SARS-CoV-2 と COVID-19 に関する備忘録 Vol.29

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Lasting liver injury following COVID-19 infection characterized by ultrasound shear wave elastography【ScienceDirect　2024年11月17日】

Abstract

Objective

To assess for lasting hepatic injury using ultrasound shear wave elastography (SWE) in patients following COVID-19 infection.

Methods

In this retrospective cohort study, patients with SWE exams between January 2019 and 2022 were categorized into three groups: 1) post-COVID-19 subjects with positive COVID-19 PCR assay, 2) random sample of contemporaneous unexposed patients with only negative prior COVID-19 PCR tests, and 3) random sample of pre-pandemic patients to address possible undiagnosed COVID-19 infection in the contemporaneous group. The average difference in median Young’s modulus between post-COVID-19 patients and controls was calculated using a linear regression model after controlling for confounders.

Results

130 patients (mean age ± SD, 56 years ± 13; 66 women) were evaluated, including 30 patients after COVID-19 infection (mean age ± SD, 53 years ± 11; 15 women), 50 contemporaneous unexposed patients (mean age ± SD, 55 years ± 13; 27 men), and 50 pre-pandemic patients (mean age ± SD, 58 years ± 13; 28 women). SWE scans were performed on General Electric LOGIQ E9 or E10 an average of 44 (range, 12–81) weeks after COVID-19 infection. COVID-19 infection was associated with an average increase in median Young’s modulus of 1.5 kPa (95 % CI [0.44, 2.355], p = 0.006) after controlling for age, sex, obesity, history of chronic liver disease, and time period. Post-COVID-19 patients had higher liver stiffness compared to contemporaneous controls (median = 7.58 vs 5.99 kPa, p = 0.001) but not pre-pandemic controls (median = 7.00 kPa, p = 0.51).

Conclusions

COVID-19 infection is associated with increased liver stiffness, which may reflect lasting hepatic injury such as ongoing inflammation or the development of fibrosis. US SWE may serve as a noninvasive tool for long-term liver health monitoring after COVID-19 infection.

◆Manipulation of Host Cholesterol by SARS-CoV-2【bioRxiv　2024年11月14日】

Abstract

SARS-CoV-2 infection is associated with alterations in host lipid metabolism, including disruptions in cholesterol homeostasis. However, the specific mechanisms by which viral proteins influence cholesterol remain incompletely understood. Here, we report that SARS-CoV-2 infection induces cholesterol sequestration within lysosomes, with the viral protein ORF3a identified as the primary driver of this effect. Mechanistically, we found that ORF3a interacts directly with the HOPS complex subunit VPS39 through a hydrophobic interface formed by residues W193 and Y184. A W193A mutation in ORF3a significantly rescues cholesterol egress and corrects the mislocalization of the lysosomal cholesterol transporter NPC2, which is caused by defective trafficking of the trans-Golgi network (TGN) sorting receptor, the cation-independent mannose-6-phosphate receptor (CI-MPR). We further observed a marked reduction in bis(monoacylglycero)phosphate (BMP), a lipid essential for lysosomal cholesterol egress, in both SARS-CoV-2-infected cells and ORF3a-expressing cells, suggesting BMP reduction as an additional mechanism of SARS-CoV-2-caused cholesterol sequestration. Inhibition of lysosomal cholesterol egress using the compound U18666A significantly decreased SARS-CoV-2 infection, highlighting a potential viral strategy of manipulating lysosomal cholesterol to modulate host cell susceptibility. Our findings reveal that SARS-CoV-2 ORF3a disrupts cellular cholesterol transport by altering lysosomal protein trafficking and BMP levels, providing new insights into virus-host interactions that contribute to lipid dysregulation in infected cells.

◆Chronic Viral Reactivation and Associated Host Immune Response and Clinical Outcomes in Acute COVID-19 and Post-Acute Sequelae of COVID-19【bioRxiv　2024年11月16日】

Abstract

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS- CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood.

Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae, Enteroviridae, and Anelloviridae families during acute stage of COVID-19 (0-40 days post- hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue.

Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID- 19 and PASC.

Competing Interest Statement

The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines which list Florian Krammer as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, Merck and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. Viviana Simon is a co-inventor on a patent filed relating to SARS-CoV-2 serological assays (the “Serology Assays”). Ofer Levy is a named inventor on patents held by Boston Children’s Hospital relating to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK) and is a co-founder of and advisor to Ovax, Inc. Charles Cairns serves as a consultant to bioMerieux and is funded for a grant from Bill & Melinda Gates Foundation. James A Overton is a consultant at Knocean Inc. Jessica Lasky-Su serves as a scientific advisor of Precion Inc. Scott R. Hutton, Greg Michelloti and Kari Wong are employees of Metabolon Inc. Vicki Seyfert-Margolis is a current employee of MyOwnMed. Nadine Rouphael reports grants or contracts with Merck, Sanofi, Pfizer, Vaccine Company, Quidel, Lilly and Immorna, and has participated on data safety monitoring boards for Moderna, Sanofi, Seqirus, Pfizer, EMMES, ICON, BARDA, Imunon, CyanVac and Micron. Nadine Rouphael has also received support for meetings/travel from Sanofi and Moderna and honoraria from Virology Education. Adeeb Rahman is a current employee of Immunai Inc. Steven Kleinstein is a consultant related to ImmPort data repository for Peraton. Nathan Grabaugh is a consultant for Tempus Labs and the National Basketball Association. Akiko Iwasaki is a consultant for 4BIO, Blue Willow Biologics, Revelar Biotherapeutics, RIGImmune, Xanadu Bio, Paratus Sciences. Monika Kraft receives research funds paid to her institution from NIH, ALA; Sanofi, Astra-Zeneca for work in asthma, serves as a consultant for Astra-Zeneca, Sanofi, Chiesi, GSK for severe asthma; is a co-founder and CMO for RaeSedo, Inc, a company created to develop peptidomimetics for treatment of inflammatory lung disease. Esther Melamed received research funding from Babson Diagnostics and honorarium from Multiple Sclerosis Association of America and has served on the advisory boards of Genentech, Horizon, Teva, and Viela Bio. Carolyn Calfee receives research funding from NIH, FDA, DOD, Roche-Genentech and Quantum Leap Healthcare Collaborative as well as consulting services for Janssen, Vasomune, Gen1e Life Sciences, NGMBio, and Cellenkos. Wade Schulz was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to Hugo Health, a personal health information platform; cofounder of Refactor Health, an AI-augmented data management platform for health care; and has received grants from Merck and Regeneron Pharmaceutical for research related to COVID-19. Grace A McComsey received research grants from Redhill, Cognivue, Pfizer, and Genentech, and served as a research consultant for Gilead, Merck, Viiv/GSK, and Jenssen. Linda N. Geng received research funding paid to her institution from Pfizer, Inc.

◆Excess weight increases the risk for neurological and neuropsychiatric symptoms in post-COVID-19 condition: A systematic review and meta-analysis【medRxiv　2024年11月20日】

Abstract

Background/purpose: Excess weight has been identified as a potential risk factor for the development of post-COVID-19 condition (PCC). This review investigates whether excess weight increases the risk of neurological and neuropsychiatric symptoms associated with PCC.
Methods: Studies published up to July 2023 were searched independently across eight electronic databases to evaluate the risk of developing neurological and neuropsychiatric symptoms more than 12 weeks post-infection between exposure and controls groups (excess weight vs. normal weight; obesity vs. non-obesity). Meta-analyses were conducted under a random-effects model. Results: Of the 10,122 abstracts screened, 18 studies (n = 139,091 adults) met the inclusion criteria and reported PCC symptoms according to nutritional status. These studies included 79,050 individuals with excess weight vs 57,926 normal-weight individuals and 30,694 individuals with obesity vs 107,612 non-obese individuals. The presence of excess weight in PCC significantly increased the risk of depression (RR = 1.21; 95% CI: 1.03–1.42), headache (RR = 1.21; 95% CI: 1.09–1.35), memory issues (RR = 1.43; 95% CI: 1.24–1.65), sleep disturbance (RR = 1.31; 95% CI: 1.16–1.48), and vertigo (RR = 1.21; 95% CI: 1.04– 1.41). Obesity significantly increased the risk of headache (RR = 1.41; 95% CI: 1.34– 1.49), smell disorder (RR = 1.15; 95% CI: 1.09–1.21), taste disorder (RR = 1.21; 95% CI: 1.07–1.36), and vertigo (RR = 1.44; 95% CI: 1.35–1.53). Conclusions: Excess weight or obesity increases the risk of experiencing neuro-symptoms related to PCC. Individuals with these conditions urgently need enhanced personalized care management in current post-pandemic context.

◆Towards a cure for long COVID: the strengthening case for persistently replicating SARS-CoV-2 as a driver of post-acute sequelae of COVID-19【WILEY Online Library　2024年11月24日】

New insights into post-acute sequelae of coronavirus disease 2019 (PASC) or long COVID are emerging at great speed. Proposed mechanisms driving long COVID include the overlapping pathologies of immune and inflammatory dysregulation, microbiota dysbiosis, autoimmunity, endothelial dysfunction, abnormal neurological signalling, reactivation of endogenous herpesviruses, and persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this commentary, we describe some of these advances that indicate that long COVID may be driven by “long infection” and that persistent replicating SARS-CoV-2 may be the potentially mechanistically unifying driver for long COVID.

◆COVID-19 Pneumonia Diagnosed by Bronchoalveolar Lavage Fluid, With CD4 T-cell Depletion Contributing to Prolonged Infection: Two Case Reports【Cureus　2024年11月25日】

Abstract

Irrespective of the underlying disease, patients treated with cluster of differentiation 20 (CD20) antibodies have a higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) long or severe infection, and there are pitfalls in this diagnosis. We herein report two patients with COVID-19 pneumonia diagnosed by bronchoalveolar lavage fluid (BALF) during lymphoma remission. Nasopharyngeal swabs (NSs) were polymerase chain reaction (PCR)-negative for SARS-CoV-2, and the virus was only detectable in the lungs. In patients with B-cell depletion, the early performance of bronchoalveolar lavage (BAL) is important for diagnosing COVID-19 pneumonia and ruling out opportunistic infections when any evidence of suspected viral pneumonia is observed on computed tomography (CT), even if the NS specimens are PCR-negative and they have no upper respiratory symptoms. In addition, blood tests with lymphocytopenia, BALF with decreased CD4/CD8 ratio, and increased neutralizing antibody titer suggested that not only low humoral immune responses but also CD4 T-cell depletion by bendamustine were associated with virus clearance. Even if neutralizing antibodies are adequate, we must be careful of prolonged COVID-19 due to CD4 T-cell depletion and low humoral immune responses.

◆SARS-CoV-2 infection in hiPSC-derived neurons is cathepsin-dependent and causes accumulation of HIF1ɑ and phosphorylated tau【bioRxiv　2024年11月23日】

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to infect the human brain and a subset of human neurons in vitro. We have previously demonstrated that the virus enters the human induced pluripotent stem cell (hiPSC)-derived neurons via an endosomal-lysosomal pathway, which is dependent on low levels of angiotensin-converting enzyme 2 (ACE2) and independent of transmembrane serine protease 2 (TMPRSS2). Here, we use hiPSC-derived neurons overexpressing ACE2 in co-culture with human astrocytes to show that the infection with both SARS-CoV-2 Wuhan and Omicron XBB.1.5 variants is dependent on cathepsins and can be efficiently blocked by an inhibitor of cathepsin B (CA-074-ME). The result was reproducible in non-transgenic hiPSC-derived cortical organoids. The cathepsin L inhibitor SB412515 was less effective against the Wuhan strain but equally effective against the Omicron variant. Using PCR and reinfection assays, we show that SARS-CoV-2 can replicate in neurons in 2D co-cultures. Interestingly, the infectivity of the newly produced virions declined at 24 hours post-infection despite a further increase in released viral RNA at later time points, suggesting the possible activation of an antiviral response in neurons and/or astrocytes, which is supported by a correspondent increase in the levels of secreted cytokines. Furthermore, the number of infected neurons decreased within five days, suggesting that SARS-CoV-2 infection eventually leads to the death of the target neuronal cell in vitro. The infection also caused the accumulation of the hypoxia-inducible stress factor HIF1-α in infected neurons under normoxia. Finally, we confirm and expand the previous finding that in SARS-CoV-2 infected neurons, the microtubule-associated protein tau is hyperphosphorylated at multiple loci, including S202/T205, and mislocalized to the soma of the infected neurons. Hyperphosphorylation and mislocalization of tau are hallmarks of Alzheimer’s disease (AD) and other ‘tauopathies’. Our data provides further evidence supporting the neurodegenerative potential of SARS-CoV-2 infection.

Summary The recent COVID-19 pandemic has raised concerns about the potential for SARS-CoV-2 to infect the brain and worsen brain diseases like Alzheimer’s disease. Research has shown that SARS-CoV-2 can indeed infect the human brain, including a small number of neurons and other brain cells in laboratory settings.

In our previous studies, we identified the endosomal pathway as the route the virus uses to enter neuronal cells. In this study, we build on that work by demonstrating that inhibitors of endo-lysosomal cathepsin proteases can block this neuronal infection. We also found that infectious progeny virions are released from the infected neuronal cells.

Importantly, the infection proves harmful to the host cells, as evidenced by a decrease in the number of infected cells in experimental cultures over a five-day period. Additionally, we confirm and expand on earlier findings that SARS-CoV-2 infection leads to the phosphorylation and altered localization of the tau protein, a process associated with brain diseases like Alzheimer’s.

Finally, we observed an increase in the production of inflammatory cytokines following neuronal infection with SARS-CoV-2, along with an accumulation of the stress marker protein HIF-1α in neurons. This protein has been linked to other viral infections and Alzheimer’s disease. Overall, our data suggest that SARS-CoV-2 exhibits neurodegenerative characteristics.

◆Long COVID Brain Fog Linked to Lung Function【PR Newswire RSNA　2024年11月26日】

According to the National Center for Health Statistics, approximately 17.6% of adults in the U.S. have experienced a post-COVID condition commonly referred to as long COVID. People with long COVID may exhibit a wide variety of symptoms, including difficulty concentrating (“brain fog”), change in sense of smell or taste, fatigue, joint or muscle pain, dyspnea (shortness of breath), digestive symptoms, and more. These symptoms may persist for weeks, months, or even years after COVID-19 infection.

Researchers from the University of Iowa in Iowa City set out to assess associations between pulmonary MRI gas exchange, structural and functional brain MRI, and cognition in long COVID patients. In pulmonary gas exchange, oxygen moves from the lungs to the bloodstream, while carbon dioxide moves from the bloodstream to the lungs.

“This is the first time that MRI has been used to jointly assess lung and brain function to investigate their relationship in long COVID,” said the study’s lead author Keegan Staab, B.S., graduate research assistant in the Department of Radiology at the University of Iowa in Iowa City. “This research is new in that it combines multiple unique imaging types to study a multiorgan relationship in a disease population.”

Senior study author Sean B. Fain, Ph.D., professor and vice chair for research in the Department of Radiology at the University of Iowa, added, “If these findings can be generalized to the long COVID population, the study suggests that there may be a causative relationship between cognitive dysfunction and lung dysfunction, suggesting a potential treatment strategy using methods that target improved gas exchange.”

For the study, 10 female and 2 male patients (median age: 59 years) who had persistent dyspnea and/or fatigue following the resolution of acute COVID-19 infection were recruited from a post-COVID-19 clinic. Hyperpolarized Xe pulmonary MRI, structural and functional brain MRI, pulmonary function tests and cognitive tests were acquired.

“129Xe MRI allows for advanced measurements of ventilation and gas exchange,” Staab said. “The literature also indicates that 129Xe may be more sensitive to pulmonary injury compared to standard breathing tests, making it better suited to study long COVID in which patients typically have normal breathing tests.”

Perceived cognitive difficulties were measured using Patient-Reported Outcomes Measurement Information System, and objective cognitive performance was assessed using the National Institutes of Health Toolbox V3 Cognition Battery.

“There was a range of cognitive difficulties among the patients in the study,” Staab said. “Some were mild and indicated slight dysfunction, while others were more serious and indicated that some patients have slow thinking and trouble concentrating several times per day.”

The results showed that lower pulmonary gas exchange may be associated with cognitive dysfunction, as well as lower gray matter and white matter volumes in patients with long COVID. In addition, the researchers observed significant relationships suggesting that increased cerebral blood flow is associated with decreased gas exchange in long COVID patients.

Staab said larger studies are needed to investigate the association between gas exchange and cerebral blood flow in long COVID.

“This relationship could be a compensatory mechanism where lower lung function is compensated by higher cardiac output and higher brain perfusion,” he said. “It’s also a possibility that the disease mechanism that impairs pulmonary gas exchange also leads to higher brain perfusion through downstream vascular injury in both lung and brain.”

Based on the findings of this study, gas exchange abnormalities may help identify long COVID patients who require additional treatment or long-term management.

Other co-authors are Marrissa J. McIntosh, Ph.DDD., Jonathan L. Percy, B.S., Andrew D. Hahn, Ph.DDD., Natally AlArab, M.D., Conner J. Wharff, B.S. B.A. RT(R)(MR), Eric Bruening, M.S., Alejandro P. Comellas, M.D., Eric A. Hoffman, Ph.DDD., Carinda Linkenmeyer, M.A.E., Tara Lanning, B.S., and Karin F. Hoth, Ph.DDD.