Search

Background and Purpose: Neuropsychiatric complications of SARS-CoV-2 infection, also known as neurologic postacute sequelae of SARS-CoV-2 infection (NeuroPASC), affect 10%-60% of infected individuals. There is growing evidence that NeuroPASC is a multi system immune dysregulation disease affecting the brain. The behavioral manifestations of NeuroPASC, such as impaired processing speed, executive function, memory retrieval, and sustained attention, suggest widespread WM involvement. Although previous work has documented WM damage following acute SARS-CoV-2 infection, its involvement in NeuroPASC is less clear. We hypothesized that macrostructural and microstructural WM differences in NeuroPASC participants would accompany cognitive and immune system differences., Materials and Methods: In a cross-sectional study, we screened a total of 159 potential participants and enrolled 72 participants, with 41 asymptomatic controls (NoCOVID) and 31 NeuroPASC participants matched for age, sex, and education. Exclusion criteria included neurologic disorders unrelated to SARS-CoV-2 infection. Assessments included clinical symptom questionnaires, psychometric tests, brain MRI measures, and peripheral cytokine levels. Statistical modeling included separate multivariable regression analyses of GM/WM/CSF volume, WM microstructure, cognitive, and cytokine concentration between-group differences., Results: NeuroPASC participants had larger cerebral WM volume than NoCOVID controls (β = 0.229; 95% CI: 0.017-0.441; t = 2.16; P = .035). The most pronounced effects were in the prefrontal and anterior temporal WM. NeuroPASC participants also exhibited higher WM mean kurtosis, consistent with ongoing neuroinflammation. NeuroPASC participants had more self-reported symptoms, including headache, and lower performance on measures of attention, concentration, verbal learning, and processing speed. A multivariate profile analysis of the cytokine panel showed different group cytokine profiles (Wald-type-statistic = 44.6, P = .046), with interferon (IFN)-λ1 and IFN-λ2/3 levels higher in the NeuroPASC group., Conclusions: NeuroPASC participants reported symptoms of lower concentration, higher fatigue, and impaired cognition compatible with WM syndrome. Psychometric testing confirmed these findings. NeuroPASC participants exhibited larger cerebral WM volume and higher WM mean kurtosis than NoCOVID controls. These findings suggest that immune dysregulation could influence WM properties to produce WM volume increases and consequent cognitive effects and headaches. Further work will be needed to establish mechanistic links among these variables., (© 2024 by American Journal of Neuroradiology.)

Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are "noncanonical" immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function., Competing Interests: Competing interests statement:R.E.S. is on the scientific advisory of Miromatrix, Inc. and Lime Therapeutics and is a consultant for Alnylam, Inc. D.C.W. is on the scientific advisory boards of Pano Therapeutics, Inc., and Medical Excellent Capital.

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTDs), including coronavirus disease 2019 (COVID-19), but there are minimal data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. In this study, we used histology and high-dimensional imaging to characterize fatal lung disease in Malawian adults with (n = 9) and without (n = 7) COVID-19, and we generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved COVID-19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in US, European and Asian cohorts, by type I/III interferon (IFN) responses, particularly in blood-derived monocytes, and in the Malawian cohort, by response to IFN-γ in lung-resident macrophages. HIV status had minimal impact on histology or immunopathology. Our study provides a data resource and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Kidney involvement occurs in almost one third of patients hospitalised with coronavirus disease 2019 (COVID-19) and is associated with increased disease severity. This review aims to outline the spectrum of kidney pathology involved in COVID-19. Literature was reviewed systematically on the databases Medline OVID and Scopus in search of case reports, case series, cohort studies and autopsy studies of patients with COVID-19 who underwent kidney biopsies. Studies were published between August 2020 and November 2021. Fourteen studies consisting of 159 patients were included in this review. Acute tubular necrosis is the most common pathology followed by collapsing glomerulopathy, occurring in 40.1% and 28.9% of patients respectively. Of the 46 patients with collapsing glomerulopathy, 44 were of African descent with high-risk apolipoprotein L1 genotypes. Less common glomerular diseases include membranous nephropathy, secondary focal segmental glomerulosclerosis, minimal change disease and primary focal segmental glomerulosclerosis occurring in 5%, 4.4%, 3.1% and 2.5% of patients respectively. Glomerulonephritis occurred in a minority of patients. Direct viral infection has not been found as a definitive aetiology. Acute kidney injury occurs frequently in hospitalised COVID-19 patients and is associated with increased morbidity and mortality. The mechanisms underpinning acute kidney injury are multifactorial. Acute tubular necrosis is the most common. Collapsing glomerulopathy is the most common glomerular injury and is strongly linked to apolipoprotein L1 genotypes. Improved understanding of COVID-19-related kidney pathologies can guide treatment to improve patient outcomes and reduce progression of chronic kidney disease. The longitudinal impact of COVID-19-related kidney disease requires further research., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

A life-threatening complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is acute respiratory distress syndrome. Our understanding of the pathologic changes in coronavirus disease 2019 (COVID-19) is based almost exclusively on post-mortem analyses of adults. These studies established several hallmarks of SARS-CoV-2 lung infection, including diffuse alveolar damage, microvascular thrombi, and acute bronchopneumonia. We describe a fatal example of COVID pneumonia in a 9-year-old girl who presented with fever 10 months following the diagnosis of ALK-positive anaplastic large cell lymphoma (ALCL). A chest computed tomography scan revealed left upper lobe lung consolidation and nodular airspace disease, and an initial SARS-CoV-2 nasopharyngeal swab (RT-PCR) was negative. A subsequent lung biopsy performed due to concern for relapsed ALCL demonstrated sheets of intra-alveolar and interstitial macrophages, and macrophage-rich fibrinous exudates. Immunohistochemical and in-situ hybridization stains confirmed these macrophages as the predominant SARS-CoV-2-infected cell type. Subsequent RT-PCR testing of upper and lower respiratory tract samples was positive for SARS-CoV-2 infection. Whole genome sequencing confirmed the presence of the B.1.617.2 (Delta) variant. This biopsy illustrates the histopathologic features of early COVID pneumonia in antemortem lung tissue from a pediatric patient, and establishes macrophages as a potential source of SARS-CoV-2 amplification., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

COVID-19 commonly presents as pneumonia, with those most severely affected progressing to respiratory failure. Patient responses to SARS-CoV-2 infection are varied, with comorbidities acting as major contributors to varied outcomes. Focusing on one such major comorbidity, we assessed whether pharmacological induction of type 1 diabetes mellitus (T1DM) would increase the severity of lung injury in a murine model of COVID-19 pneumonia utilizing wild-type mice infected with mouse-adapted SARS-CoV-2. Hyperglycemic mice exhibited increased weight loss and reduced blood oxygen saturation in comparison with their euglycemic counterparts, suggesting that these animals indeed experienced more severe lung injury. Transcriptomic analysis revealed a significant impairment of the adaptive immune response in the lungs of diabetic mice compared with those of control. To expand the limited options available for tissue analysis due to biosafety restrictions, we also employed a new technique to digest highly fixed tissue into a single-cell suspension, originally designed for scRNA-Seq, which we then adapted for flow cytometric analysis. Flow immunophenotyping and scRNA-Seq confirmed impaired recruitment of T-cells into the lungs of T1DM animals. In addition, scRNA-Seq revealed a distinct, highly inflammatory macrophage profile in the diabetic cohort that correlates with the more severe infection these mice experienced clinically, allowing insight into a possible mechanism for this phenomenon. Recognizing the near certainty that respiratory viruses will continue to present significant public health concerns for the foreseeable future, our study provides key insights into how T1DM results in a much more severe infection and identifies possible targets to ameliorate comorbidity-associated severe disease. NEW & NOTEWORTHY We define the exacerbating effects of type 1 diabetes mellitus (T1DM) on COVID-19 pneumonia severity in mice. Hyperglycemic mice experienced increased weight loss and reduced oxygen saturation. Transcriptomic analysis revealed impaired immune responses in diabetic mice, while flow cytometry and single-cell RNA sequencing confirmed reduced T-cell recruitment and an inflammatory macrophage profile. In addition, we introduced a novel technique for tissue analysis, enabling flow cytometric analysis on highly fixed tissue samples.

COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shinsuke Yasuda reports a relationship with AbbVie Inc. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Asahi Kasei Pharma Corporation that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Chugai Pharmaceutical Co Ltd. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with CSL Behring that includes: funding grants. Shinsuke Yasuda reports a relationship with Eisai Inc. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with ImmunoForge that includes: funding grants. Shinsuke Yasuda reports a relationship with Mitsubishi Tanabe Pharma Corporation that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Ono Pharmaceutical Co Ltd. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Eli Lilly that includes: speaking and lecture fees. Shinsuke Yasuda reports a relationship with GlaxoSmithKline that includes: speaking and lecture fees. Shinsuke Yasuda reports a relationship with Pfizer Inc. that includes: speaking and lecture fees. Tadashi Hosoya reports a relationship with Sony Corporation that includes: funding grants. Tadashi Hosoya reports a relationship with Terumo life science foundation that includes: funding grants. Mari Kamiya reports a relationship with GlaxoSmithKline that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although the novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily manifests as severe respiratory distress, its impact on the cardiovascular system is also notable. Studies reveal that COVID-19 patients often suffer from certain vascular diseases, partly attributed to increased proliferation or altered phenotype of vascular smooth muscle cells (VSMCs). Although the association between COVID-19 and VSMCs is recognized, the precise mechanism underlying SARS-CoV-2's influence on VSMC phenotype remains largely under-reviewed. In this context, while there is a consistent body of literature dissecting the effect of COVID-19 on the cardiovascular system, few reports delve into the potential role of VSMC switching in the pathophysiology associated with COVID-19 and the molecular mechanisms involved therein. This review dissects and critiques the link between COVID-19 and VSMCs, with particular attention to pathways involving cholesterol, calcium, and phosphate. These pathways underpin the interaction between the virus and VSMCs. Such interaction promotes VSMC proliferation, and eventually potentiates vascular calcification as well as worsens prognosis in patients with COVID-19., (© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. Here we show that the host E3-ubiquitin ligase TRIM7 acts as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibit increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients reveal that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus shows reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Clinical data indicate that COVID-19 causes cardiovascular complications, regardless of the severity of the disease. In this work, we have shown that SARS-CoV-2 infection causes vascular dysfunction due to the modification of endothelial cell elasticity. We used human pulmonary endothelial cells (HPAECs) expressing the ACE2 receptor as a model of the endothelium. This system mimics in vivo conditions, as it allows virus entry but not replication. As a reference, we used A549 epithelial cells, a well-described model that supports productive replication of SARS-CoV-2. We show that the infection of HPAECs results in loss of cell elasticity, which correlates with increased polymerization of actin filaments and induction of the inflammatory response. On the contrary, A549 epithelial cells supporting viral replication showed increased elasticity. We also showed that the endothelial cell elasticity were impaired after infection with Alpha, Beta and Delta variants. Consequently, we believe that nonproductive SARS-CoV-2 infection associated with loss of the endothelium elasticity may be clinically relevant and result in dysfunction and damage to this tissue., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Risk factors for the development of severe COVID-19 include several comorbidities, but age was the most striking one since elderly people were disproportionately affected by SARS-CoV-2 infection. Among the reasons for this markedly unfavorable response in the elderly, immunosenescence and inflammaging appear as major drivers of this outcome. A finding that was also notable was that hospitalized patients with severe COVID-19 have an accumulation of senescent T cells, suggesting that immunosenescence may be aggravated by SARS-CoV-2 infection. The present work was designed to examine whether these immunosenescence changes are characteristic of COVID-19 and whether it is dependent on disease severity using cross-sectional and longitudinal studies. Our cross-sectional data show that COVID-19, but not other respiratory infections, rapidly increased cellular senescence and exhaustion in CD4 and CD8 T cells during early infection. In addition, longitudinal analyses with patients from Brazil and Portugal provided evidence of increased frequencies of senescent and exhausted T cells over a 7-d period in patients with mild/moderate and severe COVID-19. Altogether, the study suggests that accelerated immunosenescence in CD4 and especially CD8 T-cell compartments may represent a common and unique outcome of SARS-CoV2 infection., Competing Interests: Conflict of interest statement. No conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, uncertainties about the virus and its dangers during pregnancy caused great uncertainty and fear, especially among pregnant women. New data suggest an increased risk of obstetric complications, including maternal complications, preterm labor, intrauterine growth restriction, hypertensive disorders, stillbirths, gestational diabetes and risk, of neonatal developmental disorders. In addition, preeclampsia (PE)-like syndromes were also induced by severe COVID-19 infection. Therefore, the aim of this study was to investigate the expression of CD68 and CD163 and PD-L1 on placental tissues from acute covid patients, patients who survived a covid-19 infection and normal term controls that are known to be dysregulated in preeclampsia cases. We examined a total of 60 placentas from women that had given birth to female or male offspring in the University Hospital Augsburg. We investigated ten acute COVID-19 females, ten acute COVID-19 males, ten post-COVID-19 females, ten post-COVID-19 males, ten female term controls, and ten male term controls. Immunohistochemical staining against CD68, CD163, and PD-L1 was performed and the expression of the markers was evaluated with an immunoreactive score (percentage score). Identity of CD163- or PD-L1 expressing cells was analyzed by double immune fluorescence analyses. In opposite to PE, CD163 positive maternal macrophages are significantly upregulated in the decidua of male acute COVID-19 placentas. PD-L1 is significantly upregulated on male acute- and post-COVID-19 decidual immune cells and on male post-COVID-19 extravillous trophoblast cells. Surprisingly the observed effects are related to the fetal gender as they were not observed in female offsprings. Further investigation is necessary to analyze especially the imprinting effect of this infection., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

The coronavirus disease 2019 (COVID-19) pandemic has reminded us of human infections with the H7N9 virus and has raised questions related to the clinical and molecular pathophysiological diversity between the two diseases. Here, we performed a proteomic approach on sera samples from patients with H7N9-virus or SARS-CoV-2-virus infection and healthy controls. Compared to SARS-CoV-2, H7N9-virus infection caused elevated neutrophil concentrations, T cell exhaustion, and increased cytokine/interleukin secretion. Cell-type deconvolution and temporal analysis revealed that T cells and neutrophils could regulate the core immunological trajectory and influence the prognosis of patients with severe H7N9-virus infection. Elevated tissue-enhanced proteins combined with alterations of clinical biochemical indexes suggested that H7N9 infection induced more severe inflammatory organ injury and dysfunction in the liver and intestine. Further mechanical analysis revealed that the high concentration of neutrophils might impact the intestinal enterocyte cells through cytokine-receptor interaction, leading to intestinal damage in patients with H7N9-virus infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The variants of concern (VOCs) of SARS-CoV-2 have exhibited different phenotypic characteristics in clinical settings which are yet to be fully explored. This study aimed to characterize the viral replication features of major VOCs of SARS-CoV-2 and their association with pathogenicity. The Alpha, Delta, and Omicron variants of SARS-CoV-2 isolated from the COVID-19 patients in Japan were propagated in VeroE6/TMPRSS2 cells. The viral replication and pathological features were evaluated by laser and electron microscopy at different time points. The results revealed that the Delta variant dominantly infected the VeroE6/TMPRSS2 cells and formed increased syncytia compared to the Alpha and Omicron variants. Relatively large numbers of virions and increased immunoreactivities of the SARS-CoV-2 N-protein were detected in the endoplasmic reticulum and intracellular vesicles of Delta-infected cells. Interestingly, the N-protein and virions were detected in the nucleus of Delta-infected cells, while such properties were not observed in the case of Alpha and Omicron variants. In addition, early nuclear membrane damage followed by severe cellular damage was prominent in Delta-infected cells. A unique mutation (G215C) in the N-protein of the Delta variant is thought to be associated with severe cell damage. In conclusion, this study highlights the distinct replicative and pathogenic characteristics of the Delta variant of SARS-CoV-2 compared to the Alpha and Omicron variants, shedding light on the potential mechanisms underlying its increased pathogenicity.

Objective: Long COVID is a condition characterised by persistent symptoms after a SARS-CoV-2 infection, with neurological manifestations being particularly frequent. Existing research suggests that long COVID patients not only report cognitive symptoms but also exhibit measurable cognitive impairment. Neuroimaging studies have identified structural alterations in brain regions linked to cognitive functions. However, most of these studies have focused on patients within months of their initial infection. This study aims to explore the longer-term cognitive effects and brain structural changes in long COVID patients, approximately two years post-infection, in a cohort from San Martín, Buenos Aires, Argentina., Methods: We conducted a cross-sectional study involving 137 participants: 109 with long COVID symptoms and 28 healthy controls. The participants underwent an initial clinical assessment, completed a structured questionnaire and standardised scales, underwent a cognitive assessment, and had a brain MRI scan. Structural MRI images were processed via FreeSurfer and FSL to obtain volumetric measures for subcortical and cortical regions, along with regional cortical thickness. Differences between groups for these variables were analysed using ANCOVA, with permutation tests applied to correct for multiple comparisons., Results: Long COVID patients reported persistent cognitive symptoms such as memory problems and brain fog, with higher levels of fatigue and reduced quality of life compared to controls. Despite subjective cognitive complaints, cognitive tests did not reveal significant differences between groups, except for the TMT-A (p = 0.05). MRI analysis revealed decreased volume in the cerebellum (p = 0.03), lingual gyrus (p = 0.04), and inferior parietal regions (p = 0.03), and reduced cortical thickness in several areas, including the left and right postcentral gyri (p = 0.02, p = 0.03) and precuneus (p = 0.01, p = 0.02)., Conclusions: This study highlights the enduring impact of long COVID on quality of life and physical activity, with specific brain structural changes identified two years post-infection. Although cognitive tests did not show clear impairment, the observed brain atrophy and significant reduction in quality of life emphasize the need for comprehensive interventions and further longitudinal studies to understand the long-term effects of long COVID on cognition and brain health., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the HIGA Eva Peron Research Bioethics Committee (OHRP registration number IRB00002792). All subjects provided written informed consent. All methods were performed in accordance with the relevant guidelines and regulations. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

To investigate the characteristics of acute visual dysfunction and fundus lesions in patients with COVID-19 pneumonia. A retrospective case series study was conducted. Data from 48 patients (96 eyes) with COVID-19 infection who presented to our ophthalmology department with acute onset visual disturbance between December 5, 2022, and February 28, 2023 were collected. Asymptomatic patients and those who had already recovered were excluded. Data collected included patient demographics, ophthalmic examinations, multicolor imaging (MCI), infrared autofluorescence (IR), spectral-domain optical coherence tomography (OCT), fundus fluorescein angiography (FFA). Of the 48 patients, 15 were male and 33 were female, with a mean age of 32 years. All patients had bilateral involvement. OCT showed hyperreflective signals in the outer plexiform layer and outer nuclear layer of the macular region in all 96 eyes of 48 patients (100%). Additionally, 66 eyes of 33 patients (68.8%) of eyes demonstrated abnormal reflectivity in the ellipsoid and interdigitation zones. MCI revealed petaloid or wedge-shaped hyperreflective areas in the macula in 46 (47.9%) of eyes, corresponding to hyporeflective areas on IR. Cotton-wool spots were observed in the peripapillary or posterior pole area in 54 (56.3%) of eyes. COVID-19 infection can lead to acute, bilateral, symmetric, and widespread retinal damage. Characteristic findings can be observed in ophthalmological examinations such as OCT, MCI, and IR., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics statement Due to the retrospective nature of the study, the ethics committee of Henan Provincial People’s Hospital waived the need of obtaining informed consent’ in the manuscript.All methods were carried out in accordance with relevant guidelines and regulations.All experimental protocols were approved by Henan Provincial People’s Hospital., (© 2024. The Author(s).)

COVID-19 is an infectious disease caused by SARS-CoV-2; over the course of the disease, a dysregulated immune response leads to excessive inflammation that damages lung parenchyma and compromises its function. One of the cell lineages classically associated with pathological inflammatory processes is mast cells (MCs). MCs and their mediators have been associated with COVID-19; we previously reported the role of carboxypeptidase A3 (CPA3) in severe COVID-19. However, sequelae of SARS-CoV-2 infection have been poorly studied. In patients who successfully resolve the infection, one of the reported sequelae is pulmonary fibrosis (PF). The etiology and exact mechanisms are unknown, and few studies exist. Therefore, the aim of this study was to evaluate whether MCs are associated with PF development after SARS-CoV-2 infection. Our findings demonstrate that during severe cases of SARS-CoV-2 infection, there is an increased amount of CPA3 + MCs in areas with pneumonia, around thrombotic blood vessels, and in fibrotic tissue. Moreover, higher numbers of CPA3-expressing MCs correlate with fibrotic tissue development (r = 0.8323; p = 0.001170). These results suggest that during COVID-19, exacerbated inflammation favors the recruitment or expansion of MCs and CPA3 expression in the lungs, which favors tissue damage and a failure of repair mechanisms, leading to fibrosis.

Despite the tremendous advancements in the knowledge of the pathophysiology and clinical aspects of SARS-CoV-2 infection, still many issues remain unanswered, especially in the long-term effects. Mounting evidence suggests that pulmonary fibrosis (PF) is one of the most severe complications associated with COVID-19. Therefore, understanding the molecular mechanisms behind its development is helpful to develop successful therapeutic strategies. Epithelial to mesenchymal transition (EMT) and its cell specific variants endothelial to mesenchymal transition (EndMT) and mesothelial to mesenchymal transition (MMT) are physio-pathologic cellular reprogramming processes induced by several infectious, inflammatory and biomechanical stimuli. Cells undergoing EMT acquire invasive, profibrogenic and proinflammatory activities by secreting several extracellular mediators. Their activity has been implicated in the pathogenesis of PF in a variety of lung disorders, including idiopathic pulmonary fibrosis (IPF) and COVID-19. Aim of this article is to provide an updated survey of the cellular and molecular mechanisms, with emphasis on EMT-related processes, implicated in the genesis of PF in IFP and COVID-19., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation-and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms-it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms.

Coronavirus disease 2019 (COVID-19) represents the novel respiratory infectious disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by rapid spread throughout the world. Reactive oxygen species (ROS) account for cellular metabolic by-products, and excessive ROS accumulation can induce oxidative stress due to insufficient endogenous antioxidant ability. In the case of oxidative stress, ROS production exceeds the cellular antioxidant capacity, thus leading to cell death. SARS-CoV-2 can activate different cell death pathways in the context of infection in host cells, such as neutrophil extracellular trap (NET)osis, ferroptosis, apoptosis, pyroptosis, necroptosis and autophagy, which are closely related to ROS signalling and control. In this review, we comprehensively elucidated the relationship between ROS generation and the death of host cells after SARS-CoV-2 infection, which leads to the development of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies against SARS-CoV-2., (© 2024. The Author(s).)

Studies suggest that the dynamic changes in cellular response might correlate with disease severity and outcomes in SARS-CoV-2 patients. The study aimed to investigate the dynamic changes of lymphocyte subsets in patients with COVID-19. In this regard, 53 patients with COVID-19 were prospectively included, classified as mild, moderate, and severe. The peripheral lymphocyte profiles (LyT, LyB, and NK cells), as well as CD4+/CD8+, CD3+/CD19+, CD3+/NK and CD19+/NK ratios, and their dynamic changes during hospitalization and correlation with disease severity and outcome were assessed. We found significant differences in CD3+ lymphocytes between severity groups ( p < 0.0001), with significantly decreased CD3+CD4+ and CD3+CD8+ in patients with severe disease ( p < 0.0001 and p = 0.048, respectively). Lower CD3+/CD19+ and CD3+/NK ratios among patients with severe disease ( p = 0.019 and p = 0.010, respectively) were found. The dynamic changes of lymphocyte subsets showed a significant reduction in NK cells (%) and a significant increase in CD3+CD4+ and CD3+CD8+ cells in patients with moderate and severe disease. The ROC analysis on the relationship between CD3+ cells and fatal outcome yielded an AUC of 0.723 (95% CI 0.583-0.837; p = 0.007), while after addition of age and SpO 2 , ferritin and NLR, the AUC significantly improved to 0.927 (95%CI 0.811-0.983), p < 0.001 with a sensitivity of 90.9% (95% CI 58.7-99.8%) and specificity of 85.7% (95% CI 69.7-95.2%). The absolute number of CD3+ lymphocytes might independently predict fatal outcomes in COVID-19 patients and T-lymphocyte subset evaluation in high-risk patients might be useful in estimating disease progression.

Background: Numerous studies have investigated the molecular properties that contribute to the symptoms of COVID-19, such as the virus's genetic makeup, its replication mechanisms, and how it interacts with host cells. However, identifying the immunopathological properties, such as the immune system's response, cytokine levels, and the presence of specific biomarkers, that are associated with the severity of the infection remains crucial for developing effective treatments and preventions., Methods: We analyzed blood protein factor profiles from 420 individuals to identify features differentiating between test-negative healthy, asymptomatic, and symptomatic individuals using statistical comparison and the least absolute shrinkage and selection operator (i.e., LASSO) algorithm. Additionally, we examined single-cell RNA sequencing data from 141 individuals to identify specific cell types associated with the COVID-19 symptoms., Results: Healthy individuals who tested negative had distinct blood protein factor levels compared to asymptomatic individuals. We identified two key protein factors, Serpin A10 and Complement C9, that differentiate between asymptomatic and symptomatic patients. Symptomatic patients showed lower levels of CD4 +  T naïve, CD4 +  T effector & memory, and CD8 +  T naïve cells, along with higher levels of CD14 +  classical monocytes compared to asymptomatic patients. Additionally, CD16 +  non-classical monocytes, major producers of C1QA/B/C, appeared to contribute to the observed Complement C9 levels., Conclusions: These findings advance our understanding of the immunopathological mechanisms underlying COVID-19 and may inform the development of targeted therapies and preventative measures. Future research should focus on further elucidating these mechanisms and exploring their potential clinical applications in managing COVID-19 severity., (© 2024. The Author(s).)

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 triggered a swift global spread, leading to a devastating pandemic. Alarmingly, approximately one in four individuals diagnosed with coronavirus disease 2019 (COVID-19) experience varying degrees of cognitive impairment, raising concerns about a potential increase in neurological sequelae cases. Neuroinflammation seems to be the key pathophysiological hallmark linking mild respiratory COVID-19 to cognitive impairment, fatigue, and neurological sequelae in COVID-19 patients, highlighting the interaction between the nervous and immune systems following SARS-CoV-2 infection. Several hypotheses have been proposed to explain how the virus disrupts physiological pathways to trigger inflammation within the CNS, potentially leading to neuronal damage. These include neuroinvasion, systemic inflammation, disruption of the lung and gut-brain axes, and reactivation of latent viruses. This review explores the potential origins of neuroinflammation and the underlying neuroimmune cross-talk, highlighting important unanswered questions in the field. Addressing these fundamental issues could enhance our understanding of the virus's impact on the CNS and inform strategies to mitigate its detrimental effects., (© 2024 The Author(s). Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Elucidating the detailed features of emerging SARS-CoV-2 strains both in vitro and in vivo is indispensable for the development of effective vaccines or drugs against viral infection. We thoroughly characterized the virological and pathogenic features of eight different pandemic SARS-CoV-2 strains, from the WT strain to current circulating sublineage EG.5.1, both in vitro and in vivo. Besides detailed virological features observed in Vero E6 cells, the Omicron variants, from BA.1 to EG.5.1, exhibited enhanced infectious effects to upper respiratory tract in K18 human angiotensin-converting enzyme (ACE2) (K18 hACE2) transgenic mice. Both XBB.1.9.1 and EG.5.1 presented stronger tropism to brain, which could be the main reason for the increased lethal effects on mice. In addition, the pathogenesis comparisons among all these viruses in C57BL/6JGpt mice indicated that Omicron variant BA.1 and two new sublineages XBB.1.9.1 and EG.5.1 possessed dual tropisms to both human and mice, which were further confirmed by subsequent bioinformatic analyses and actual affinity comparison between viral RBDs and mouse or human receptor ACE2. Furthermore, the immunocompromised BKS-db mice were found to be more susceptible to Omicron strains compared to C57BL/6JGpt mice, which revealed that viral infectivity was determined by both its affinity to the host receptor and host immunocompetence. Thus, this study not only contributes to a systematic understanding of the pathogenic features of SARS-CoV-2 in mice, but also provides new insights to combat potential future surges of new SARS-CoV-2 variants., (© 2024 Wiley Periodicals LLC.)

Introduction: The angiotensin-converting enzyme 2 (ACE2), which is expressed in cerebral vascular endothelial cells (CVECs), has been currently identified as a functional receptor for SARS-CoV-2., Methods: We specifically induced injury to ACE2-expressing CVECs in mice and evaluated the effects of such targeted damage through magnetic resonance imaging (MRI) and cognitive behavioral tests. In parallel, we recruited a single-center cohort of COVID-19 survivors and further assessed their brain microvascular injury based on cognition and emotional scales, cranial MRI scans, and blood proteomic measurements., Results: Here, we show an array of pathological and behavioral alterations characteristic of cerebral small vessel disease (CSVD) in mice that targeted damage to ACE2-expressing CVECs, and COVID-19 survivors. These CSVD-like manifestations persist for at least 7 months post-recovery from COVID-19., Discussion: Our findings suggest that SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae, underscoring the imperative for heightened clinical vigilance in mitigating or treating SARS-CoV-2-mediated cerebral endothelial injury throughout infection and convalescence., Highlights: Cerebral small vessel disease-associated changes were observed after targeted damage to angiotensin-converting enzyme 2-expressing cerebral vascular endothelial cells. SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae. Clinical vigilance is needed in preventing SARS-CoV-2-induced cerebral endothelial damage during infection and recovery., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Coronavirus disease 2019 (COVID-19) has been suggested to increase the risk of memory decline and Alzheimer's disease (AD), the main cause of dementia in the elderly. However, direct evidence about whether COVID-19 induces AD-like neuropathological changes in the brain, especially post recovery from acute infection, is still lacking. Here, using postmortem human brain samples, we found abnormal accumulation of hyperphosphorylated tau protein in the hippocampus and medial entorhinal cortex within 4-13 months post clinically recovery from acute COVID-19, together with prolonged activation of glia cells and increases in inflammatory factors, even though no SARS-COV-2 invasion was detected in these regions. By contrast, COVID-19 did not change beta-amyloid deposition and hippocampal neuron number, and had limited effects on AD-related pathological phenotypes in olfactory circuits including olfactory bulb, anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral entorhinal cortex. These results provide neuropathological evidences linking COVID-19 with prognostic increase of risk for AD., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: According to person-by-environment models, individual differences in traits may moderate the association between stressors and the development of psychopathology; however, findings in the literature have been inconsistent and little literature has examined adolescent brain structure as a moderator of the effects of stress on adolescent internalizing symptoms. The COVID-19 pandemic presented a unique opportunity to examine the associations between stress, brain structure, and psychopathology. Given links of cortical morphology with adolescent depression and anxiety, the current study investigated whether cortical morphology moderated the relationship between stress from the COVID-19 pandemic and the development of internalizing symptoms in familial high-risk adolescents., Methods: Prior to the COVID-19 pandemic, 72 adolescents (27 male) completed a measure of depressive and anxiety symptoms and underwent magnetic resonance imaging. T1-weighted images were acquired to assess cortical thickness and surface area. Approximately 6 to 8 months after COVID-19 was declared a global pandemic, adolescents reported their depressive and anxiety symptoms and pandemic-related stress., Results: Adjusting for pre-pandemic depressive and anxiety symptoms and stress, increased pandemic-related stress was associated with increased depressive but not anxiety symptoms. This relationship was moderated by cortical thickness and surface area in the anterior cingulate and cortical thickness in the medial orbitofrontal cortex such that increased stress was only associated with increased depressive and anxiety symptoms among adolescents with lower cortical surface area and higher cortical thickness in these regions., Conclusions: Results further our understanding of neural vulnerabilities to the associations between stress and internalizing symptoms in general and during the COVID-19 pandemic in particular., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Long coronavirus disease 2019 (COVID-19) is linked to an increased risk of post-acute sequelae affecting the pulmonary and extrapulmonary organ systems. Up to 20% of COVID-19 patients may proceed to a more serious form, such as severe pneumonia, acute respiratory distress syndrome (ARDS), or pulmonary fibrosis. Still, the majority of patients may only have mild, self-limiting sickness. Of particular concern is the possibility of parenchymal fibrosis and lung dysfunction in long-term COVID-19 patients. Furthermore, it has been observed that up to 43% of individuals hospitalized with COVID-19 also had acute renal injury (AKI). Care for kidney, brain, lung, cardiovascular, liver, ocular, and tissue injuries should be included in post-acute COVID-19 treatment. As a powerful immunomodulatory tool in regenerative medicine, dental stem cells (DSCs) have drawn much interest. Numerous immune cells and cytokines are involved in the excessive inflammatory response, which also has a significant effect on tissue regeneration. A unique reservoir of stem cells (SCs) for treating acute lung injury (ALI), liver damage, neurological diseases, cardiovascular issues, and renal damage may be found in tooth tissue, according to much research. Moreover, a growing corpus of in vivo research is connecting DSC-derived extracellular vesicles (DSC-EVs), which are essential paracrine effectors, to the beneficial effects of DSCs. DSC-EVs, which contain bioactive components and therapeutic potential in certain disorders, have been shown as potentially effective therapies for tissue damage after COVID-19. Consequently, we explore the properties of DSCs in this work. Next, we'll look at how SARS-CoV-2 affects tissue damage. Lastly, we have looked at the use of DSCs and DSC-EVs in managing COVID-19 and chronic tissue damage, such as injury to the heart, brain, lung, and other tissues., Competing Interests: Declarations Ethics Approval and Consent to Participate Not applicable. Consent for Publication All authors consent for the publication Competing Interests The authors declare that they have no competing interests, (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

SARS-CoV-2 mediated infection instigated a scary pandemic state since 2019. They created havoc comprising death, imbalanced social structures, and a wrecked global economy. During infection, the inflammation and associated cytokine storm generate a critical pathological situation in the human body, especially in the lungs. By the passage of time of infection, inflammatory disorders, and multiple organ damage happen which might lead to death, if not treated properly. Until now, many pathological parameters have been used to understand the progress of the severity of COVID-19 but with limited success. Bioactive lipid mediators have the potential of initiating and resolving inflammation in any disease. The connection between lipid storm and inflammatory states of SARS-CoV-2 infection has surfaced and got importance to understand and mitigate the pathological states of COVID-19. As the role of eicosanoids in COVID-19 infection is not well defined, available information regarding this issue has been accumulated to address the possible network of eicosanoids related to the initiation of inflammation, promotion of cytokine storm, and resolution of inflammation, and highlight possible strategies for treatment and drug discovery related to SARS-CoV-2 infection in this study. Understanding the involvement of eicosanoids in exploration of cellular events provoked by SARS-CoV-2 infection has been summarized as an important factor to deescalate any upcoming catastrophe imposed by the lethal variants of this micro-monster. Additionally, this study also recognized the eicosanoid based drug discovery, treatment, and strategies for managing the severity of SARS-COV-2 infection., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Severe acute syndrome coronavirus 2 can invade a variety of tissues, including the testis. Even though this virus is scarcely found in human semen polymerase chain reaction tests, autopsy studies confirm the viral presence in all testicular cell types, including spermatozoa and spermatids., Objective: To investigate whether the severe acute syndrome coronavirus 2 is present inside the spermatozoa of negative polymerase chain reaction-infected men up to 3 months after hospital discharge., Materials and Methods: This cross-sectional study included 13 confirmed moderate-to-severe COVID-19 patients enrolled 30-90 days after the diagnosis. Semen samples were obtained and examined with real-time polymerase chain reaction for RNA detection and by transmission electron microscopy., Results: In moderate-to-severe clinical scenarios, we identified the severe acute syndrome coronavirus 2 inside spermatozoa in nine of 13 patients up to 90 days after discharge from the hospital. Moreover, some DNA-based extracellular traps were reported in all studied specimens., Discussion and Conclusion: Although severe acute syndrome coronavirus 2 was not present in the infected men's semen, it was intracellularly present in the spermatozoa till 3 months after hospital discharge. The Electron microscopy (EM) findings also suggest that spermatozoa produce nuclear DNA-based extracellular traps, probably in a cell-free DNA-dependent manner, similar to those previously described in the systemic inflammatory response to COVID-19. In moderate-to-severe cases, the blood-testes barrier grants little defence against different pathogenic viruses, including the severe acute syndrome coronavirus 2. The virus could also use the epididymis as a post-testicular route to bind and fuse to the mature spermatozoon and possibly accomplish the reverse transcription of the single-stranded viral RNA into proviral DNA. These mechanisms can elicit extracellular cell-free DNA formation. The potential implications of our findings for assisted conception must be addressed, and the evolutionary history of DNA-based extracellular traps as preserved ammunition in animals' innate defence might improve our understanding of the severe acute syndrome coronavirus 2 pathophysiology in the testis and spermatozoa., (© 2024 American Society of Andrology and European Academy of Andrology.)

COVID-19, an infectious disease caused by SARS-CoV-2, was declared a pandemic by the WHO in 2020. Psychiatric symptoms including sleep disturbance, memory impairment, and depression are associated with SARS-CoV-2 infection. These symptoms are causes long-term mental and physical distress in recovering patients; however, the underlying mechanism is unclear. In this study, we determined the effects of SARS-CoV-2 infection on brain tissue using k18hACE2 mice. Using brain tissue from 18hACE2 mice infected with SARS-CoV-2 through intranasal administration, SARS-CoV-2 spike protein and RNA were analyzed by immunohistochemical staining and in-situ hybridization. Immunohistochemical analysis revealed that Tryptophan hydroxylase 2 (TPH2)-positive cells and SARS-CoV-2 spike protein were co-localized in the ventral tegmental area of SARS-CoV-2-infected mice. We observed decreased TPH2 expression and increased accumulation of phosphorylated tau protein and Phospho-Histone H2A.X (γH2AX) expression in the ventral tegmental region. In addition, activation of glycogen synthase kinase 3β (GSK3β) was induced by SARS-CoV-2 infection. Overall, our results suggest that SARS-CoV-2 infection of TPH2-positive cells in the ventral tegmental area induces neuronal cell death through increased accumulation of phosphorylated tau. Attenuation of the GSK3β pathway and decreased serotonin synthesis through suppression of TPH2 expression may contribute to the development of neurological symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Imai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It remains unclear whether pulmonary fibrosis-like changes differ in patients with different SARS-CoV-2 variants. This study aimed to compare pulmonary fibrotic changes between two SARS-CoV-2 variant periods (delta vs. pre-delta) in critically ill patients with SARS-CoV-2 pneumonia. Clinical data and chest CT images of patients with SARS-CoV-2 pneumonia receiving mechanical ventilation were collected from 10 hospitals in South Korea over two periods: delta (July-December, 2021; n = 64) and pre-delta (February, 2020-June, 2021; n = 120). Fibrotic changes on chest CT were evaluated through visual assessment. Of 184 patients, the mean age was 64.6 years, and 60.5% were ale. Fibrosis-like changes on chest CT (median 51 days from enrollment to follow up CT scan, interquartile range 27-76 days) were identified in 75.3%. Delta group showed more fibrosis-like changes (≥ 2) (69.8% vs. 43.1%, P = 0.001) and more frequent reticulation and architectural distortion+/-parenchymal band than pre-delta group. Even after propensity score matching with clinical variables, delta group had more severe (≥ 2) fibrosis-like changes (71.4% vs. 38.8%, P = 0.001), and more frequent reticulation and architectural distortion+/-parenchymal band than pre-delta group. Our data suggest that critically ill patients with SARS-CoV-2 in delta period had more severe pulmonary fibrosis-like changes than those in pre-delta period., (© 2024. The Author(s).)

The SARS-CoV-2 pandemic has highlighted the challenges posed by the emergence and rapid global spread of previously unknown viruses. Early investigations on the pathogenesis of newly identified viruses are often hampered by a lack of appropriate sample material and conventional detection methods. In this study, viral replication within the lungs of SARS-CoV-2-infected Syrian golden hamsters was assessed by immunolabeling dsRNA intermediates with three different monoclonal antibodies in formalin-fixed, paraffin-embedded tissue samples. The presence of dsRNA was compared to viral antigen levels, viral titers, and genomic RNA replicates using three different variants of concern and an ancestral virus strain at a single time point and during the course of infection with an ancestral variant, and then validated using fluorescent 2-plex in situ hybridization. The results indicate that the detection of viral infection using anti-dsRNA antibodies is restricted to an early phase of infection with high viral replication activity. Additionally, the combined detection of dsRNA intermediates and viral antigens may help to bridge the interpretation gaps between viral antigen levels and viral titers at a single time point. Further testing in other viral infections or species is needed to assess the potential of dsRNA as an early marker for viral infections.

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options.

Background: The Golden Syrian hamster (Mesocricetus auratus), Ferrets (Mustela putorius furo), and macaques have been described as useful laboratory animals naturally susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Objectives: To study the mechanism of lung injury, we describe the histopathological features of SARS-CoV-2 infection in Golden Syrian hamsters inoculated intranasally with the A.2 Brazilian strain., Methods: Hamsters were intranasally inoculated with the A.2 variant and euthanised at 3-, 5-, 10- and 15-days post-inoculation. The physical examination and body weight were recorded daily. Neutralising antibodies and viral RNA load of the respiratory tract were assessed during necropsies., Findings: The coronavirus disease 2019 (COVID-19) model presented body weight loss, high levels of respiratory viral RNA load, severe segmentary pneumonitis, and bronchial fistula besides lymphatic trapping and infiltration, like the human SARS-COV-2 pathogenesis. The presence of subepithelial lymphoeosinophilic infiltrate was highlighted in our results; it contributed to the detachment of SARS-CoV-2 nucleocapsid-positive epithelial cells resulting in the infectious cell plugs., Main Conclusions: The SARS-CoV-2 caused segmentary pneumonia and vascular damage. In our comprehension, the infectious cell plugs, as being aspirated from the upper respiratory tract into the terminal bronchial lumen, work as a "Trojan horse", thus contributing to the dissemination of the SARS-CoV-2 infection into specific regions of the deep lung parenchyma.

Understanding the immune response to COVID-19 is challenging due to its high variability among individuals. To identify differentially expressed cytokines between the deteriorating and recovering phases, we analyzed the Electronic Health Records (EHR) and cytokine profile data in a COVID-19 cohort of 444 infected patients and 145 non-infected healthy individuals. We categorized each patient's progression into Deterioration Phase (DP) and Recovery Phase (RP) using longitudinal neutrophil, lymphocyte and lactate dehydrogenase levels. A random forest model was built using healthy and severe patients to compute the contribution of each cytokine toward disease progression using Shapley Additive Explanations (SHAP). SHAP values were used for supervised clustering to identify DP and RP-related samples and their associated cytokines. The identified clusters effectively discriminated DP and RP samples, suggesting that the cytokine profiles differed between deteriorating and recovering health conditions. Especially, CXCL10, GDF15, PTX3, and TNFSF10 were differentially expressed between the DP and RP samples, which are involved in the JAK-STAT, NF- κ B, and MAPK signaling pathways contributing to the inflammatory response. Collectively, we characterized the immune response in terms of disease progression of COVID-19 with deteriorating and recovering health conditions., (© 2024. The Author(s).)

The coronavirus disease 2019 (COVID-19) reportedly exacerbates cancer outcomes. However, how COVID-19 influences cancer prognosis and development remains poorly understood. Here, we investigated the effect of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), the etiological agent of COVID-19, on cellular cancer phenotypes the expression of cancer-related markers, and various proinflammatory cytokines. We infected prostate (22RV1) and colorectal (DLD-1) cancer cell lines, which express angiotensin-converting enzyme 2 (ACE2), with spike pseudovirus (sPV) and laboratory stocks of live SARS-CoV-2 viruses. After infection, we quantified changes in the cellular cancer phenotypes, the gene expression levels of some cancer markers, including Ki-67, BCL-2, VIM, MMP9, and VEGF, and proinflammatory cytokines. Phenotypic analysis was performed using MTT and wound healing assays, whereas gene expression analysis was carried out using real-time quantitative PCR (RT-qPCR). We show that SARS-CoV-2 infection impacts several key cellular pathways involved in cell growth, apoptosis, and migration, in prostate and colorectal cancer cells. Our results suggest that SARS-CoV-2 infection does influence various cancer cellular phenotypes and expression of molecular cancer markers and proinflammatory cytokines, albeit in a cell-type-specific manner. Our findings hint at the need for further studies and could have implications for evaluating the impact of other viruses on cancer progression., (© 2024. The Author(s).)

Animal models that are susceptible to SARS-CoV-2 infection and develop clinical signs like human COVID-19 are desired to understand viral pathogenesis and develop effective medical countermeasures. The golden Syrian hamster is important for the study of SARS-CoV-2 since hamsters are naturally susceptible to SARS-CoV-2. However, infected hamsters show only limited clinical disease and resolve infection quickly. In this study, we describe development of human angiotensin-converting enzyme 2 (hACE2) transgenic hamsters as a model for COVID-19. During development of the model for SARS-CoV-2, we observed that different hACE2 transgenic hamster founder lines varied in their susceptibility to SARS-CoV-2 lethal infection. The highly susceptible hACE2 founder lines F0F35 and F0M41 rapidly progress to severe infection and death within 6 days post-infection (p.i.). Clinical signs included lethargy, weight loss, dyspnea, and mortality. Lethality was observed in a viral dose-dependent manner with a lethal dose as low as 1 × 10 0.15 CCID 50 . In addition, virus shedding from highly susceptible lines was detected in oropharyngeal swabs on days 2-5 p.i., and virus titers were observed at 10 5.5-6.5 CCID 50 in lung and brain tissue by day 4 p.i.. Histopathology revealed that infected hACE2-hamsters developed rhinitis, tracheitis, bronchointerstitial pneumonia, and encephalitis. Mortality in highly susceptible hACE2-hamsters can be attributed to neurologic disease with contributions from the accompanying respiratory disease. In contrast, virus challenge of animals from less susceptible founder lines, F0M44 and F0M51, resulted in only 0-20% mortality. To demonstrate utility of this SARS-CoV-2 infection model, we determined the protective effect of the TLR3 agonist polyinosinic-polycytidylic acid (Poly (I:C)). Prophylactic treatment with Poly (I:C) significantly improved survival in highly susceptible hACE2-hamsters. In summary, our studies demonstrate that hACE2 transgenic hamsters differ in their susceptibility to SARS-CoV-2 infection, based on the transgenic hamster founder line, and that prophylactic treatment with Poly (I:C) was protective in this COVID-19 model of highly susceptible hACE2-hamsters.

Background: The pathophysiology of protracted symptoms after COVID-19 is unclear. This study aimed to determine if long-COVID is associated with differences in baseline characteristics, markers of white matter diffusivity in the brain, and lower scores on objective cognitive testing., Methods: Individuals who experienced COVID-19 symptoms for more than 60 days post-infection (long-COVID) (n = 56) were compared to individuals who recovered from COVID-19 within 60 days of infection (normal recovery) (n = 35). Information regarding physical and mental health, and COVID-19 illness was collected. The National Institute of Health Toolbox Cognition Battery was administered. Participants underwent magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). Tract-based spatial statistics were used to perform a whole-brain voxel-wise analysis on standard DTI metrics (fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity), controlling for age and sex. NIH Toolbox Age-Adjusted Fluid Cognition Scores were used to compare long-COVID and normal recovery groups, covarying for Age-Adjusted Crystallized Cognition Scores and years of education. False discovery rate correction was applied for multiple comparisons., Results: There were no significant differences in age, sex, or history of neurovascular risk factors between the groups. The long-COVID group had significantly (p < 0.05) lower mean diffusivity than the normal recovery group across multiple white matter regions, including the internal capsule, anterior and superior corona radiata, corpus callosum, superior fronto-occiptal fasciculus, and posterior thalamic radiation. However, the effect sizes of these differences were small (all β<|0.3|) and no significant differences were found for the other DTI metrics. Fluid cognition composite scores did not differ significantly between the long-COVID and normal recovery groups (p > 0.05)., Conclusions: Differences in diffusivity between long-COVID and normal recovery groups were found on only one DTI metric. This could represent subtle areas of pathology such as gliosis or edema, but the small effect sizes and non-specific nature of the diffusion indices make pathological inference difficult. Although long-COVID patients reported many neuropsychiatric symptoms, significant differences in objective cognitive performance were not found., Competing Interests: Declaration of competing interest WGH is a Consultant to Newron, AbbVie and Boehringer Ingelheim. Other authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Excessive alarmins S100A8/A9 escalate the inflammation and even exacerbate immune-driven thrombosis and multi-organ damage. However, the regulatory mechanisms of S100A8/A9 expression in infectious diseases remain unclear. In this study, high-dimensional transcriptomic data analyses revealed a high proportion of CD14 + FCN1 hi macrophages within the pulmonary niche post-severe SARS-CoV-2 infection. By constructing the S100-coexpression gene list and supervised module scoring, we found that CD14 + FCN1 hi macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14 + FCN1 hi cells lacked the positive regulatory activity of transcription factor PPARγ, and lost their differentiation ability towards mature macrophages. Ex vivo experiments further validated that the epithelial cells with high ORF-3a expression promoted the expression and secretion of S100A8/A9 through ANXA1/SAA1-FPR1 signaling. S100A8/A9 heterodimers, as well as the co-localization of S100A8/A9 with microtubules, were both diminished by the FPR1 inhibitor. Phospho-kinase protein array indicated that STAT3 promoted transcription, and PLC-γ and ERK1/2 pathways were involved in the hetero-dimerization and unconventional secretion of S100A8/A9. Our study highlights the pivotal role of FPR1 signaling in the excessive production of S100A8/A9 and provides a promising target for the prevention and control of severe COVID-19 and post-acute COVID-19 sequelae., (© 2024. The Author(s).)

To improve the prognosis of patients suffering from pulmonary diseases, such as lung cancer, early diagnosis and treatment are crucial. The analysis of CT images is invaluable for diagnosis, whereas high quality segmentation of the airway tree are required for intervention planning and live guidance during bronchoscopy. Recently, the Multi-domain Airway Tree Modeling (ATM'22) challenge released a large dataset, both enabling training of deep-learning based models and bringing substantial improvement of the state-of-the-art for the airway segmentation task. The ATM'22 dataset includes a large group of COVID'19 patients and a range of other lung diseases, however, relatively few patients with severe pathologies affecting the airway tree anatomy was found. In this study, we introduce a new public benchmark dataset (AeroPath), consisting of 27 CT images from patients with pathologies ranging from emphysema to large tumors, with corresponding trachea and bronchi annotations. Second, we present a multiscale fusion design for automatic airway segmentation. Models were trained on the ATM'22 dataset, tested on the AeroPath dataset, and further evaluated against competitive open-source methods. The same performance metrics as used in the ATM'22 challenge were used to benchmark the different considered approaches. Lastly, an open web application is developed, to easily test the proposed model on new data. The results demonstrated that our proposed architecture predicted topologically correct segmentations for all the patients included in the AeroPath dataset. The proposed method is robust and able to handle various anomalies, down to at least the fifth airway generation. In addition, the AeroPath dataset, featuring patients with challenging pathologies, will contribute to development of new state-of-the-art methods. The AeroPath dataset and the web application are made openly available., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Støverud et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Coronavirus disease 2019 (COVID-19) has been associated with various systemic complications, including potential impacts on ocular health. Recent studies have suggested that COVID-19 may lead to changes in retinal structure, particularly in the neuroretinal and retinal nerve fiber layers (RNFL). This study aimed to examine changes in neuroretinal and RNFL of the optic dics based on optical coherence tomography (OCT) in patients hospitalized due to COVID-19 bilateral pneumonia at 2 time points after discharge. A prospective study involved 49 patients with COVID-19 bilateral pneumonia hospitalized between March and May 2021. Baseline ocular evaluations were conducted 2 months post-discharge, with follow-up examinations 6 months later. Retinal parameters, including RNFL and ganglion cell layers (GCL), were assessed. Control group of healthy individuals also underwent similar ophthalmic examinations for comparative analysis. We found that the average thickness of the retinal nerve fiber layer (RNFL) of the optic disc was lower in the COVID-19 group than in controls (p≤0.01). The ganglion cell layer (GCL) was thicker in the inner inferior ring (p=0.008) but thinner in the outer superior, outer nasal, and outer inferior rings (p=0.044, p<0.01, and p<0.01, respectively). OCT parameters were assessed according to sex. At 6 months, the RNFL of the inner inferior and outer temporal rings was thinner in women than in men (p=0.022 and p=0.020, respectively). The GCL of the inner temporal and outer temporal rings was also thinner in women than in men (p=0.004 and p=0.005, respectively). In conclusion: at 6-month follow-up, RNFL and GCL thickness was significantly lower in some areas of the retina compared with baseline. COVID-19 seems to cause changes in the macular retina, highlighting the need for ophthalmologic screening of patients with a history of SARS-CoV-2 infection.

Background: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive., Methods: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection., Findings: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion., Interpretation: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC., Funding: Funding is listed in the Acknowledgements section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

SARS-CoV-2 infection is considered as a multi-organ disease, and several studies highlighted the relevance of the virus infection in the induction of vascular injury and tissue morphological alterations, including placenta. In this study, immunohistochemical analyses were carried out on placenta samples derived from women with COVID-19 infection at delivery (SARS-CoV-2 PCR+) or women healed from a COVID-19 infection (SARS-CoV-2 negative at delivery, SARS-CoV-2 PCR-) or women who gave birth before 2019 (Control). Angiotensin Converting Enzyme 2 (ACE2) receptor, Cluster of differentiation 147 (CD147), endothelial CD34 marker, Vascular Endothelial Growth Factor (VEGF) and total Microtubule-associated protein 1 Light Chain 3B marker (LC3B) were investigated in parallel with SPIKE protein by standard IHC. Multiplexed Immunohistochemical Consecutive Staining on Single Slide (MICSSS) was used to examine antigen co-expression in the same specimen. SPIKE protein was detected in villi and decidua from women with ongoing infection, with no significant differences in SPIKE staining between both biopsy sites. VEGF was significantly increased in SARS-CoV-2 PCR + biopsies compared to control and SARS-CoV-2 PCR- samples, and MICSSS method showed the co-localization of SPIKE with VEGF and CD34. The induction of autophagy, as suggested by the LC3B increase in SARS-CoV-2 PCR + biopsies and the co-expression of LC3B with SPIKE protein, may explain one of the different mechanisms by which placenta may react to infection. These data could provide important information on the impact that SARS-CoV-2 may have on the placenta and mother-to-fetus transmission., (© 2024. The Author(s).)

The COVID-19, caused by SARS-CoV-2, first affects the respiratory tract but evidence is emerging that the virus, reaching the central nervous system (CNS), can lead to severe neurological disorders. In particular, CoV infection could cause an acceleration of the neurodegenerative process. On the other hand, patients diagnosed with Alzheimer's disease (AD) develop more serious forms of COVID-19 with worse relapses. Therefore, understanding the connection between the two pathologies, AD and infection by coronavirus, could help in the development of new therapeutic approaches to counter them. We used the SH-SY5Y cell line differentiated into neurons, as widely used in studies of AD if supplemented with exogenous fibrillary β-amyloid (Aβ). As a glial counterpart, human microglia (HMC3) and astrocytic (D54MG) cell lines were used to create co-cultures with neurons via transwell systems. In these experimental models, we generated infection with the Human Coronavirus OC43 (HCoV-OC43), a low-risk model of SARS-CoV-2. Our results suggest that the infection by HCoV-OC43 leads to a neurotoxic effect not depending on an already present event of Aβ deposition. Indeed, unlike microglia, neurons and even more astrocytes are susceptible to CoV infection and, although the infection does not show a cytotoxic effect in the neurons in the first few days, significant alterations at a biochemical and morphological level have been observed, suggesting that the neurons are reacting to a stressful condition, including the prodromal and neurodegenerative features of AD. Interestingly, the interaction of infected astrocytes with the neurons resulted in the manifestation of signs of neurodegeneration, such as amyloid-beta deposition. By using exogenous fibrillary Aβ, as an AD in vitro model, our data suggest that there is an aggravating effect both on the infection itself and on the neurological disease progression. In conclusion, the results of this study suggest a causal interplay between HCoV-OC43 and neurological diseases and demonstrate that the co-presence of different CNS cell populations is the necessary condition to study the pathogenic effects in vitro as a whole., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to investigate oral mucosal changes in patients with confirmed moderate-scale severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Methods: We analyzed 85 COVID-19 patients (50 males, 35 females) with an average age of 53.6 years, treated at the prehospital infectious disease center and Aldent University Clinic in Tirana, Albania, from May 2021 to June 2022., Results: Elevated C-reactive protein levels were observed in 82 patients (±44.20), with 20 patients showing significant fibrinogen increase (mean ± 5.85 g/L), and 22 patients having elevated D-Dimer (mean ± 336.6 mg/mL). Despite the absence of anticoagulant history, 13 patients exhibited bleeding. Xerodermia, xerostomia, and angular cheilitis were noted, with 41 patients displaying angular cheilitis. In 82 patients, oral mucosal and tongue examinations revealed color changes from white to bright yellow, with brown edema. Pigmentation in the fixed gingiva of upper and lower front teeth was observed in 35 patients., Conclusions: Oral mucosal changes during COVID-19 appear more influenced by drug treatment and disease progression than the infection itself, suggesting that secondary factors play a significant role. Despite the oral cavity's potential for viral entry, these changes seem connected to other underlying causes.

In adults, monocytes and neutrophils play important roles in the hyperinflammatory responses characteristic of severe forms of SARS-CoV-2 infection. We assessed leukocyte activation in 55 children attending the emergency department for acute fever between March 2020 and September 2021. The following markers were analyzed by flow cytometry: CD169 and HLA-DR on monocytes, CD64 and CD16 on neutrophils, and CD38 on lymphocytes TCD8. Fifteen of the children had SARS-CoV-2 infection, 15 had bacterial infections, and 15 had inflammatory diseases. We observed overexpression of CD169 on monocytes and CD38 on T lymphocytes in all patients with a diagnosis of SARS-CoV-2, while overexpression of CD64 on neutrophils was observed with bacterial infections and inflammatory diseases. There was a decrease in the expression of HLA-DR on monocytes in the bacterial infection and inflammatory pathology groups. Leukocyte analysis identifies distinct activation patterns in children during SARS-CoV-2 infections, bacterial infections, and inflammatory diseases., Competing Interests: Conflict of interest. F.M. and P.B. are Beckman Coulter employees., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The glucose-6-phosphate dehydrogenase (G6PD) deficiency is X-linked and is the most common enzymatic deficiency disorder globally. It is a crucial enzyme for the pentose phosphate pathway and produces NADPH, which plays a vital role in regulating the oxidative stress of many cell types. The deficiency of G6PD primarily causes hemolytic anemia under oxidative stress triggered by food, drugs, or infection. G6PD-deficient patients infected with SARS-CoV-2 showed an increase in hemolysis and thrombosis. Patients also exhibited prolonged COVID-19 symptoms, ventilation support, neurological impacts, and high mortality. However, the mechanism of COVID-19 severity in G6PD deficient patients and its neurological manifestation is still ambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, we observed a significant reduction in NADPH level and an increase in basal reactive oxygen species (ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impairs induced nitric oxide synthase (iNOS) mediated nitric oxide (NO) production, which plays a fundamental role in inhibiting viral replication. Surprisingly, we also observed that the deficiency of the G6PD-NADPH axis reduced lysosomal acidification and free radical production, further abrogating the lysosomal clearance of viral particles. Thus, impairment of NO production, lysosomal functions, and redox dysregulation in G6PD deficient microglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)