Brain imaging before and after COVID-19 in UK Biobank (preprint)

There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS- CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID- 19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all |Z|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in post hoc disease studies, the availability of pre- infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the in vivo hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge (preprint)

BackgroundThe medium-term effects of Coronavirus disease (COVID-19) on multiple organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. MethodsFifty-eight COVID-19 patients post-hospital discharge and 30 comorbidity-matched controls were prospectively enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. FindingsAt 2-3 months from disease-onset, 64% of patients experienced persistent breathlessness and 55% complained of significant fatigue. On MRI, tissue signal abnormalities were seen in the lungs (60%), heart (26%), liver (10%) and kidneys (29%) of patients. COVID-19 patients also exhibited tissue changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domain relative to controls. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance (405{+/-}118m vs 517{+/-}106m in controls, p<0.0001) were significantly reduced in patients. The extent of extra-pulmonary MRI abnormalities and exercise tolerance correlated with serum markers of ongoing inflammation and severity of acute illness. Patients were more likely to report symptoms of moderate to severe anxiety (35% versus 10%, p=0.012) and depression (39% versus 17%, p=0.036) and a significant impairment in all domains of quality of life compared to controls. InterpretationA significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of breathlessness, fatigue, anxiety, depression and exercise limitation at 2-3 months from disease-onset. Persistent lung and extra-pulmonary organ MRI findings are common. In COVID-19 survivors, chronic inflammation may underlie multiorgan abnormalities and contribute to impaired quality of life. FundingNIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19 (preprint)

SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection whereas distal alveolar differentiation (AT2[->]AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19 which can be immediately utilized to investigate COVID-19 pathogenesis, and vet new therapies and vaccines.

3D reconstruction of SARS-CoV-2 infection in ferrets emphasizes focal infection pattern in the upper respiratory tract (preprint)

The visualization of viral pathogens in infected tissues is an invaluable tool to understand spatial virus distribution, localization, and cell tropism in vivo. Commonly, virus-infected tissues are analyzed using conventional immunohistochemistry in paraffin-embedded thin sections. Here, we demonstrate the utility of volumetric three-dimensional (3D) immunofluorescence imaging using tissue optical clearing and light sheet microscopy to investigate host-pathogen interactions of pandemic SARS-CoV-2 in ferrets at a mesoscopic scale. The superior spatial context of large, intact samples (> 150 mm3) allowed detailed quantification of interrelated parameters like focus-to-focus distance or SARS-CoV-2-infected area, facilitating an in-depth description of SARS-CoV-2 infection foci. Accordingly, we could confirm a preferential infection of the ferret upper respiratory tract by SARS-CoV-2 and emphasize a distinct focal infection pattern in nasal turbinates. Conclusively, we present a proof-of-concept study for investigating critically important respiratory pathogens in their spatial tissue morphology and demonstrate the first specific 3D visualization of SARS-CoV-2 infection.

Molecular mechanism of SARS-CoV-2 inactivation by temperature (preprint)

Recent studies have shown that SARS-CoV-2 virus can be inactivated by effect of heat, even though, little is known about the molecular changes induced by the temperature. Here, we unravel the basics of such inactivation mechanism over the SARS-CoV-2 spike glycoprotein by executing atomistic molecular dynamics simulations. Both the closed down and open up states, which determine the accessibility to the receptor binding domain, were considered. Results suggest that the spike undergoes drastic changes in the topology of the hydrogen bond network while salt bridges are mainly preserved. Reorganization in the hydrogen bonds structure produces conformational variations in the receptor binding subunit and explain the thermal inactivation of the virus. Conversely, the macrostructure of the spike is preserved at high temperature because of the retained salt bridges. The proposed mechanism has important implications for engineering new approaches to inactivate the SARS-CoV-2 virus.

Homegrown Ultraviolet Germicidal Irradiation for Hospital-Based N95 Decontamination during the COVID-19 Pandemic (preprint)

Coronavirus disease (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is responsible for the 2020 global pandemic and characterized by high transmissibility and morbidity. Healthcare workers (HCWs) are at risk of contracting COVID-19, and this risk is mitigated through the use of personal protective equipment such as N95 Filtering Facepiece Respirators (FFRs). The high demand for FFRs is not currently met by global supply chains, potentially placing HCWs at increased exposure risk. Effective FFR decontamination modalities exist, which could maintain respiratory protection for HCWs in the midst of the current pandemic, through the decontamination and re-use of FFRs. Here, we present a locally-implemented ultraviolet-C germicidal irradiation (UVGI)-based FFR decontamination pathway, utilizing a home-built UVGI array assembled entirely with previously existing components available at our institution. We provide recommendations on the construction of similar systems, as well as guidance and strategies towards successful institutional implementation of FFR decontamination.