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2.
Front Immunol ; 12: 788769, 2021.
Article in English | MEDLINE | ID: covidwho-1581323

ABSTRACT

COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has threatened public health worldwide. Host antiviral immune responses are essential for viral clearance and disease control, however, remarkably decreased immune cell numbers and exhaustion of host cellular immune responses are commonly observed in patients with COVID-19. This is of concern as it is closely associated with disease severity and poor outcomes. Human leukocyte antigen-G (HLA-G) is a ligand for multiple immune inhibitory receptors, whose expression can be upregulated by viral infections. HLA-G/receptor signalling, such as engagement with immunoglobulin-like transcript 2 (ILT-2) or ILT-4, not only inhibit T and natural killer (NK) cell immune responses, dendritic cell (DC) maturation, and B cell antibody production. It also induces regulatory cells such as myeloid-derived suppressive cells (MDSCs), or M2 type macrophages. Moreover, HLA-G interaction with CD8 and killer inhibitory receptor (KIR) 2DL4 can provoke T cell apoptosis and NK cell senescence. In this context, HLA-G can induce profound immune suppression, which favours the escape of SARS-CoV-2 from immune attack. Although detailed knowledge on the clinical relevance of HLA-G in SARS-CoV-2 infection is limited, we herein review the immunopathological aspects of HLA-G/receptor signalling in SARS-CoV-2 infection, which could provide a better understanding of COVID-19 disease progression and identify potential immunointerventions to counteract SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , HLA-G Antigens/immunology , Immune Tolerance/immunology , Humans , SARS-CoV-2/immunology
3.
Front Immunol ; 12: 792448, 2021.
Article in English | MEDLINE | ID: covidwho-1581318

ABSTRACT

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis via enzyme-linked immunospot assay. We found that circulating inflammatory markers were significantly higher early after bacterial sepsis compared with SARS-CoV-2. Both cohorts exhibited profound immune suppression through 21 days (suppressed HLA-DR expression, reduced mononuclear cell IFN-gamma production), and expanded numbers of myeloid-derived suppressor cells (MDSCs). In addition, MDSC expansion and ex vivo production of IFN-gamma and TNF-alpha were resolving over time in bacterial sepsis, whereas in SARS-CoV-2, immunosuppression and inflammation were accelerating. Despite less severe initial physiologic derangement, SARS-CoV-2 patients had similar incidence of secondary infections (23% vs 30%) as bacterial sepsis patients. Finally, COVID patients who developed secondary bacterial infections exhibited profound immunosuppression evident by elevated sPD-L1 and depressed HLA-DR. Although both bacterial sepsis and SARS-CoV-2 are associated with inflammation and immune suppression, their immune dyscrasia temporal patterns and clinical outcomes are different. SARS-CoV-2 patients had less severe early inflammation and organ dysfunction but had persistent inflammation and immunosuppression and suffered worse clinical outcomes, especially when SARS-CoV-2 infection was followed by secondary bacterial infection.


Subject(s)
Bacterial Infections/immunology , COVID-19/immunology , Immune Tolerance/immunology , Sepsis/immunology , Adult , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2
4.
Front Immunol ; 12: 755579, 2021.
Article in English | MEDLINE | ID: covidwho-1556334

ABSTRACT

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the "dysregulated host response" to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immune Tolerance/immunology , Adaptive Immunity/genetics , Aged , COVID-19/diagnosis , COVID-19/genetics , Coinfection/diagnosis , Coinfection/genetics , Coinfection/immunology , Cross-Sectional Studies , Cytokine Release Syndrome/genetics , Female , Gene Expression Profiling , Humans , Immune Tolerance/genetics , Inflammation/genetics , Intensive Care Units , Male , Middle Aged , Patient Discharge , SARS-CoV-2/isolation & purification , Smell/genetics , Taste/genetics
5.
Front Immunol ; 12: 733418, 2021.
Article in English | MEDLINE | ID: covidwho-1450812

ABSTRACT

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and abnormal fatigability due to the antibodies against postsynaptic receptors. Despite the individual discrepancy, patients with MG share common muscle weakness, autoimmune dysfunction, and immunosuppressive treatment, which predispose them to infections that can trigger or exacerbate MG. Vaccination, as a mainstay of prophylaxis, is a major management strategy. However, the past years have seen growth in vaccine hesitancy, owing to safety and efficacy concerns. Ironically, vaccines, serving as an essential and effective means of defense, may induce similar immune cross-reactivity to what they are meant to prevent. Herein, we outline the progress in vaccination, review the current status, and postulate the clinical association among MG, vaccination, and immunosuppression. We also address safety and efficacy concerns of vaccination in MG, in relation to COVID-19. Since only a handful of studies have reported vaccination in individuals with MG, we further review the current clinical studies and guidelines in rheumatic diseases. Overall, our reviews offer a reference to guide future vaccine clinical decision-making and improve the management of MG patients.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Myasthenia Gravis/immunology , Myasthenia Gravis/pathology , SARS-CoV-2/immunology , Autoimmunity/immunology , Humans , Immune Tolerance/immunology , Influenza Vaccines/immunology , Risk , Vaccination/adverse effects
7.
Nature ; 592(7853): 277-282, 2021 04.
Article in English | MEDLINE | ID: covidwho-1387425

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , COVID-19/virology , Evolution, Molecular , Mutagenesis/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Chronic Disease , Genome, Viral/drug effects , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing , Humans , Immune Evasion/drug effects , Immune Evasion/genetics , Immune Evasion/immunology , Immune Tolerance/drug effects , Immune Tolerance/immunology , Immunization, Passive , Male , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/immunology , Mutation , Phylogeny , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Viral Load/drug effects , Virus Shedding
8.
Cytokine ; 146: 155637, 2021 10.
Article in English | MEDLINE | ID: covidwho-1333350

ABSTRACT

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immune Tolerance/immunology , Immunity, Innate/immunology , Interferon-gamma/immunology , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Humans , Interferon-gamma/therapeutic use , Receptors, Interferon/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Signal Transduction/immunology
9.
PLoS Pathog ; 17(7): e1009721, 2021 07.
Article in English | MEDLINE | ID: covidwho-1298084

ABSTRACT

Severe COVID-19 is characterized by extensive pulmonary complications, to which host immune responses are believed to play a role. As the major arm of innate immunity, neutrophils are one of the first cells recruited to the site of infection where their excessive activation can contribute to lung pathology. Low-density granulocytes (LDGs) are circulating neutrophils, whose numbers increase in some autoimmune diseases and cancer, but are poorly characterized in acute viral infections. Using flow cytometry, we detected a significant increase of LDGs in the blood of acute COVID-19 patients, compared to healthy controls. Based on their surface marker expression, COVID-19-related LDGs exhibit four different populations, which display distinctive stages of granulocytic development and most likely reflect emergency myelopoiesis. Moreover, COVID-19 LDGs show a link with an elevated recruitment and activation of neutrophils. Functional assays demonstrated the immunosuppressive capacities of these cells, which might contribute to impaired lymphocyte responses during acute disease. Taken together, our data confirms a significant granulocyte activation during COVID-19 and suggests that granulocytes of lower density play a role in disease progression.


Subject(s)
COVID-19/immunology , Granulocytes/classification , Acute Disease , Adult , Aged , COVID-19/blood , Case-Control Studies , Cohort Studies , Convalescence , Disease Progression , Female , Follow-Up Studies , Granulocytes/cytology , Humans , Immune Tolerance/immunology , Male , Middle Aged , Scavenger Receptors, Class E/analysis , Severity of Illness Index
10.
Neuroimmunomodulation ; 28(1): 1-21, 2021.
Article in English | MEDLINE | ID: covidwho-1206095

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has devastating effects on the population worldwide. Given this scenario, the extent of the impact of the disease on more vulnerable individuals, such as pregnant women, is of great concern. Although pregnancy may be a risk factor in respiratory virus infections, there are no considerable differences regarding COVID-19 severity observed between pregnant and nonpregnant women. In these circumstances, an emergent concern is the possibility of neurodevelopmental and neuropsychiatric harm for the offspring of infected mothers. Currently, there is no stronger evidence indicating vertical transmission of SARS-CoV-2; however, the exacerbated inflammatory response observed in the disease could lead to several impairments in the offspring's brain. Furthermore, in the face of historical knowledge on possible long-term consequences for the progeny's brain after infection by viruses, we must consider that this might be another deleterious facet of COVID-19. In light of neuroimmune interactions at the maternal-fetal interface, we review here the possible harmful outcomes to the offspring brains of mothers infected by SARS-CoV-2.


Subject(s)
COVID-19/immunology , Neurodevelopmental Disorders/physiopathology , Neuroimmunomodulation/immunology , Pregnancy Complications, Infectious/immunology , Prenatal Exposure Delayed Effects/physiopathology , COVID-19/metabolism , COVID-19/physiopathology , Cytokine Release Syndrome/immunology , Decidua/immunology , Female , Humans , Immune Tolerance/immunology , Infectious Disease Transmission, Vertical , Neuroimmunomodulation/physiology , Placenta/immunology , Pregnancy , Pregnancy Complications, Infectious/metabolism , Pregnancy Complications, Infectious/physiopathology , SARS-CoV-2 , Umbilical Cord/immunology
11.
Cell Immunol ; 362: 104302, 2021 04.
Article in English | MEDLINE | ID: covidwho-1085577

ABSTRACT

MDSC are a heterogeneous population of immature myeloid cells that are released by biological stress such as tissue damage and inflammation. Conventionally, MDSC are known for their detrimental role in chronic inflammation and neoplastic conditions. However, their intrinsic functions in immunoregulation, wound healing, and angiogenesis are intended to protect from over-reactive immune responses, maintenance of immunotolerance, tissue repair, and homeostasis. Paradoxically, under certain conditions, MDSC can impair protective immune responses and exacerbate the disease. The transition from protective to harmful MDSC is most likely driven by environmental and epigenetic mechanisms induced by prolonged exposure to unresolved inflammatory triggers. Here, we review several examples of the dual impact of MDSC in conditions such as maternal-fetal tolerance, self-antigens immunotolerance, obesity-associated cancer, sepsis and trauma. Moreover, we also highlighted the evidence indicating that MDSC have a role in COVID-19 pathophysiology. Finally, we have summarized the evidence indicating epigenetic mechanisms associated with MDSC function.


Subject(s)
Myeloid-Derived Suppressor Cells/immunology , Animals , COVID-19/immunology , Epigenesis, Genetic , Female , Humans , Immune Tolerance/immunology , Inflammation/immunology , Male , Neoplasms/immunology , Obesity/immunology , Pregnancy , Wound Healing/immunology
12.
Int J Mol Sci ; 21(22)2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-918209

ABSTRACT

Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined "trained immunity" and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The "exposome" is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality.


Subject(s)
Betacoronavirus/immunology , Cell Lineage/immunology , Coronavirus Infections/immunology , Immunity, Innate/immunology , Immunologic Memory/immunology , Pneumonia, Viral/immunology , COVID-19 , DNA Methylation/genetics , Dendritic Cells/immunology , Exposome , Histone Code/genetics , Humans , Immune Tolerance/immunology , Killer Cells, Natural/immunology , Macrophages/immunology , Pandemics , SARS-CoV-2
13.
Immunol Cell Biol ; 99(2): 177-191, 2021 02.
Article in English | MEDLINE | ID: covidwho-894767

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a zoonosis like most of the great plagues sculpting human history, from smallpox to pandemic influenza and human immunodeficiency virus. When viruses jump into a new species the outcome of infection ranges from asymptomatic to lethal, historically ascribed to "genetic resistance to viral disease." People have exploited these differences for good and bad, for developing vaccines from cowpox and horsepox virus, controlling rabbit plagues with myxoma virus and introducing smallpox during colonization of America and Australia. Differences in resistance to viral disease are at the core of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) crisis, yet our understanding of the mechanisms in any interspecies leap falls short of the mark. Here I review how the two key parameters of viral disease are countered by fundamentally different genetic mechanisms for resistance: (1) virus transmission, countered primarily by activation of innate and adaptive immune responses; and (2) pathology, countered primarily by tolerance checkpoints to limit innate and adaptive immune responses. I discuss tolerance thresholds and the role of CD8 T cells to limit pathological immune responses, the problems posed by tolerant superspreaders and the signature coronavirus evasion strategy of eliciting only short-lived neutralizing antibody responses. Pinpointing and targeting the mechanisms responsible for varying pathology and short-lived antibody were beyond reach in previous zoonoses, but this time we are armed with genomic technologies and more knowledge of immune checkpoint genes. These known unknowns must now be tackled to solve the current COVID-19 crisis and the inevitable zoonoses to follow.


Subject(s)
COVID-19 , Immune Tolerance/immunology , Immunity, Innate/genetics , SARS-CoV-2/immunology , Virus Diseases/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/physiology , Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Humans , Immune Tolerance/genetics , Rabbits , SARS-CoV-2/genetics , Viral Zoonoses/genetics , Viral Zoonoses/immunology , Virus Diseases/genetics
14.
Front Immunol ; 11: 572567, 2020.
Article in English | MEDLINE | ID: covidwho-886164

ABSTRACT

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.


Subject(s)
Decidua/immunology , Placenta/immunology , Virus Diseases/immunology , Adaptive Immunity/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Dengue/immunology , Dengue/pathology , Female , Hemorrhagic Fever, Ebola/immunology , Hemorrhagic Fever, Ebola/pathology , Hepatitis E/immunology , Hepatitis E/pathology , Humans , Immune Tolerance/immunology , Immunity, Innate/immunology , Influenza, Human/immunology , Influenza, Human/pathology , Lassa Fever/immunology , Lassa Fever/pathology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pregnancy
15.
JCI Insight ; 5(17)2020 09 03.
Article in English | MEDLINE | ID: covidwho-781300

ABSTRACT

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-É£ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-É£ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-É£ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.


Subject(s)
Adaptive Immunity/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immune Tolerance/immunology , Immunity, Innate/immunology , Pneumonia, Viral/immunology , Sepsis/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Case-Control Studies , Critical Illness , Enzyme-Linked Immunospot Assay , Female , Healthy Volunteers , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-6/immunology , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Pandemics , SARS-CoV-2 , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Young Adult
16.
Anesth Analg ; 131(4): 993-999, 2020 10.
Article in English | MEDLINE | ID: covidwho-760675

ABSTRACT

BACKGROUND: The cellular immune system is of pivotal importance with regard to the response to severe infections. Monocytes/macrophages are considered key immune cells in infections and downregulation of the surface expression of monocytic human leukocyte antigen-DR (mHLA-DR) within the major histocompatibility complex class II reflects a state of immunosuppression, also referred to as injury-associated immunosuppression. As the role of immunosuppression in coronavirus disease 2019 (COVID-19) is currently unclear, we seek to explore the level of mHLA-DR expression in COVID-19 patients. METHODS: In a preliminary prospective monocentric observational study, 16 COVID-19-positive patients (75% male, median age: 68 [interquartile range 59-75]) requiring hospitalization were included. The median Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score in 9 intensive care unit (ICU) patients with acute respiratory failure was 30 (interquartile range 25-32). Standardized quantitative assessment of HLA-DR on monocytes (cluster of differentiation 14+ cells) was performed using calibrated flow cytometry at baseline (ICU/hospital admission) and at days 3 and 5 after ICU admission. Baseline data were compared to hospitalized noncritically ill COVID-19 patients. RESULTS: While normal mHLA-DR expression was observed in all hospitalized noncritically ill patients (n = 7), 89% (8 of 9) critically ill patients with COVID-19-induced acute respiratory failure showed signs of downregulation of mHLA-DR at ICU admission. mHLA-DR expression at admission was significantly lower in critically ill patients (median, [quartiles]: 9280 antibodies/cell [6114, 16,567]) as compared to the noncritically ill patients (30,900 antibodies/cell [26,777, 52,251]), with a median difference of 21,508 antibodies/cell (95% confidence interval [CI], 14,118-42,971), P = .002. Reduced mHLA-DR expression was observed to persist until day 5 after ICU admission. CONCLUSIONS: When compared to noncritically ill hospitalized COVID-19 patients, ICU patients with severe COVID-19 disease showed reduced mHLA-DR expression on circulating CD14+ monocytes at ICU admission, indicating a dysfunctional immune response. This immunosuppressive (monocytic) phenotype remained unchanged over the ensuing days after ICU admission. Strategies aiming for immunomodulation in this population of critically ill patients should be guided by an immune-monitoring program in an effort to determine who might benefit best from a given immunological intervention.


Subject(s)
Coronavirus Infections/immunology , Critical Illness , HLA-DR Antigens/biosynthesis , HLA-DR Antigens/immunology , Immune Tolerance/immunology , Pneumonia, Viral/immunology , APACHE , Aged , Antibodies/analysis , Antibodies/immunology , COVID-19 , Coronavirus Infections/therapy , Critical Care , Down-Regulation/immunology , Female , Humans , Immunotherapy , Lipopolysaccharide Receptors/immunology , Male , Middle Aged , Monocytes/immunology , Pandemics , Pneumonia, Viral/therapy , Prospective Studies , Respiratory Insufficiency/immunology , Respiratory Insufficiency/physiopathology
17.
Obes Facts ; 13(4): 439-452, 2020.
Article in English | MEDLINE | ID: covidwho-713418

ABSTRACT

Accumulating evidence suggests that obesity is a major risk factor for the initiation, progression, and outcomes of coronavirus disease 2019 (COVID-19). The European Association for the Study of Obesity (EASO), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the concomitant obesity and COVID-19 pandemics and their impact on health and society at large. In this perspective, we will address the inherent immunological perturbations and alterations in the renin-angiotensin-aldosterone system in patients with obesity and COVID-19, and discuss how these impairments may underlie the increased susceptibility and more detrimental outcomes of COVID-19 in people with obesity. Clearly, this has important implications for preventive measures, vaccination, and future therapeutic strategies to combat COVID-19. Furthermore, we will highlight important knowledge gaps and provide suggestions for future research and recommendations for policy actions. Since many new reports on COVID-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward further understanding, research initiatives, and clinical management of COVID-19.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Obesity/complications , Obesity/immunology , Pneumonia, Viral/immunology , COVID-19 , Coronavirus , Coronavirus Infections/therapy , Disease Susceptibility , Humans , Immune Tolerance/immunology , Immunocompetence/immunology , Pandemics , Peptidyl-Dipeptidase A , Pneumonia, Viral/therapy , Prognosis , Renin-Angiotensin System/physiology , Risk Factors , SARS-CoV-2
18.
Endocrinology ; 161(9)2020 09 01.
Article in English | MEDLINE | ID: covidwho-690822

ABSTRACT

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17ß-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.


Subject(s)
Coronavirus Infections/immunology , Estradiol/immunology , Immunomodulation/immunology , Pneumonia, Viral/immunology , Progesterone/immunology , Antibody Formation/immunology , Betacoronavirus , COVID-19 , Contraceptives, Oral, Hormonal/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Cytokine Release Syndrome/immunology , Drug Repositioning , Estradiol/therapeutic use , Estrogen Replacement Therapy , Estrogens/therapeutic use , Female , Humans , Immune Tolerance/immunology , Immunity, Innate/immunology , Male , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Pregnancy , Pregnancy Complications, Infectious/immunology , Progesterone/therapeutic use , Progestins/therapeutic use , SARS-CoV-2 , Selective Estrogen Receptor Modulators/therapeutic use , Severity of Illness Index , Sex Factors
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