The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.
Adenosine Monophosphate/therapeutic use* ; Alanine/therapeutic use* ; Alveolar Epithelial Cells/virology* ; Antibodies, Neutralizing/therapeutic use* ; COVID-19/virology* ; Down-Regulation ; Drug Discovery ; Human Embryonic Stem Cells/metabolism* ; Humans ; Immunity ; Lipid Metabolism ; Lung/virology* ; RNA, Viral/metabolism* ; SARS-CoV-2/physiology* ; Virus Replication/drug effects*

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

The ongoing pandemic of Coronavirus disease 19 (COVID-19) is caused by a newly discovered β Coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination. Here we examined, using ELISA, the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6-7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection. All samples were positive for IgGs against the S- and N-proteins of SARS-CoV-2. Notably, 14 samples available at 6-7 months post-infection all showed significant neutralizing activities in a pseudovirus assay, with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2. Furthermore, in 10 blood samples from cases at 6-7 months post-infection used for memory T-cell tests, we found that interferon γ-producing CD4
Adaptive Immunity/physiology* ; Adult ; Aged ; Antibodies, Neutralizing/blood* ; COVID-19/immunology* ; Cohort Studies ; Female ; Humans ; Immunoglobulin G/blood* ; Male ; Middle Aged ; SARS-CoV-2/immunology* ; T-Lymphocytes/physiology* ; Time Factors ; Viral Proteins/immunology*

Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.
Alarmins/physiology* ; C-Reactive Protein/physiology* ; Diabetic Nephropathies/etiology* ; Endocytosis ; Humans ; Immunity, Innate ; Mannose-Binding Lectin/physiology* ; Pathogen-Associated Molecular Pattern Molecules ; Receptors, Pattern Recognition/physiology* ; Serum Amyloid P-Component/physiology* ; Signal Transduction

Ion channels are a widespread class of membrane proteins that help establish and control cell membrane potential by allowing the passive diffusion of inorganic ions with high specificity through cell membrane. They are widely distributed in various cells and tissues, and their normal structure and function are of fundamental importance for all living organisms. The rapid advances in molecular cloning, protein structure analysis, patch clamp recordings and other technologies have greatly promoted the research on the biophysical and molecular properties of ion channels, and made significant progress in the study of the relationship between ion channels and pathophysiology as well. The immune system is made up of immune cells and organs that work together to protect the body and respond to infection and disease. Remarkably, recent basic and clinical research has revealed that ion channels are frequently and abundantly expressed in immune cells and have crucial roles in immune cell development and immune response. This review summarized recent progress in the roles of ion channels in immune cells, including the expression and regulation of ion channels in immune cells, the effects of ion flux mediated by ion channels on lymphocyte development, and functional roles of ion channels in both innate and adaptive immune responses. We also discussed some unresolved and insufficiently addressed issues in the current research, so as to provide an informative reference for better understanding the functional roles of ion channels in the immune system and further elucidation of their function from a physiological and pathological point of view.
Cell Membrane ; Immunity ; physiology ; Ion Channels ; immunology ; Membrane Proteins ; Research ; trends

Traumatic injury of the central nervous system (CNS) including brain and spinal cord remains a leading cause of morbidity and disability in the world. Delineating the mechanisms underlying the secondary and persistent injury versus the primary and transient injury has been drawing extensive attention for study during the past few decades. The sterile neuroinflammation during the secondary phase of injury has been frequently identified substrate underlying CNS injury, but as of now, no conclusive studies have determined whether this is a beneficial or detrimental role in the context of repair. Recent pioneering studies have demonstrated the key roles for the innate and adaptive immune responses in regulating sterile neuroinflammation and CNS repair. Some promising immunotherapeutic strategies have been recently developed for the treatment of CNS injury. This review updates the recent progress on elucidating the roles of the innate and adaptive immune responses in the context of CNS injury, the development and characterization of potential immunotherapeutics, as well as outstanding questions in this field.
Adaptive Immunity ; Astrocytes ; physiology ; Brain Injuries, Traumatic ; immunology ; therapy ; Histone Deacetylases ; therapeutic use ; Humans ; Immunity, Innate ; immunology ; Immunotherapy ; methods ; Inflammasomes ; drug effects ; physiology ; Macrophage Activation ; Spinal Cord Injuries ; immunology ; therapy

T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.
Animals ; Cell Physiological Phenomena ; Humans ; Immunity, Cellular ; physiology ; Metabolic Networks and Pathways ; immunology ; T-Lymphocytes ; immunology ; metabolism

Genes play an important role in the immune system response, and different gene loci may result in different vaccine immune response rates. This review focuses on the correlation between gene polymorphisms and vaccine immune response in order to investigate the influence of gene polymorphisms on the immune response to vaccines. It discusses the effect of an individual's immune response after vaccination at genetic level and provides a scientific basis for individualized immune development strategies. It reveals that human leukocyte antigen genes, various cytokines and their receptor genes, and Toll-like receptor genes all affect the vaccine immune response.
Cytokines ; Genetic Variation/immunology* ; Humans ; Immune System ; Immunity/physiology* ; Immunity, Active/immunology* ; Immunogenetics ; Polymorphism, Genetic ; Vaccination ; Vaccines/immunology*

Innate lymphoid cells (ILCs) are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed.
Animals ; Humans ; Immunity, Innate ; physiology ; Inflammation ; immunology ; Lymphocytes ; immunology ; Skin ; immunology

Research on innate lymphoid cells (ILC) has recently been a fast paced topic of immunological research. As ILCs are able to produce signature Th cytokine, ILCs have garnered considerable attention and have been described to represent the innate counterpart of the CD4 T helper (Th) cells. The development and function of ILCs are precisely regulated by a network of crucial transcription factors, which are also involved in the development or differentiation of conventional natural killer (cNK) cells and T cells. In this review, we will summarize the key transcriptional regulators and their functions through each phases of ILC development. With the phase of ILC lineage commitment, we will focus in particular on the roles of the transcription regulators Id2 and GATA-3, which in collaboration with other transcriptional factors, are critically involved in the generation of ILC fate determined progenitors. Once an ILC lineage has been established, several other transcription factors are required for the specification and functional regulation of distinct mature ILC subsets. Thus, a comprehensive understanding of the interactions and regulatory mechanisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.
Animals ; GATA3 Transcription Factor ; immunology ; Humans ; Immunity, Innate ; physiology ; Inhibitor of Differentiation Protein 2 ; immunology ; Killer Cells, Natural ; immunology ; T-Lymphocytes, Helper-Inducer ; immunology