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Frontiers in Immunology 2023The SARS-CoV-2 mediated COVID-19 pandemic has impacted millions worldwide. Hyper-inflammatory processes, including cytokine storm, contribute to long-standing tissue...
INTRODUCTION
The SARS-CoV-2 mediated COVID-19 pandemic has impacted millions worldwide. Hyper-inflammatory processes, including cytokine storm, contribute to long-standing tissue injury and damage in COVID-19. The metabolism of sphingolipids as regulators of cell survival, differentiation, and proliferation has been implicated in inflammatory signaling and cytokine responses. Sphingosine-kinase-1 (SK1) and ceramide-synthase-2 (CERS2) generate metabolites that regulate the anti- and pro-apoptotic processes, respectively. Alterations in SK1 and CERS2 expression may contribute to the inflammation and tissue damage during COVID-19. The central objective of this study is to evaluate structural changes in the lung post-SARS-CoV-2 infection and to investigate whether the sphingolipid rheostat is altered in response to SARS-CoV-2 infection.
METHODS
Central and peripheral lung tissues from COVID-19+ or control autopsies and resected lung tissue from COVID-19 convalescents were subjected to histologic evaluation of airspace and collagen deposisiton, and immunohistochemical evaluation of SK1 and CERS2.
RESULTS
Here, we report significant reduction in air space and increase in collagen deposition in lung autopsy tissues from patients who died from COVID-19 (COVID-19) and COVID-19 convalescent individuals. SK1 expression increased in the lungs of COVID-19 autopsies and COVID-19 convalescent lung tissue compared to controls and was mostly associated with Type II pneumocytes and alveolar macrophages. No significant difference in CERS2 expression was noted. SARS-CoV-2 infection upregulates SK1 and increases the ratio of SK1 to CERS2 expression in lung tissues of COVID-19 autopsies and COVID-19 convalescents.
DISCUSSION
These data suggest an alteration in the sphingolipid rheostat in lung tissue during COVID-19, suggesting a potential contribution to the inflammation and tissue damage associated with viral infection.
Topics: Humans; SARS-CoV-2; COVID-19; Sphingolipids; Pandemics; Lung; Inflammation; Collagen
PubMed: 37868972
DOI: 10.3389/fimmu.2023.1216278 -
EBioMedicine Mar 2024In 2022 and 2023, novel reassortant H3N8 influenza viruses infected three people, marking the first human infections with viruses of this subtype.
BACKGROUND
In 2022 and 2023, novel reassortant H3N8 influenza viruses infected three people, marking the first human infections with viruses of this subtype.
METHODS
Here, we generated one of these viruses (A/Henan/4-10CNIC/2022; hereafter called A/Henan/2022 virus) by using reverse genetics and characterized it.
FINDINGS
In intranasally infected mice, reverse genetics-generated A/Henan/2022 virus caused weight loss in all five animals (one of which had to be euthanized) and replicated efficiently in the respiratory tract. Intranasal infection of ferrets resulted in minor weight loss and moderate fever but no mortality. Reverse genetics-generated A/Henan/2022 virus replicated efficiently in the upper respiratory tract of ferrets but was not detected in the lungs. Virus transmission via respiratory droplets occurred in one of four pairs of ferrets. Deep-sequencing of nasal swab samples from inoculated and exposed ferrets revealed sequence polymorphisms in the haemagglutinin protein that may affect receptor-binding specificity. We also tested 90 human sera for neutralizing antibodies against reverse genetics-generated A/Henan/2022 virus and found that some of them possessed neutralizing antibody titres, especially sera from older donors with likely exposure to earlier human H3N2 viruses.
INTERPRETATION
Our data demonstrate that reverse genetics-generated A/Henan/2022 virus is a low pathogenic influenza virus (of avian influenza virus descent) with some antigenic resemblance to older human H3N2 viruses and limited respiratory droplet transmissibility in ferrets.
FUNDING
This work was supported by the Japan Program for Infectious Diseases Research and Infrastructure (JP23wm0125002), and the Japan Initiative for World-leading Vaccine Research and Development Centers (JP233fa627001) from the Japan Agency for Medical Research and Development (AMED).
Topics: Humans; Animals; Mice; Orthomyxoviridae Infections; Influenza A Virus, H3N8 Subtype; Influenza A Virus, H3N2 Subtype; Ferrets; Lung; Weight Loss; Influenza, Human
PubMed: 38408394
DOI: 10.1016/j.ebiom.2024.105034 -
Frontiers in Immunology 2023Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of...
INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.
METHODS
To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.
RESULTS
IV significantly downregulated albumin uptake, independently of activation of the TGF-β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.
DISCUSSION
Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.
Topics: Animals; Mice; Alveolar Epithelial Cells; Low Density Lipoprotein Receptor-Related Protein-2; Biological Transport; Albumins; Orthomyxoviridae Infections; Orthomyxoviridae
PubMed: 37727782
DOI: 10.3389/fimmu.2023.1260973 -
Respiratory Medicine Dec 2023The pulmonary manifestations of Systemic Lupus Erythematosus (SLE) in pediatric patients are poorly understood and the pulmonary manifestations reported from the adult...
The pulmonary manifestations of Systemic Lupus Erythematosus (SLE) in pediatric patients are poorly understood and the pulmonary manifestations reported from the adult population are generally extrapolated to the pediatric population. In the present work, the review of 228 files was carried out, in which the pulmonary manifestations, symptoms and antibody levels of the patients treated at the Hospital Regional de Alta Especialidad de Ixtapaluca (HRAEI), State of Mexico, Mexico, were identified. Statistical significance between groups was estimated using the Chi-square and Mann-Whitney U test. The main pulmonary manifestations identified were pleurisy (14 %), pulmonary hemorrhage (3.9 %), pulmonary thromboembolism (0.9 %), acute lupus pneumonitis (0.4 %), pulmonary arterial hypertension (0.4 %), and small lung syndrome (0.4 %). While the initial symptomatology was dyspnea with an incidence of 9.6 %, the mean oxygen saturation in the population was 96.87 %. Pleural effusion was identified as the most frequent pulmonary manifestation in radiographic changes. No statistically significant difference was found in antibody levels when comparing the groups. The most common pulmonary manifestation associated with SLE is pleurisy, however, the range of pulmonary manifestations in this type of patient can be very varied, as well as the presentation of each of them.
Topics: Adult; Humans; Child; Lupus Erythematosus, Systemic; Lung Diseases; Lung; Pleurisy; Pleural Effusion
PubMed: 37926179
DOI: 10.1016/j.rmed.2023.107456 -
Academic Radiology Dec 2023This systematic review and meta-analysis aimed to investigate the radiological predictors of post-coronavirus disease 19 (COVID-19) pulmonary fibrosis and incomplete... (Meta-Analysis)
Meta-Analysis Review
RATIONALE AND OBJECTIVES
This systematic review and meta-analysis aimed to investigate the radiological predictors of post-coronavirus disease 19 (COVID-19) pulmonary fibrosis and incomplete absorption of pulmonary lesions.
MATERIALS AND METHODS
We systematically searched PubMed, EMBASE, and Web of Science for studies reporting the predictive value of radiological findings in patients with post-COVID-19 lung residuals published through November 11, 2022. The pooled odds ratios with a 95% confidence interval (CI) were assessed. The random-effects model was used due to the heterogeneity of the true effect sizes.
RESULTS
We included 11 studies. There were 1777 COVID-19-positive patients, and 1014 (57%) were male. All studies used chest computed tomography (CT) as a radiologic tool. Moreover, chest X-ray (CXR) and lung ultrasound were used in two studies, along with a CT scan. CT severity score (CTSS), Radiographic Assessment of Lung Edema score (RALE), interstitial score, lung ultrasound score (LUS), patchy opacities, abnormal CXR, pleural traction, and subpleural abnormalities were found to be predictors of post-COVID-19 sequels. CTSS and consolidations were the most common predictors among included studies. Pooled analysis revealed that pulmonary residuals in patients with initial consolidation are about four times more likely than in patients without this finding (odds ratio: 3.830; 95% CI: 1.811-8.102, I2: 4.640).
CONCLUSION
Radiological findings can predict the long-term pulmonary sequelae of COVID-19 patients. CTSS is an important predictor of lung fibrosis and COVID-19 mortality. Lung fibrosis can be diagnosed and tracked using the LUS. Changes in RALE score during hospitalization can be used as an independent predictor of mortality.
Topics: Humans; Male; Female; COVID-19; SARS-CoV-2; Pulmonary Fibrosis; Respiratory Sounds; Lung; Disease Progression
PubMed: 37491177
DOI: 10.1016/j.acra.2023.06.002 -
Frontiers in Cellular and Infection... 2023Nocardiosis is an infectious disease caused by that primarily affects immunocompromised hosts. is a common opportunistic pathogen that causes disease in humans,...
Nocardiosis is an infectious disease caused by that primarily affects immunocompromised hosts. is a common opportunistic pathogen that causes disease in humans, including pulmonary and extrapulmonary infection. spp. infection is uncommon, and infection with and is even rarer. A 59-year-old immunocompetent woman with risk factors for environmental exposure developed nocardiosis and presented to the hospital with a cough, shortness of breath, hemoptysis, and a back abscess. An enhanced computed tomography (CT) of the chest revealed partial destruction of the right lung, as well as consolidation of the right upper lobe. Rare pathogens and were detected by metagenomic next-generation sequencing (mNGS) from abscess on the back and lung puncture tissue, respectively. She was treated with a combination of antibiotics and was finally discharged with a good prognosis. In this case, we present a patient who was successfully diagnosed with and infection using mNGS. This importance of using mNGS in pathogen detection and the effective use of antibiotics in treating patients with long-term rare infections is highlighted in this report.
Topics: Female; Humans; Middle Aged; Mycobacterium abscessus; Abscess; East Asian People; Nocardia; Nocardia Infections; Anti-Bacterial Agents; Lung
PubMed: 37655298
DOI: 10.3389/fcimb.2023.1229298 -
QJM : Monthly Journal of the... Jul 2023Pulmonary fibrosis is a sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that currently lacks effective preventative or therapeutic... (Review)
Review
Pulmonary fibrosis is a sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that currently lacks effective preventative or therapeutic measures. Post-viral lung fibrosis due to SARS-CoV-2 has been shown to be progressive on selected patients using imaging studies. Persistent infiltration of macrophages and monocytes, a main feature of SARS-CoV-2 pulmonary fibrosis, and long-lived circulating inflammatory monocytes might be driving factors promoting the profibrotic milieu in the lung. The upstream signal(s) that regulates the presence of these immune cells (despite complete viral clearance) remains to be explored. Current data indicate that much of the stimulating signals are localized in the lungs. However, an ongoing low-grade systemic inflammation in long Coronavirus Disease 2019 (COVID-19) symptoms suggests that certain non-pulmonary regulators such as epigenetic changes in hematopoietic stem cells might be critical to the chronic inflammatory response. Since nearly one-third of the world population have been infected, a timely understanding of the underlying pathogenesis leading to tissue remodeling is required. Herein, we review the potential pathogenic mechanisms driving lung fibrosis following SARS-CoV-2 infection based upon available studies and our preliminary findings (Graphical abstract).
Topics: Humans; Pulmonary Fibrosis; COVID-19; SARS-CoV-2; Lung; Inflammation
PubMed: 36018274
DOI: 10.1093/qjmed/hcac206 -
American Journal of Respiratory Cell... Aug 2023Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct...
Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2-infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells.
Topics: Humans; COVID-19; Angiotensin-Converting Enzyme 2; SARS-CoV-2; Endothelial Cells; Culture Media, Conditioned; Peptidyl-Dipeptidase A; Lung; Inflammation; Complement System Proteins
PubMed: 37071849
DOI: 10.1165/rcmb.2022-0373OC -
Frontiers in Cellular and Infection... 2023Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved... (Review)
Review
Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved organ, with NTM pulmonary diseases causing serious health issues in patients with underlying lung disease. Moreover, NTM infections have been steadily increasing worldwide in recent years. NTM are also naturally resistant to many antibiotics, specifically anti-tuberculosis (anti-TB) drugs. The lack of drugs targeting NTM infections and the increasing drug resistance of NTM have further made treating these mycobacterial diseases extremely difficult. The currently recommended NTM treatments rely on the extended indications of existing drugs, which underlines the difficulties of new antibiotic discovery against NTM. Another challenge is determining which drug combinations are most effective against NTM infection. To a certain extent, anti-NTM drug development depends on using already available antibiotics and compounds. Here, we aimed to review new antibiotics or compounds with good antibacterial activity against NTM, focusing on their mechanisms of action, and antibacterial activities.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Antitubercular Agents; Lung
PubMed: 37850054
DOI: 10.3389/fcimb.2023.1243457 -
Viruses Apr 2024Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV...
Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.
Topics: Animals; Exosomes; Mesenchymal Stem Cells; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; NF-kappa B; Signal Transduction; Muromegalovirus; Disease Models, Animal; Mice, Inbred C57BL; Macrophages; Cytomegalovirus Infections; Lung; Pneumonia, Viral; Herpesviridae Infections; Pneumonia
PubMed: 38675960
DOI: 10.3390/v16040619