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Cell Nov 2023Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse...
Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.
Topics: Animals; Mice; Biofilms; Lung; Mycobacterium tuberculosis; Tuberculosis; Virulence; Biomechanical Phenomena
PubMed: 37865090
DOI: 10.1016/j.cell.2023.09.016 -
Clinics in Chest Medicine Dec 2023Nontuberculous mycobacterial (NTM) isolation and pulmonary disease (NTM-PD) have continued to increase in most regions of the world, driven mainly by Mycobacterium... (Review)
Review
Nontuberculous mycobacterial (NTM) isolation and pulmonary disease (NTM-PD) have continued to increase in most regions of the world, driven mainly by Mycobacterium avium. Single-center studies also support increasing trends as well as a persistent burden of undiagnosed NTM among persons suspected of having tuberculosis (TB), in countries with moderate-to-high TB prevalence. Cumulative exposure to water and soil presents an increased risk to susceptible hosts, and trace metals in water supply are recently recognized risk factors. Establishing standard case definitions for subnational and national surveillance systems with mandatory notification of NTM-PD are needed to allow comparisons within and across countries and regions.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Lung; Lung Diseases; Tuberculosis
PubMed: 37890910
DOI: 10.1016/j.ccm.2023.08.012 -
Nature Sep 2023Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises...
Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function. Endothelial dysfunction can exacerbate tissue damage, yet it is unclear whether the lung endothelium promotes host resistance against viral pathogens. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is highly active in lung endothelial cells and protects against influenza-induced lung vascular leakage. Loss of AHR in endothelia exacerbates lung damage and promotes the infiltration of red blood cells and leukocytes into alveolar air spaces. Moreover, barrier protection is compromised and host susceptibility to secondary bacterial infections is increased when endothelial AHR is missing. AHR engages tissue-protective transcriptional networks in endothelia, including the vasoactive apelin-APJ peptide system, to prevent a dysplastic and apoptotic response in airway epithelial cells. Finally, we show that protective AHR signalling in lung endothelial cells is dampened by the infection itself. Maintenance of protective AHR function requires a diet enriched in naturally occurring AHR ligands, which activate disease tolerance pathways in lung endothelia to prevent tissue damage. Our findings demonstrate the importance of endothelial function in lung barrier immunity. We identify a gut-lung axis that affects lung damage following encounters with viral pathogens, linking dietary composition and intake to host fitness and inter-individual variations in disease outcome.
Topics: Animals; Humans; Mice; Apelin; Diet; Endothelial Cells; Endothelium; Epithelial Cells; Erythrocytes; Influenza, Human; Intestines; Leukocytes; Ligands; Lung; Orthomyxoviridae Infections; Pulmonary Alveoli; Receptors, Aryl Hydrocarbon
PubMed: 37587341
DOI: 10.1038/s41586-023-06287-y -
Cell Apr 2024Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses...
Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1 sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.
Topics: Animals; Female; Male; Mice; Biofilms; Escherichia coli; Hypothermia; Inflammation; Lung; Pneumonia; Pseudomonas aeruginosa; Sensory Receptor Cells; Polysaccharides, Bacterial; Escherichia coli Infections; Pseudomonas Infections; Nociceptors
PubMed: 38518773
DOI: 10.1016/j.cell.2024.03.001 -
ELife Jul 2023The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4 T helper cells, but not CD8 T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.
Topics: Humans; SARS-CoV-2; COVID-19; CD8-Positive T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Lung
PubMed: 37523305
DOI: 10.7554/eLife.84790 -
Signal Transduction and Targeted Therapy Aug 2023Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis...
Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis of breast cancer. Infection with pathogens such as viruses and bacteria can alter the immune status of the lung. However, the effect of chronic inflammation caused by bacteria on the formation of a premetastatic niche within the lung is unclear, and the contribution of specific immune mediators to tumor metastasis also remains largely undetermined. Here, we used a mouse model revealing that chronic pulmonary bacterial infection augmented breast cancer lung metastasis by recruiting a distinct subtype of tumor-infiltrating MHCII neutrophils into the lung, which exhibit cancer-promoting properties. Functionally, MHCII neutrophils enhanced the lung metastasis of breast cancer in a cell-intrinsic manner. Furthermore, we identified CCL2 from lung tissues as an important environmental signal to recruit and maintain MHCII neutrophils. Our findings clearly link bacterial-immune crosstalk to breast cancer lung metastasis and define MHCII neutrophils as the principal mediator between chronic infection and tumor metastasis.
Topics: Mice; Animals; Neutrophils; Persistent Infection; Lung; Lung Neoplasms; Pneumonia; Bacteria; Bacterial Infections; Tumor Microenvironment
PubMed: 37563136
DOI: 10.1038/s41392-023-01542-0 -
Nature Apr 2024Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome (ARDS), for which there are no effective...
Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.
Topics: Animals; Female; Humans; Male; Mice; Alveolar Epithelial Cells; Influenza A virus; Lung Injury; Mice, Inbred C57BL; Necroptosis; Orthomyxoviridae Infections; Protein Kinase Inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases; Respiratory Distress Syndrome
PubMed: 38600381
DOI: 10.1038/s41586-024-07265-8 -
Nature Dec 2023People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown....
People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Chromatin; Dendritic Cells; Diabetes Complications; Diabetes Mellitus; Disease Susceptibility; Glucose; Histones; Hyperglycemia; Lung; T-Lymphocytes; Virus Diseases; Viruses; Disease Models, Animal; Humans
PubMed: 38093014
DOI: 10.1038/s41586-023-06803-0 -
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