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Acta Neuropathol Commun ; 10(1): 124, 2022 Sep 05.
Article in English | MEDLINE | ID: covidwho-2009477


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.

COVID-19 , Induced Pluripotent Stem Cells , Animals , Cricetinae , Humans , Mesocricetus , SARS-CoV-2
Biomolecules ; 12(5)2022 04 25.
Article in English | MEDLINE | ID: covidwho-1809689


Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February-April 2020) and the second/third (November 2020-April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published.

COVID-19 , Adult , Autopsy , Brain , COVID-19/epidemiology , Humans , RNA, Viral , SARS-CoV-2
Brain ; 144(9): 2696-2708, 2021 10 22.
Article in English | MEDLINE | ID: covidwho-1185655


Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Brain Infarction/pathology , Brain/pathology , COVID-19/pathology , Hypoxia-Ischemia, Brain/pathology , Intracranial Hemorrhages/pathology , Acute Kidney Injury/complications , Acute Kidney Injury/physiopathology , Acute Kidney Injury/therapy , Adult , Aged , Aged, 80 and over , Bacteremia/complications , Brain/metabolism , Brain Infarction/complications , COVID-19/complications , COVID-19/physiopathology , Coronavirus Nucleocapsid Proteins/metabolism , Female , Humans , Hypoxia-Ischemia, Brain/complications , Inflammation , Intensive Care Units , Intracranial Hemorrhages/complications , Male , Microglia/pathology , Middle Aged , Neurons/pathology , Phagocytosis , Phosphoproteins/metabolism , Pulmonary Embolism/complications , Pulmonary Embolism/physiopathology , RNA, Viral/metabolism , Renal Dialysis , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Survival Rate , T-Lymphocytes/pathology , Venous Thrombosis/complications , Venous Thrombosis/physiopathology