima, M., Nascimento, D. C., Schneider, A. H., Caetité, D., Tavares, L. A., Paiva, I. M., Rosales, R., Colón, D., Martins, R., Castro, I. A., Almeida, G. M., Lopes, M. I. F., Benatti, M. N., Bonjorno, L. P., Giannini, M. C., … Cunha, F. Q. (2020). SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. The Journal of Experimental Medicine, 217, 1-12.
Wang, L., Ren, Z., Ma, L., Han, Y., Wei, W., Jiang, E., & Ji, X. Y. (2021). Progress in research on SARS-CoV-2 infection causing neurological diseases and its infection mechanism. Frontiers in Neurology, 11, 1-9.
Wauters, E., et al. (2021). Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Research, 31, 272-290. https://doi.org/10.1038/s41422-020-00455-9
Whitaker, M., Elliott, J., Chadeau-Hyam, M., Riley, S., Darzi, A., Cooke, G., Ward, H., & Elliott, P. (2022). Persistent COVID-19 symptoms in a community study of 606,434 people in England. Nature Communications, 13(1), 1957. https://doi.org/10.1038/s41467-022-29521-z
Witkowski, M., Tizian, C., Ferreira-Gomes, M., Niemeyer, D., Jones, T. C., Heinrich, F., Frischbutter, S., Angermair, S., Hohnstein, T., Mattiola, I., Nawrath, P., McEwen, S., Zocche, S., Viviano, E., Heinz, G. A., Maurer, M., Kölsch, U., Chua, R. L., Aschman, T., … Diefenbach, A. (2021). Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells. Nature, 600(7888), 295-301. https://doi.org/10.1038/s41586-021-04142-6
Wölfel, R., Corman, V. M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M. A., Niemeyer, D., Jones, T. C., Vollmar, P., Rothe, C., Hoelscher, M., Bleicker, T., Brünink, S., Schneider, J., Ehmann, R., Zwirglmaier, K., Drosten, C., & Wendtner, C. (2020). Virological assessment of hospitalized patients with COVID-2019. Nature, 581(7809), 465-469. https://doi.org/10.1038/s41586-020-2196-x
Wu, F., Zhao, S., Yu, B., Chen, Y. M., Wang, W., Song, Z. G., Hu, Y., Tao, Z. W., Tian, J. H., Pei, Y. Y., Yuan, M. L., Zhang, Y. L., Dai, F. H., Liu, Y., Wang, Q. M., Zheng, J. J., Xu, L., Holmes, E. C., & Zhang, Y. Z. (2020). A new coronavirus associated with human respiratory disease in China. Nature, 579, 265-269. https://doi.org/10.1038/s41586-020-2008-3
Wu, J., Shi, Y., Pan, X., Wu, S., Hou, R., Zhang, Y., Zhong, T., Tang, H., du, W., Wang, L., Wo, J., Mu, J., Qiu, Y., Yang, K., Zhang, L. K., Ye, B. C., & Qi, N. (2021). SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO. Cell Reports, 34, 108761.
Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., Calcuttawala, K., Vest, R. T., Berdnik, D., Lu, N., Hahn, O., Gate, D., McNerney, M. W., Channappa, D., Cobos, I., … Wyss-Coray, T. (2021). Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature, 595, 565-571.
Yesilkaya, U. H., Sen, M., & Balcioglu, Y. H. (2021). COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway. Journal of Clinical Neuroscience, 87, 153-155.
Yin, X., Riva, L., Pu, Y., Martin-Sancho, L., Kanamune, J., Yamamoto, Y., Sakai, K., Gotoh, S., Miorin, L., de Jesus, P. D., Yang, C. C., Herbert, K. M., Yoh, S., Hultquist, J. F., García-Sastre, A., & Chanda, S. K. (2021). MDA5 governs the innate immune response to SARS-CoV-2 in lung epithelial cells. Cell Reports, 34, 108628.
Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., Si, H. R., Zhu, Y., Li, B., Huang, C. L., Chen, H. D., Chen, J., Luo, Y., Guo, H., Jiang, R. D., Liu, M. Q., Chen, Y., Shen, X. R., Wang, X., … Shi, Z. L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579, 270-273. https://doi.org/10.1038/s41586-020-2012-7