Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 23
Filter
1.
Commun Biol ; 5(1): 242, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1751765

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are limited therapeutic options for the prevention and treatment of SARS-CoV-2 infections. We evaluated the antiviral activity of sulforaphane (SFN), the principal biologically active phytochemical derived from glucoraphanin, the naturally occurring precursor present in high concentrations in cruciferous vegetables. SFN inhibited in vitro replication of six strains of SARS-CoV-2, including Delta and Omicron, as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN should be explored as a potential agent for the prevention or treatment of coronavirus infections.


Subject(s)
Antiviral Agents/therapeutic use , Common Cold/drug therapy , Coronavirus Infections/drug therapy , Coronavirus OC43, Human , Isothiocyanates/therapeutic use , SARS-CoV-2 , Sulfoxides/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , COVID-19/drug therapy , Caco-2 Cells , Chlorocebus aethiops , Common Cold/virology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/immunology , Drug Synergism , Humans , Lung/immunology , Lung/virology , Macrophages, Alveolar/immunology , Male , Mice, Transgenic , Spleen/immunology , T-Lymphocytes/immunology , Vero Cells , Viral Load
3.
Front Immunol ; 12: 660632, 2021.
Article in English | MEDLINE | ID: covidwho-1325522

ABSTRACT

The novel SARS-CoV-2virus that caused the disease COVID-19 is currently a pandemic worldwide. The virus requires an alveolar type-2 pneumocyte in the host to initiate its life cycle. The viral S1 spike protein helps in the attachment of the virus on toACE-2 receptors present on type-2 pneumocytes, and the S2 spike protein helps in the fusion of the viral membrane with the host membrane. Fusion of the SARS-CoV-2virus and host membrane is followed by entry of viral RNA into the host cells which is directly translated into the replicase-transcriptase complex (RTC) following viral RNA and structural protein syntheses. As the virus replicates within type-2 pneumocytes, the host immune system is activated and alveolar macrophages start secreting cytokines and chemokines, acting as an inflammatory mediator, and chemotactic neutrophils, monocytes, natural NK cells, and CD8+ T cells initiate the local phagocytosis of infected cells. It is not the virus that kills COVID-19 patients; instead, the aberrant host immune response kills them. Modifying the response from the host immune system could reduce the high mortality due to SARS-CoV-2 infection. The present study examines the viral life cycle intype-2 pneumocytes and resultant host immune response along with possible therapeutic targets.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Immunomodulation , SARS-CoV-2/pathogenicity , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Host-Pathogen Interactions/immunology , Humans , Immunity , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , SARS-CoV-2/physiology
4.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311200

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.


Subject(s)
COVID-19/etiology , Pneumonia, Viral/etiology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/physiology , Autopsy , COVID-19/epidemiology , COVID-19/pathology , Cytokines/biosynthesis , Humans , Lung/immunology , Lung/pathology , Lung/virology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Models, Biological , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Virus/physiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Severity of Illness Index
5.
Front Immunol ; 12: 682871, 2021.
Article in English | MEDLINE | ID: covidwho-1247869

ABSTRACT

Macrophages are cells that mediate both innate and adaptive immunity reactions, playing a major role in both physiological and pathological processes. Systemic SARS-CoV-2-associated complications include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation syndrome, edema, and pneumonia. These are predominantly effects of massive macrophage activation that collectively can be defined as macrophage activation syndrome. In this review we focus on the role of macrophages in COVID-19, as pathogenesis of the new coronavirus infection, especially in cases complicated by ARDS, largely depends on macrophage phenotypes and functionalities. We describe participation of monocytes, monocyte-derived and resident lung macrophages in SARS-CoV-2-associated ARDS and discuss possible utility of cell therapies for its treatment, notably the use of reprogrammed macrophages with stable pro- or anti-inflammatory phenotypes.


Subject(s)
COVID-19/pathology , Macrophages/immunology , Respiratory Distress Syndrome/pathology , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Cell- and Tissue-Based Therapy , Humans , Inflammation , Lung/immunology , Lung/pathology , Macrophage Activation , Macrophages/transplantation , Macrophages, Alveolar/immunology , Monocytes/immunology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/therapy , SARS-CoV-2
6.
Sci Transl Med ; 13(596)2021 06 02.
Article in English | MEDLINE | ID: covidwho-1225692

ABSTRACT

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.


Subject(s)
Antibodies, Viral/chemistry , COVID-19/immunology , Immunoglobulin G/chemistry , Macrophages, Alveolar/immunology , Glycosylation , Humans , Inflammation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
7.
Immunity ; 54(6): 1200-1218.e9, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1213288

ABSTRACT

Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/ß-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of ß-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, ß-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted ß-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This ß-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by ß-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.


Subject(s)
COVID-19/immunology , COVID-19/virology , Cell Self Renewal/immunology , Host-Pathogen Interactions/immunology , Macrophages/immunology , SARS-CoV-2/immunology , Biomarkers , COVID-19/metabolism , Cytokines/metabolism , Disease Susceptibility/immunology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inflammation Mediators/metabolism , Macrophages/cytology , Macrophages/metabolism , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Signal Transduction
8.
J Clin Invest ; 131(4)2021 02 15.
Article in English | MEDLINE | ID: covidwho-1172781

ABSTRACT

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.


Subject(s)
Aging/immunology , Cellular Microenvironment/immunology , Lung/immunology , Macrophages, Alveolar/immunology , Aging/pathology , Animals , Humans , Lung/pathology , Macrophages, Alveolar/pathology , Mice , Mice, Transgenic , RNA-Seq
9.
Cell Rep Med ; 2(4): 100242, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1155661

ABSTRACT

Severe SARS-CoV-2 infection often leads to the development of acute respiratory distress syndrome (ARDS), with profound pulmonary patho-histological changes post-mortem. It is not clear whether ARDS from SARS-CoV-2 is similar to that observed in influenza H1N1, another common viral cause of lung injury. Here, we analyze specific ARDS regions of interest utilizing a spatial transcriptomic platform on autopsy-derived lung tissue from patients with SARS-CoV-2 (n = 3), H1N1 (n = 3), and a dual infected individual (n = 1). Enhanced gene signatures in alveolar epithelium, vascular tissue, and lung macrophages identify not only increased regional coagulopathy but also increased extracellular remodeling, alternative macrophage activation, and squamous metaplasia of type II pneumocytes in SARS-CoV-2. Both the H1N1 and dual-infected transcriptome demonstrated an enhanced antiviral response compared to SARS-CoV-2. Our results uncover regional transcriptional changes related to tissue damage/remodeling, altered cellular phenotype, and vascular injury active in SARS-CoV-2 and present therapeutic targets for COVID-19-related ARDS.


Subject(s)
COVID-19/pathology , Influenza, Human/pathology , Lung/pathology , Transcriptome , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19/complications , COVID-19/virology , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/complications , Influenza, Human/virology , Lung/metabolism , Lymphocyte Activation , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Metaplasia , Phenotype , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , SARS-CoV-2/isolation & purification , Spatial Analysis
10.
Immunity ; 54(3): 542-556.e9, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1101300

ABSTRACT

A combination of vaccination approaches will likely be necessary to fully control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we show that modified vaccinia Ankara (MVA) vectors expressing membrane-anchored pre-fusion stabilized spike (MVA/S) but not secreted S1 induced strong neutralizing antibody responses against SARS-CoV-2 in mice. In macaques, the MVA/S vaccination induced strong neutralizing antibodies and CD8+ T cell responses, and conferred protection from SARS-CoV-2 infection and virus replication in the lungs as early as day 2 following intranasal and intratracheal challenge. Single-cell RNA sequencing analysis of lung cells on day 4 after infection revealed that MVA/S vaccination also protected macaques from infection-induced inflammation and B cell abnormalities and lowered induction of interferon-stimulated genes. These results demonstrate that MVA/S vaccination induces neutralizing antibodies and CD8+ T cells in the blood and lungs and is a potential vaccine candidate for SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Genetic Vectors/genetics , SARS-CoV-2/immunology , Vaccines, DNA/immunology , Vaccinia virus/genetics , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, Viral/genetics , Antigens, Viral/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/genetics , Disease Models, Animal , Gene Expression , Gene Order , Immunophenotyping , Lung/immunology , Lung/pathology , Lung/virology , Macaca , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/pathology , Mice , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Vaccination/methods , Vaccines, DNA/genetics
11.
Nature ; 590(7847): 635-641, 2021 02.
Article in English | MEDLINE | ID: covidwho-1019856

ABSTRACT

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.


Subject(s)
COVID-19/immunology , COVID-19/virology , Macrophages, Alveolar/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , COVID-19/genetics , Cohort Studies , Humans , Interferon-gamma/immunology , Interferons/immunology , Interferons/metabolism , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/virology , Pneumonia, Viral/genetics , RNA-Seq , SARS-CoV-2/immunology , Signal Transduction/immunology , Single-Cell Analysis , T-Lymphocytes/metabolism , Time Factors
12.
Cytokine Growth Factor Rev ; 59: 101-110, 2021 06.
Article in English | MEDLINE | ID: covidwho-1014439

ABSTRACT

GM-CSF acts as a pro-inflammatory cytokine and a key growth factor produced by several immune cells such as macrophages and activated T cells. In this review, we discuss recent studies that point to the crucial role of GM-CSF in the immune response against infections. Upon induction, GM-CSF activates four main signalling networks including the JAK/STAT, PI3K, MAPK, and NFκB pathways. Many of these transduction pathways such as JAK/STAT signal via proteins commonly activated with other antiviral signalling cascades, such as those induced by IFNs. GM-CSF also helps defend against respiratory infections by regulating alveolar macrophage differentiation and enhancing innate immunity in the lungs. Here, we also summarize the numerous clinical trials that have taken advantage of GM-CSF's mechanistic attributes in immunotherapy. Moreover, we discuss how GM-CSF is used as an adjuvant in vaccines and how its activity is interfered with to reduce inflammation such as in the case of COVID-19. This review brings forth the current knowledge on the antiviral actions of GM-CSF, the associated signalling cascades, and its application in immunotherapy.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Antiviral Agents , COVID-19 Vaccines/immunology , COVID-19/immunology , Granulocyte-Macrophage Colony-Stimulating Factor , MAP Kinase Signaling System , SARS-CoV-2/immunology , Animals , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/immunology , Macrophages, Alveolar/immunology , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use
13.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Article in English | MEDLINE | ID: covidwho-925848

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Subject(s)
Bronchoalveolar Lavage Fluid/immunology , Coronavirus Infections/immunology , Inflammation/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Leukocytes/immunology , Lung/immunology , Macrophages, Alveolar/immunology , Pneumonia, Viral/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/therapy , Drug Combinations , Female , Humans , Hydroxychloroquine/therapeutic use , Intensive Care Units , Interleukin-10/immunology , Italy , Leukocytes, Mononuclear/virology , Lopinavir/therapeutic use , Lung/cytology , Lung/virology , Lymphocytes/immunology , Male , Microscopy, Electron, Transmission , Middle Aged , Neutrophils/immunology , Pandemics , Pneumonia, Viral/therapy , Prognosis , Prospective Studies , Respiration, Artificial/methods , Ritonavir/therapeutic use , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Survival Rate , Virion/metabolism , Virion/ultrastructure
14.
Cell ; 184(2): 460-475.e21, 2021 01 21.
Article in English | MEDLINE | ID: covidwho-917237

ABSTRACT

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Azetidines/administration & dosage , COVID-19/drug therapy , COVID-19/immunology , Macaca mulatta , Neutrophil Infiltration/drug effects , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Animals , COVID-19/physiopathology , Cell Death/drug effects , Cell Degranulation/drug effects , Disease Models, Animal , Inflammation/drug therapy , Inflammation/genetics , Inflammation/immunology , Janus Kinases/antagonists & inhibitors , Lung/drug effects , Lung/immunology , Lung/pathology , Lymphocyte Activation/drug effects , Macrophages, Alveolar/immunology , SARS-CoV-2/physiology , Severity of Illness Index , T-Lymphocytes/immunology , Virus Replication/drug effects
15.
EMBO Rep ; 21(12): e51252, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-895751

ABSTRACT

Respiratory infections, like the current COVID-19 pandemic, target epithelial cells in the respiratory tract. Alveolar macrophages (AMs) are tissue-resident macrophages located within the lung. They play a key role in the early phases of an immune response to respiratory viruses. AMs are likely the first immune cells to encounter SARS-CoV-2 during an infection, and their reaction to the virus will have a profound impact on the outcome of the infection. Interferons (IFNs) are antiviral cytokines and among the first cytokines produced upon viral infection. In this study, AMs from non-infectious donors are challenged with SARS-CoV-2. We demonstrate that challenged AMs are incapable of sensing SARS-CoV-2 and of producing an IFN response in contrast to other respiratory viruses, like influenza A virus and Sendai virus, which trigger a robust IFN response. The absence of IFN production in AMs upon challenge with SARS-CoV-2 could explain the initial asymptotic phase observed during COVID-19 and argues against AMs being the sources of pro-inflammatory cytokines later during infection.


Subject(s)
COVID-19/immunology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , SARS-CoV-2/immunology , Antiviral Agents/immunology , COVID-19/virology , Cells, Cultured , Cytokines/immunology , Epithelial Cells/immunology , Epithelial Cells/virology , Humans , Immune Evasion , Interferon Type I/immunology , Lung/immunology , Lung/virology , Pandemics
16.
Mol Med ; 26(1): 98, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-894987

ABSTRACT

BACKGROUND: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. METHOD: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. RESULTS: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. CONCLUSIONS: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.


Subject(s)
Benzylidene Compounds/pharmacology , Hyperoxia/immunology , Macrophages, Alveolar/drug effects , Pseudomonas Infections/drug therapy , Pyridines/pharmacology , Ventilator-Induced Lung Injury/drug therapy , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors , Animals , Disease Models, Animal , HMGB1 Protein/metabolism , Hyperoxia/diet therapy , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Male , Mice , Mice, Inbred C57BL , Phagocytosis/drug effects , Pseudomonas aeruginosa , RAW 264.7 Cells
17.
Rev Med Virol ; 30(5): e2140, 2020 09.
Article in English | MEDLINE | ID: covidwho-848179

ABSTRACT

A knowledge-based cybernetic framework model representing the dynamics of SARS-CoV-2 inside the human body has been studied analytically and in silico to explore the pathophysiologic regulations. The following modeling methodology was developed as a platform to introduce a predictive tool supporting a therapeutic approach to Covid-19 disease. A time-dependent nonlinear system of ordinary differential equations model was constructed involving type-I cells, type-II cells, SARS-CoV-2 virus, inflammatory mediators, interleukins along with host pulmonary gas exchange rate, thermostat control, and mean pressure difference. This formalism introduced about 17 unknown parameters. Estimating these unknown parameters requires a mathematical association with the in vivo sparse data and the dynamic sensitivities of the model. The cybernetic model can simulate a dynamic response to the reduced pulmonary alveolar gas exchange rate, thermostat control, and mean pressure difference under a very critical condition based on equilibrium (steady state) values of the inflammatory mediators and system parameters. In silico analysis of the current cybernetical approach with system dynamical modeling can provide an intellectual framework to help experimentalists identify more active therapeutic approaches.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Host-Pathogen Interactions/immunology , Lung/immunology , Nonlinear Dynamics , Pneumonia, Viral/immunology , Acute-Phase Proteins/antagonists & inhibitors , Acute-Phase Proteins/genetics , Acute-Phase Proteins/immunology , Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/growth & development , Body Temperature , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/virology , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Lung/drug effects , Lung/virology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Gas Exchange/drug effects , Pulmonary Gas Exchange/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
18.
Life Sci ; 258: 118166, 2020 Oct 01.
Article in English | MEDLINE | ID: covidwho-703163

ABSTRACT

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Respiratory Distress Syndrome/physiopathology , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/pathology , Animals , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Humans , Immunity, Innate , Inflammation/etiology , Inflammation/immunology , Inflammation/physiopathology , Inflammation/therapy , Macrophage Activation , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Neutrophil Activation , Pandemics , Platelet Activation , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Thrombophilia/etiology , Thrombophilia/immunology , Thrombophilia/physiopathology , Thrombophilia/therapy
20.
Front Immunol ; 11: 1625, 2020.
Article in English | MEDLINE | ID: covidwho-688729

ABSTRACT

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections , Drug Delivery Systems , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Pandemics , Pneumonia, Viral , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
SELECTION OF CITATIONS
SEARCH DETAIL