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1.
Life Sci Alliance ; 5(6)2022 06.
Article in English | MEDLINE | ID: covidwho-1732625

ABSTRACT

Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1-mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1ß production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1ß expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1 -/- mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.


Subject(s)
COVID-19/pathology , Carrier Proteins/metabolism , Inflammasomes/metabolism , /metabolism , Animals , COVID-19/immunology , Caspase 1/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Patient Acuity , Proteasome Endopeptidase Complex/metabolism
2.
Cells ; 11(4)2022 02 11.
Article in English | MEDLINE | ID: covidwho-1688673

ABSTRACT

Transmembrane proteins of adherens and tight junctions are known targets for viruses and bacterial toxins. The coronavirus receptor ACE2 has been localized at the apical surface of epithelial cells, but it is not clear whether ACE2 is localized at apical Cell-Cell junctions and whether it associates with junctional proteins. Here we explored the expression and localization of ACE2 and its association with transmembrane and tight junction proteins in epithelial tissues and cultured cells by data mining, immunoblotting, immunofluorescence microscopy, and co-immunoprecipitation experiments. ACE2 mRNA is abundant in epithelial tissues, where its expression correlates with the expression of the tight junction proteins cingulin and occludin. In cultured epithelial cells ACE2 mRNA is upregulated upon differentiation and ACE2 protein is widely expressed and co-immunoprecipitates with the transmembrane proteins ADAM17 and CD9. We show by immunofluorescence microscopy that ACE2 colocalizes with ADAM17 and CD9 and the tight junction protein cingulin at apical junctions of intestinal (Caco-2), mammary (Eph4) and kidney (mCCD) epithelial cells. These observations identify ACE2, ADAM17 and CD9 as new epithelial junctional transmembrane proteins and suggest that the cytokine-enhanced endocytic internalization of junction-associated protein complexes comprising ACE2 may promote coronavirus entry.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Intercellular Junctions/metabolism , Intercellular Junctions/virology , ADAM17 Protein/metabolism , Adherens Junctions/metabolism , Angiotensin-Converting Enzyme 2/genetics , Cadherins/metabolism , Carrier Proteins/metabolism , Cell Line , Cell Membrane Permeability , Coronavirus/metabolism , Epithelial Cells/metabolism , Epithelial Cells/virology , Gene Expression/genetics , Tetraspanin 29/metabolism , Tight Junction Proteins/metabolism , Tight Junctions/metabolism , Transcriptome/genetics
4.
Cell Rep ; 37(8): 110049, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1509642

ABSTRACT

Positive-strand RNA viruses replicate in close association with rearranged intracellular membranes. For hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), these rearrangements comprise endoplasmic reticulum (ER)-derived double membrane vesicles (DMVs) serving as RNA replication sites. Cellular factors involved in DMV biogenesis are poorly defined. Here, we show that despite structural similarity of viral DMVs with autophagosomes, conventional macroautophagy is dispensable for HCV and SARS-CoV-2 replication. However, both viruses exploit factors involved in autophagosome formation, most notably class III phosphatidylinositol 3-kinase (PI3K). As revealed with a biosensor, PI3K is activated in cells infected with either virus to produce phosphatidylinositol 3-phosphate (PI3P) while kinase complex inhibition or depletion profoundly reduces replication and viral DMV formation. The PI3P-binding protein DFCP1, recruited to omegasomes in early steps of autophagosome formation, participates in replication and DMV formation of both viruses. These results indicate that phylogenetically unrelated HCV and SARS-CoV-2 exploit similar components of the autophagy machinery to create their replication organelles.


Subject(s)
Autophagy/physiology , Hepacivirus/physiology , SARS-CoV-2/physiology , Viral Replication Compartments/metabolism , Autophagosomes/metabolism , Carrier Proteins/metabolism , Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class III Phosphatidylinositol 3-Kinases/metabolism , Humans , Phosphatidylinositol Phosphates/metabolism , RNA, Viral/biosynthesis , Viral Nonstructural Proteins/metabolism , Virus Replication
5.
Eur J Clin Microbiol Infect Dis ; 40(11): 2295-2303, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1479485

ABSTRACT

The aim of this study is to present the first nationwide microbiological and epidemiological study of invasive group A Streptococcus (iGAS) disease in Spain. One thousand eight hundred ninety-three iGAS isolates were analyzed over 2007-2019. emm typing was performed by sequencing the gene's variable 5' end, exotoxin genes were identified by PCR, and antimicrobial susceptibility explored via the E test and disk diffusion. Five hundred twenty-three isolates were associated with sepsis, 292 with cellulitis, 232 with scarlet fever, 153 with pneumonia, 141 with streptococcal toxic shock syndrome, and 94 with necrotizing fasciitis. The most prevalent emm types were emm1 (449/1893 isolates), emm89 (210/1893), emm3 (208/1893), emm4 (150/1893), emm12 (112/1893) emm6 (107/1893), emm87 (89/1893), emm28 (88/1893), emm75 (78/1893), emm77 (78/1893), emm11 (58/1893), and emm22 (35/1893). emm1, emm3, emm4, and emm6 were the predominant types affecting children (mostly respiratory infections), while emm11, emm77, and emm89 prevailed in the elderly (mostly skin infections). Each emm type was associated with one or more exotoxin gene (spe, sme, and ssa) profiles. speA was detected in 660 isolates, speB in 1829, speC in 1014, speF in 1826, speG in 1651, speJ in 716, speH in 331, smeZ in 720, and ssa in 512. Isolates with speA were associated with the most severe infections. Penicillin susceptibility was universal. Two hundred twenty-four isolates were resistant to tetracycline, 169 to erythromycin, and 81 to clindamycin. Tetracycline, erythromycin, and clindamycin resistance rates declined over the study period. The above information could serve as the basis for continued surveillance efforts designed to control disease cause by this bacterium.


Subject(s)
Streptococcal Infections/microbiology , Streptococcus pyogenes/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Child , Child, Preschool , Erythromycin/pharmacology , Exotoxins/genetics , Exotoxins/metabolism , Female , Humans , Infant , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Microbial Sensitivity Tests , Middle Aged , Penicillins/pharmacology , Spain/epidemiology , Streptococcal Infections/epidemiology , Streptococcus pyogenes/classification , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/genetics , Young Adult
6.
Front Immunol ; 12: 757691, 2021.
Article in English | MEDLINE | ID: covidwho-1463478

ABSTRACT

The increase in confirmed COVID-19 cases and SARS-CoV-2 variants calls for the development of safe and broad cross-protective vaccines. The RBD of the spike protein was considered to be a safe and effective candidate antigen. However, the low immunogenicity limited its application in vaccine development. Herein, we designed and obtained an RBD heptamer (mHla-RBD) based on a carrier protein-aided assembly strategy. The molecular weight of mHla-RBD is up to 450 kDa, approximately 10 times higher than that of the RBD monomer. When formulated with alum adjuvant, mHla-RBD immunization significantly increased the immunogenicity of RBD, as indicated by increased titers of RBD-specific antibodies, neutralizing antibodies, Th2 cellular immune response, and pseudovirus neutralization activity, when compared to RBD monomer. Furthermore, we confirmed that RBD-specific antibodies predominantly target conformational epitopes, which was approximately 200 times that targeting linear epitopes. Finally, a pseudovirus neutralization assay revealed that neutralizing antibodies induced by mHla-RBD against different SARS-CoV-2 variants were comparable to those against the wild-type virus and showed broad-spectrum neutralizing activity toward different SARS-CoV-2 variants. Our results demonstrated that mHla-RBD is a promising candidate antigen for development of SARS-CoV-2 vaccines and the mHla could serve as a universal carrier protein for antigen design.


Subject(s)
Bacterial Proteins/metabolism , COVID-19 Vaccines/immunology , COVID-19/immunology , Carrier Proteins/metabolism , Hemolysin Proteins/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Th2 Cells/immunology , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Broadly Neutralizing Antibodies/metabolism , Cell Line , Escherichia coli Proteins , Humans , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Protein Domains/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
7.
Proteins ; 90(1): 164-175, 2022 01.
Article in English | MEDLINE | ID: covidwho-1340286

ABSTRACT

TMEM106B is an integral membrane protein of late endosomes and lysosomes involved in neuronal function, its overexpression being associated with familial frontotemporal lobar degeneration, and point mutation linked to hypomyelination. It has also been identified in multiple screens for host proteins required for productive SARS-CoV-2 infection. Because standard approaches to understand TMEM106B at the sequence level find no homology to other proteins, it has remained a protein of unknown function. Here, the standard tool PSI-BLAST was used in a nonstandard way to show that the lumenal portion of TMEM106B is a member of the late embryogenesis abundant-2 (LEA-2) domain superfamily. More sensitive tools (HMMER, HHpred, and trRosetta) extended this to predict LEA-2 domains in two yeast proteins. One is Vac7, a regulator of PI(3,5)P2 production in the degradative vacuole, equivalent to the lysosome, which has a LEA-2 domain in its lumenal domain. The other is Tag1, another vacuolar protein, which signals to terminate autophagy and has three LEA-2 domains in its lumenal domain. Further analysis of LEA-2 structures indicated that LEA-2 domains have a long, conserved lipid-binding groove. This implies that TMEM106B, Vac7, and Tag1 may all be lipid transfer proteins in the lumen of late endocytic organelles.


Subject(s)
Carrier Proteins/metabolism , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Computational Biology/methods , Cytoplasm/metabolism , Humans , Lysosomes , Membrane Glycoproteins/chemistry , Models, Molecular , Protein Conformation , Protein Domains , Saccharomyces cerevisiae Proteins/chemistry , Vacuoles/metabolism
8.
Front Immunol ; 12: 708149, 2021.
Article in English | MEDLINE | ID: covidwho-1337643

ABSTRACT

Microbial translocation (MT) and intestinal damage (ID) are poorly explored in COVID-19. Aims were to assess whether alteration of gut permeability and cell integrity characterize COVID-19 patients, whether it is more pronounced in severe infections and whether it influences the development of subsequent bloodstream infection (BSI). Furthermore, we looked at the potential predictive role of TM and ID markers on Intensive Care Unit (ICU) admission and in-hospital mortality. Over March-July 2020, 45 COVID-19 patients were enrolled. Markers of MT [LPB (Lipopolysacharide Binding Protein) and EndoCab IgM] and ID [I-FABP (Intestinal Fatty Acid Binding Protein)] were evaluated at COVID-19 diagnosis and after 7 days. As a control group, age- and gender-matched healthy donors (HDs) enrolled during the same study period were included. Median age was 66 (56-71) years. Twenty-one (46.6%) were admitted to ICU and mortality was 22% (10/45). Compared to HD, a high degree of MT and ID was observed. ICU patients had higher levels of MT, but not of ID, than non-ICU ones. Likewise, patients with BSI had lower EndoCab IgM than non-BSI. Interestingly, patients with high degree of MT and low ID were likely to be admitted to ICU (AUC 0.822). Patients with COVID-19 exhibited high level of MT, especially subjects admitted to ICU. COVID-19 is associated with gut permeability.


Subject(s)
COVID-19/metabolism , Intestinal Mucosa/metabolism , SARS-CoV-2/physiology , Acute-Phase Proteins/metabolism , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/mortality , COVID-19/pathology , Carrier Proteins/metabolism , Disease Progression , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Intensive Care Units , Intestinal Mucosa/pathology , Male , Membrane Glycoproteins/metabolism , Middle Aged , Predictive Value of Tests , Prognosis , Survival Analysis , Tight Junctions/metabolism
9.
Clin Immunol ; 227: 108733, 2021 06.
Article in English | MEDLINE | ID: covidwho-1198654

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for many pathological processes, including altered vascular disease development, dysfunctional thrombosis and a heightened inflammatory response. However, there is limited work to determine the underlying cellular responses induced by exposure to SARS-CoV-2 structural proteins. Thus, our objective was to investigate how human arterial adventitial fibroblasts inflammation, thrombosis and diabetic disease markers are altered in response to Spike, Nucleocapsid and Membrane-Envelope proteins. We hypothesized that after a short-term exposure to SARS-CoV-2 proteins, adventitial fibroblasts would have a higher expression of inflammatory, thrombotic and diabetic proteins, which would support a mechanism for altered vascular disease progression. After incubation, the expression of gC1qR, ICAM-1, tissue factor, RAGE and GLUT-4 was significantly up-regulated. In general, the extent of expression was different for each SARS-CoV-2 protein, suggesting that SARS-CoV-2 proteins interact with cells through different mechanisms. Thus, SARS-CoV-2 protein interaction with vascular cells may regulate vascular disease responses.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/virology , Diabetes Mellitus/virology , Fibroblasts/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Thrombosis/virology , Aorta/cytology , Aorta/metabolism , Cardiovascular Diseases/complications , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Carrier Proteins/metabolism , Cell Survival/immunology , Cell Survival/physiology , Complement System Proteins/immunology , Coronavirus Envelope Proteins/immunology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Diabetes Mellitus/metabolism , Glucose Transporter Type 4/metabolism , Humans , Inflammation/metabolism , Inflammation/virology , Intercellular Adhesion Molecule-1/metabolism , Mitochondrial Proteins/metabolism , Receptor for Advanced Glycation End Products/metabolism , Thrombosis/complications , Thrombosis/metabolism
10.
Sci Signal ; 14(675)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1186203

ABSTRACT

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a "clickable" NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus through the endolysosomal system. Thus, JPT2 is a component of the NAADP receptor complex that is essential for TPC-dependent Ca2+ signaling and control of coronaviral entry.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Calcium Signaling/physiology , Microtubule-Associated Proteins/metabolism , NADP/analogs & derivatives , SARS-CoV-2/physiology , Affinity Labels , Animals , Calcium Channels/metabolism , Carrier Proteins/metabolism , Click Chemistry/methods , Gene Knockdown Techniques , HEK293 Cells , Humans , Microtubule-Associated Proteins/antagonists & inhibitors , Microtubule-Associated Proteins/genetics , NADP/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Second Messenger Systems/physiology , Transcriptome , Virus Internalization
11.
J Inorg Biochem ; 219: 111423, 2021 06.
Article in English | MEDLINE | ID: covidwho-1129080

ABSTRACT

The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of whether SARS-CoV-2 is physically associated with human metalloproteins. Recently, high-confidence, experimentally supported protein-protein interactions between SARS-CoV-2 and human proteins were reported. In this work, 58 metalloproteins among these human targets have been identified by a structure-based approach. This study reveals that most human metalloproteins interact with the recently discovered SARS-CoV-2 orf8 protein, whose antibodies are one of the principal markers of SARS-CoV-2 infections. Furthermore, this work provides sufficient evidence to conclude that Zn2+ plays an important role in the interplay between the novel coronavirus and humans. First, the content of Zn-binding proteins in the involved human metalloproteome is significantly higher than that of the other metal ions. Second, a molecular linkage between the identified human Zn-binding proteome with underlying medical conditions, that might increase the risk of severe illness from the SARS-CoV-2 virus, has been found. Likely perturbations of host cellular metal homeostasis by SARS-CoV-2 infection are highlighted.


Subject(s)
Host-Pathogen Interactions/physiology , Metalloproteins/metabolism , Nervous System Diseases/genetics , SARS-CoV-2/pathogenicity , Viral Proteins/metabolism , COVID-19/metabolism , Carrier Proteins/metabolism , Humans , Metalloproteins/genetics , SARS-CoV-2/metabolism
13.
J Intern Med ; 289(4): 523-531, 2021 04.
Article in English | MEDLINE | ID: covidwho-796040

ABSTRACT

BACKGROUND: A high proportion of COVID-19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 and the renin-angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID-19 patients. METHODS: Plasma levels of a gut leakage marker (LPS-binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL-1ß, IL-18 and their regulatory proteins) were measured at three time points (day 1, 3-5 and 7-10) in 39 hospitalized COVID-19 patients and related to cardiac involvement. RESULTS: Compared to controls, COVID-19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT-pro-BNP levels, whereas IL-18, IL-18BP and IL-1Ra were associated with higher troponin levels. CONCLUSION: Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut-heart axis in COVID-19.


Subject(s)
COVID-19 , Chemokines, CC/metabolism , Gastrointestinal Microbiome/immunology , Heart Diseases , Inflammasomes/metabolism , Intestinal Mucosa , SARS-CoV-2 , Acute-Phase Proteins/metabolism , COVID-19/complications , COVID-19/immunology , Carrier Proteins/metabolism , Correlation of Data , Heart Diseases/immunology , Heart Diseases/virology , Humans , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/physiopathology , Membrane Glycoproteins/metabolism , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Troponin/blood
14.
Biochem Pharmacol ; 180: 114122, 2020 10.
Article in English | MEDLINE | ID: covidwho-617879

ABSTRACT

An unprecedented biological function of natural cardenolides independent of their membrane target Na+/K+-ATPase is disclosed. Previously, we reported that cardenolides impart anti-transmissible gastroenteritis coronavirus (anti-TGEV) activity through the targeting of Na+/K+-ATPase and its associated PI3K_PDK1_RSK2 signaling. Swine testis cells with Na+/K+-ATPase α1 knocked down exhibited decreased susceptibility to TGEV infectivity and attenuated PI3K_PDK1_RSK2 signaling. Herein, we further explored a Na+/K+-ATPase-independent signaling axis induced by natural cardenolides that also afforded significant anti-coronaviral activity for porcine TGEV and human HCoV-OC43. Using pharmacological inhibition and gene silencing techniques, we found that this anti-TGEV or anti-HCoV-OC43 activity was caused by JAK1 proteolysis and mediated through upstream activation of Ndfip1/2 and its effector NEDD4. This study provides novel insights into the pharmacological effects of natural cardenolides, and is expected to inform their future development as antiviral agents.


Subject(s)
Antiviral Agents/pharmacology , Cardenolides/pharmacology , Coronavirus OC43, Human/drug effects , Janus Kinase 1/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Transmissible gastroenteritis virus/drug effects , Virus Replication/drug effects , Animals , Carrier Proteins/metabolism , Cell Line , Down-Regulation/drug effects , Female , Gene Knockdown Techniques , Humans , Leupeptins , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Nedd4 Ubiquitin Protein Ligases/metabolism , Ouabain/pharmacology , Phosphorylation , Protease Inhibitors/pharmacology , Proteolysis , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Swine
15.
Am J Respir Crit Care Med ; 202(6): 812-821, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-614625

ABSTRACT

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Subject(s)
Acute-Phase Reaction/immunology , Carrier Proteins/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Cytokines/immunology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lactic Acid/metabolism , Membrane Proteins/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Thyroid Hormones/metabolism , alpha 1-Antitrypsin/immunology , Acute-Phase Reaction/metabolism , Adult , Aged , Betacoronavirus , Blotting, Western , COVID-19 , Case-Control Studies , Community-Acquired Infections/immunology , Community-Acquired Infections/metabolism , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Critical Illness , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Female , Hospitalization , Humans , Intensive Care Units , Interleukin-10/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Length of Stay , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Pandemics , Phosphorylation , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Receptors, Tumor Necrosis Factor, Type I/immunology , SARS-CoV-2 , Severity of Illness Index , alpha 1-Antitrypsin/metabolism
16.
FEBS Lett ; 594(11): 1651-1660, 2020 06.
Article in English | MEDLINE | ID: covidwho-361331

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major global challenge. The virus infects host cells using its spike glycoprotein (S-protein) and has significantly higher infectivity and mortality rates among the aged population. Here, based on bioinformatic analysis, I provide evidence that some members of the upper respiratory tract (URT) commensal bacteria express viral S-protein -binding proteins. Based on this analysis and available data showing a decline in the population of these bacteria in the elderly, I propose that some URT commensal bacteria hamper SARS-CoV-2 infectivity and that a decline in the population of these bacteria contributes to the severity of infection. Further studies should provide a better understanding of the interaction of URT bacteria and SARS-CoV-2, which may lead to new therapeutic approaches.


Subject(s)
Bacterial Proteins/metabolism , Microbial Interactions , Respiratory System/microbiology , Spike Glycoprotein, Coronavirus/metabolism , Aging , Betacoronavirus , COVID-19 , Carrier Proteins/metabolism , Computational Biology , Coronavirus Infections , Humans , Models, Molecular , Orthomyxoviridae , Pandemics , Pneumonia, Viral , Protein Structure, Secondary , Proteobacteria/metabolism , SARS-CoV-2
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