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Nature Communications Oct 2023Influenza virus infection causes increased morbidity and mortality in the elderly. Aging impairs the immune response to influenza, both intrinsically and because of...
Influenza virus infection causes increased morbidity and mortality in the elderly. Aging impairs the immune response to influenza, both intrinsically and because of altered interactions with endothelial and pulmonary epithelial cells. To characterize these changes, we performed single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA sequencing (bulk RNA-seq) on lung tissue from young and aged female mice at days 0, 3, and 9 post-influenza infection. Our analyses identified dozens of key genes differentially expressed in kinetic, age-dependent, and cell type-specific manners. Aged immune cells exhibited altered inflammatory, memory, and chemotactic profiles. Aged endothelial cells demonstrated characteristics of reduced vascular wound healing and a prothrombotic state. Spatial transcriptomics identified novel profibrotic and antifibrotic markers expressed by epithelial and non-epithelial cells, highlighting the complex networks that promote fibrosis in aged lungs. Bulk RNA-seq generated a timeline of global transcriptional activity, showing increased expression of genes involved in inflammation and coagulation in aged lungs. Our work provides an atlas of high-throughput sequencing methodologies that can be used to investigate age-related changes in the response to influenza virus, identify novel cell-cell interactions for further study, and ultimately uncover potential therapeutic targets to improve health outcomes in the elderly following influenza infection.
Topics: Humans; Female; Animals; Mice; Aged; Influenza, Human; Endothelial Cells; Lung; Epithelial Cells; Orthomyxoviridae Infections
PubMed: 37852965
DOI: 10.1038/s41467-023-42021-y -
Acta Tropica Aug 2023We report the first case of eosinophilic pleural effusion due to Anisakis spp. infection in a 39-years-old European subject hospitalized for worsening dyspnoea and...
We report the first case of eosinophilic pleural effusion due to Anisakis spp. infection in a 39-years-old European subject hospitalized for worsening dyspnoea and abdominal and thoracic pain. Lung CT scan showed bilateral pleural effusion; thoracentesis revealed significant eosinophilia (45%), with normal eosinophils in the blood. Microbiological tests on pleural effusion were negative for bacteria, SARS-CoV-2, tuberculosis, fungi and parasites. The patient used to eat raw fish; Western blot was positive for Anisakis spp. in blood and pleural effusion. In the era of globalization, unusual parasitic infections should be considered also in nonendemic countries, especially in patients with unexplained eosinophilia.
Topics: Animals; COVID-19; SARS-CoV-2; Pleural Effusion; Eosinophilia; Lung; Anisakiasis
PubMed: 37169218
DOI: 10.1016/j.actatropica.2023.106941 -
Frontiers in Cellular and Infection... 2023Lung infection is a global health problem associated with high morbidity and mortality and increasing rates of hospitalization. The correlation between pulmonary...
BACKGROUND
Lung infection is a global health problem associated with high morbidity and mortality and increasing rates of hospitalization. The correlation between pulmonary microecology and infection severity remains unclear. Therefore, the purpose of this study was to investigate the differences in lung microecology and potential biomarkers in patients with mild and severe pulmonary infection.
METHOD
Patients with pulmonary infection or suspected infection were divided into the mild group (140 cases) and the severe group (80 cases) according to pneomonia severity index (PSI) scores. Here, we used metagenomic next-generation sequencing (mNGS) to detect DNA mainly from bronchoalveolar lavage fluid (BALF) collected from patients to analyze changes in the lung microbiome of patients with different disease severity.
RESULT
We used the mNGS to analyze the pulmonary microecological composition in patients with pulmonary infection. The results of alpha diversity and beta diversity analysis showed that the microbial composition between mild and severe groups was similar on the whole. The dominant bacteria were , , , , and , among others. Linear discriminant analysis effect size (LEfSe) results showed that there were significant differences in virus composition between the mild and severe patients, especially Simplexvirus and Cytomegalovirus, which were prominent in the severe group. The random forest model screened 14 kinds of pulmonary infection-related pathogens including , , , , and . In addition, it was found that was negatively correlated with , , , , and in the mild group through co-occurrence network, while no significant correlation was found in the severe group.
CONCLUSION
Here, we describe the composition and diversity of the pulmonary microbiome in patients with pulmonary infection. A significant increase in viral replication was found in the severe group, as well as a significant difference in microbial interactions between patients with mild and severe lung infections, particularly the association between the common pathogenic bacteria and . This suggests that both pathogen co-viral infection and microbial interactions may influence the course of disease. Of course, more research is needed to further explore the specific mechanisms by which microbial interactions influence disease severity.
Topics: Humans; Pneumonia; Microbiota; Bronchoalveolar Lavage Fluid; Metagenome; Micrococcaceae; Acinetobacter; Bacillus; Coinfection; Fabaceae; High-Throughput Nucleotide Sequencing; Klebsiella; Lung; Sensitivity and Specificity
PubMed: 37900322
DOI: 10.3389/fcimb.2023.1227581 -
Nature Communications Jul 2023Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as...
Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 is among the strongest upregulated microRNAs in human COVID-19 and in mice with acute inflammatory lung damage, and it is the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of a microRNA-21 inhibitor to trimannose achieves rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reverses pathological activation of macrophages and prevents pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevents the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.
Topics: Mice; Humans; Animals; COVID-19; SARS-CoV-2; Lung; Macrophages; Pneumonia; MicroRNAs; Fibrosis
PubMed: 37507393
DOI: 10.1038/s41467-023-40185-1 -
The Journal of Clinical Investigation Jul 2023Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and... (Review)
Review
Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and impairs pulmonary function. CD4+FOXP3+ regulatory T cells (Tregs) interact with cells of both the innate and the adaptive immune system to limit acute pulmonary inflammation and promote its resolution. Tregs also provide tissue protection and coordinate lung tissue repair, facilitating a return to homeostatic pulmonary function. Here, we review Treg-mediated modulation of the host response to respiratory pathogens, focusing on mechanisms underlying how Tregs promote resolution of inflammation and repair of acute lung injury. We also discuss potential strategies to harness and optimize Tregs as a cellular therapy for patients with severe acute respiratory infection and discuss open questions in the field.
Topics: Humans; T-Lymphocytes, Regulatory; Lung; Acute Lung Injury; Pneumonia; Inflammation; Forkhead Transcription Factors
PubMed: 37463441
DOI: 10.1172/JCI170505 -
Gut Apr 2024Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear.
DESIGN
Using an mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation.
RESULTS
FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of and family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes.
CONCLUSION
The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.
Topics: Humans; Mice; Animals; Pulmonary Disease, Chronic Obstructive; Lung; Pneumonia; Inflammation; Carbohydrates
PubMed: 38331563
DOI: 10.1136/gutjnl-2023-330521 -
Journal of Thoracic Imaging Nov 2023Idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung diseases of unclear etiology and are distinguished from diffuse parenchymal lung... (Review)
Review
Idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung diseases of unclear etiology and are distinguished from diffuse parenchymal lung diseases of known cause, such as connective tissue disease-related interstitial lung diseases or hypersensitivity pneumonitis by history, physical exam, imaging, serologic testing, and, when necessary, histopathology. The 2013 American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines are the most widely accepted classification of IIPs and include the following diagnoses: idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, idiopathic lymphocytic interstitial pneumonia, idiopathic pleuro-parenchymal fibroelastosis, respiratory bronchiolitis-interstitial lung disease, and desquamative interstitial pneumonia. The gold standard for diagnosis of IIP involves multidisciplinary discussion among pulmonologists, radiologists, and pathologists. The focus of this review will be to discuss the imaging features of the most common IIPs and the role of multidisciplinary discussion as the gold standard for diagnosis.
Topics: Humans; Diagnosis, Differential; Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Idiopathic Pulmonary Fibrosis; Pneumonia; Lung
PubMed: 37505195
DOI: 10.1097/RTI.0000000000000728 -
Journal of Aerosol Medicine and... Apr 2024Inhalation of liposomes formulated with phospholipids similar to endogenous lung surfactants and lipids offers biocompatibility and versatility within the pulmonary...
Inhalation of liposomes formulated with phospholipids similar to endogenous lung surfactants and lipids offers biocompatibility and versatility within the pulmonary medicine field to treat a range of diseases such as lung cancer, cystic fibrosis and lung infections. Manipulation of the physicochemical properties of liposomes enables innovative design of the carrier to meet specific delivery, release and targeting requirements. This delivery system offers several benefits: improved pharmacokinetics with reduced toxicity, enhanced therapeutic efficacy, increased delivery of poorly soluble drugs, taste masking, biopharmaceutics degradation protection and targeted cellular therapy. This section provides an overview of liposomal formulation and delivery, together with their applications for different disease states in the lung.
Topics: Humans; Liposomes; Administration, Inhalation; Lung; Phospholipids; Pneumonia; Drug Delivery Systems
PubMed: 38640446
DOI: 10.1089/jamp.2024.29112.hxo -
The Journal of Allergy and Clinical... Oct 2023The human microbiome associated with the respiratory tract is diverse, heterogeneous, and dynamic. The diversity and complexity of the microbiome and the interactions... (Review)
Review
The human microbiome associated with the respiratory tract is diverse, heterogeneous, and dynamic. The diversity and complexity of the microbiome and the interactions between microorganisms, host cells, and the host immune system are complex and multifactorial. Furthermore, the lymphatics provide a direct highway, the gut-lung axis, for the gut microbiome to affect outcomes related to respiratory disease and the host immune response. Viral infections in the airways can also alter the presence or absence of bacterial species, which might increase the risks for allergies and asthma. Viruses infect the airway epithelium and interact with the host to promote inflammatory responses that can trigger a wheezing illness. This immune response may alter the host's immune response to microbes and allergens, leading to T2 inflammation. However, exposure to specific bacteria may also tailor the host's response long before the virus has infected the airway. The frequency of viral infections, age at infection, sampling season, geographic location, population differences, and preexisting composition of the microbiota have all been linked to changes in microbiota diversity and stability. This review aims to evaluate the current reported evidence for microbiome interactions and the influences that viral infection may have on respiratory and gut microbiota, affecting respiratory outcomes in children.
Topics: Child; Humans; Microbiota; Virus Diseases; Asthma; Lung; Bacteria; Viruses
PubMed: 37607643
DOI: 10.1016/j.jaci.2023.08.008 -
TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue.Science Translational Medicine Jan 2024Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are...
Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-β signaling through TGF-βR2 (transforming growth factor-β receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial exhibited prolonged injury and diminished vascular repair. Loss of endothelial prevented autocrine (vascular endothelial growth factor α) expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange. Angiogenic responses through TGF-βR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-β signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC deficiency during influenza injury. These studies defined a role for TGF-βR2 in lung endothelial repair and demonstrated efficacy of an efficient and safe endothelial-targeted LNP capable of delivering therapeutic mRNA cargo for vascular repair in influenza infection.
Topics: Humans; Mice; Animals; Receptor, Transforming Growth Factor-beta Type II; Influenza, Human; Vascular Endothelial Growth Factor A; Lung; Transforming Growth Factor beta; RNA, Messenger
PubMed: 38295183
DOI: 10.1126/scitranslmed.adg6229