Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

Corrigendum: Calcium homeostasis in the epididymal microenvironment: Is extracellular calcium a cofactor for matrix gla protein-dependent scavenging regulated by vitamins.

[This corrects the article DOI: 10.3389/fcell.2022.827940.].

Calcium Homeostasis in the Epididymal Microenvironment: Is Extracellular Calcium a Cofactor for Matrix Gla Protein-Dependent Scavenging Regulated by Vitamins.

In the male reproductive tract, the epididymis is an essential organ for sperm maturation, in which sperm cells acquire mobility and the ability to fertilize oocytes while being stored in a protective microenvironment. Epididymal function involves a specialized luminal microenvironment established by the epithelial cells of epididymal mucosa. Low-calcium concentration is a unique feature of this epididymal luminal microenvironment, its relevance and regulation are, however, incompletely understood. In the rat epididymis, the vitamin D-related calcium-dependent TRPV6-TMEM16A channel-coupler has been shown to be involved in fluid transport, and, in a spatially complementary manner, vitamin K2-related γ-glutamyl carboxylase (GGCX)-dependent carboxylation of matrix Gla protein (MGP) plays an essential role in promoting calcium-dependent protein aggregation. An SNP in the human GGCX gene has been associated with asthenozoospermia. In addition, bioinformatic analysis also suggests the involvement of a vitamin B6-axis in calcium-dependent MGP-mediated protein aggregation. These findings suggest that vitamins interact with calcium homeostasis in the epididymis to ensure proper sperm maturation and male fertility. This review article discusses the regulation mechanisms of calcium homeostasis in the epididymis, and the potential role of vitamin interactions on epididymal calcium homeostasis, especially the role of matrix calcium in the epididymal lumen as a cofactor for the carboxylated MGP-mediated scavenging function.

Endothelial cell biomarkers in critically ill COVID-19 patients with encephalitis.

COVID-19 is associated with encephalitis in critically ill patients and endothelial dysfunction seems to contribute to this life-threatening complication. Our objective was to determine the hallmark of endothelial activation in COVID-19-related encephalitis. In an observational study in intensive care unit (ICU), we compared vascular biomarkers of critically ill COVID-19 patients with or without encephalitis. To be classified in the encephalitis group, patients had to have new onset of central neurologic symptom, and pathological findings on either brain magnetic resonance imaging (MRI) and/or electroencephalogram (EEG). Among the 32 critically ill COVID-19 consecutive patients, 21 were categorized in the control group and 11 in the encephalitis group. Encephalitis patients had a longer ICU stay than control patients (median length [25th-75th percentile] of 52 [16-79] vs. 20.5 [11-44] days, respectively, p = 0.04). Nine-month overall follow-up mortality reached 21% (7/32 patients), with mortality rates in the encephalitis group and the control group of 27% and 19%, respectively. Encephalitis was associated with significant higher release of soluble endothelial activation markers (sE-selectin, tumor necrosis factor-α (TNF-α), interleukin 6, placental growth factor, and thrombomodulin), but these increases were correlated with TNF-α plasmatic levels. The hypoxia-inducible protein angiopoietin-like 4 (ANGPTL4) was at significantly higher levels in encephalitis patients compared to control patients (p = 0.0099), and in contrary to the other increased factors, was not correlated with TNF-α levels (r = 0.2832, p = 0.1163). Our findings suggest that COVID-19-related encephalitis is a cytokine-associated acute brain dysfunction. ANGPTL4 was the only elevated marker found in encephalitis patients, which was not correlated with systemic inflammation, suggesting that ANGPTL4 might be a relevant factor to predict encephalitis in critically ill COVID-19 patients.

Coronavirus disease 2019 crisis in Paris: A differential psychological impact between regular intensive care unit staff members and reinforcement workers.

BACKGROUND: Intensive care unit (ICU) healthcare workers (HCWs) are at the forefront of the coronavirus disease 2019 pandemic. To overcome the lack of human resources during this crisis, some ICUs had to mobilise staff from a reinforcement pool, with no or outdated ICU experience. This study aimed to investigate and to compare the psychological impact of the pandemic on regular ICU staff members and reinforcement workers. MATERIAL AND METHODS: Self-assessment questionnaires were completed by HCWs who worked from March 1 to April 30, 2020, in our 16-bed neurological ICU at La Pitié-Salpêtrière Hospital in Paris, France, which was converted to a COVID ICU. The Hospital Anxiety and Depression Scale, the Post-traumatic Stress Disorder Checklist for DSM-5, McGill Quality of Life Questionnaire-Revised, and 10-item Connor-Davidson Resilience Scale were used to assess anxiety, depression and post-traumatic stress disorder, quality of life, and resilience, respectively. RESULTS: Sixty-nine ICU HCWs completed the survey (37 from the team of regular staff members, i.e., from the public health service, and 32 from a reinforcement pool, either from non-ICU public health service or from private healthcare interim employment agencies). Prevalence of anxiety, depression, and post-traumatic stress disorder symptoms was high, at 19%, 9%, and 16%, respectively, with limited impairment in quality of life or resilience scores. Depression symptoms were observed more in regular staff members than in welcomed reinforcement workers, at 16% and 0%, respectively. CONCLUSIONS: These results revealed that during the pandemic, HCWs from the team of regular staff members were at greater risk of developing psychological disorder compared with reinforcement workers, with higher levels of depressive symptoms.

Therapeutic plasma exchange in a critically ill Covid-19 patient.

Here we describe the effect of therapeutic plasma exchange with 5% albumin as sole replacement solution for the management of Covid-19. A 74-year-old man was admitted for severe Covid-19 acute respiratory distress syndrome. Based on the growing body of evidence that cytokine release syndrome, and especially interleukin-6, plays a key role in critically ill Covid-19 patients, we decided to implement therapeutic plasma exchange as a rescue therapy. The patient's clinical status rapidly improved, and biological records showed convincing results of decrease in interleukin-6 and inflammatory parameters under treatment. This case presents a proof-of-concept for the use of therapeutic plasma exchange with 5% albumin as sole replacement solution in a critically ill Covid-19 patient with cytokine release syndrome. This could constitute a major benefit in terms of security compared to long-lasting immunosuppressive monoclonal antibodies, or to therapeutic plasma exchange with plasma as replacement fluid. Hence, we think that a further evaluation of risk-benefit balance of this therapy in severe cases of Covid-19 should rapidly be undertaken.

Neuroprognostication of Consciousness Recovery in a Patient with COVID-19 Related Encephalitis: Preliminary Findings from a Multimodal Approach.

Predicting the functional recovery of patients with severe neurological condition due to coronavirus disease 2019 (COVID-19) is a challenging task. Only limited outcome data are available, the pathophysiology is poorly understood, and the time-course of recovery is still largely unknown. Here, we report the case of a patient with COVID-19 associated encephalitis presenting as a prolonged state of unresponsiveness for two months, who finally fully recovered consciousness, functional communication, and autonomy after immunotherapy. In a multimodal approach, a high-density resting state EEG revealed a rich brain activity in spite of a severe clinical presentation. Using our previously validated algorithms, we could predict a possible improvement of consciousness in this patient. This case report illustrates the value of a multimodal approach capitalizing on advanced brain-imaging and bedside electrophysiology techniques to improve prognosis accuracy in this complex and new aetiology.

Orbitofrontal involvement in a neuroCOVID-19 patient.

Neurological manifestations of coronavirus disease 19 (COVID-19) such as encephalitis and seizures have been reported increasingly, but our understanding of COVID-19-related brain injury is still limited. Herein we describe prefrontal involvement in a patient with COVID-19 who presented prior anosmia, raising the question of a potential trans-olfactory bulb brain invasion.